First some background: When solid particles are burned, they release a variety of molecules as smoke due to the addition of energy in the form of fire. With this addition of energy, a series of chemical reactions occur that release liquid particles and gases that often are of different composition than the original compound. Most often, when an organic compound, such as cannabis, is burned, it emits gases such as carbon monoxide and hydrogen cyanide that may be harmful to the user. Aside from the stigma attached to the name, the potential harmful effects of smoke are one of the main reasons why marijuana is not widely accepted in the medical community. However, there are other ways of administration besides inhaling smoke, such oral or inhaling vapor. Vaporizers heat the cannabis to around 400⁰ F without burning the plant material, reaching the boiling point of most cannabinoids and releasing them in a mist, with not enough heat applied to release other, more harmful compounds.
The new information: In this experiment, twenty frequent cannabis smokers were used to determine the differential effects of inhaling smoke or vapor. The twenty smokers had previously reported at least two respiratory side-effects and were asked to self-report their severity of symptoms. Additionally, their forced expiratory volume (FEV1) and forced vital capacity (FVC) were measured. FEV1 refers to the maximum volume of air that can be exhaled in 1 second, and FVC refers to the total volume of air that the lung can hold. The smokers were then switched to using vaporizers for one month and the measurements were repeated. Initially, average self-reported symptoms were graded to be 26.1, FVC was 4.54L, and FEV1 was 3.22L; after 1 month of vaporizer use, average self-reported symptoms dropped to 6.92, FVC was 4.76L, and FEV1 was 3.6L. The study used 8 males and 4 females (8 of the subjects ended up smoking during the 1 month period) with an average age of 20 years. For these figures, the normal values for FVC and FEV1 should be 4.89 and 4.06L respectively. It should also be noted that approximately a quarter (3) of the subjects also reported tobacco use.
What this means: The results of this experiment indicate that utilizing vaporized cannabis instead of smoke may improve respiratory side-effects and overall pulmonary function. Additionally, this study only represented the improvement after one month of switching to vaporized cannabis, and improvements may increase with an increased time interval. Therefore, utilizing cannabis in vaporized form is significantly safer than smoking it.
Earleywine, M. and Van Dam, N.T. “Pulmonary Function in Cannabis Users: Support for a Clinical Trial of the Vaporizer.” The International Journal on Drug Policy. (2010): preprint.
Thursday, May 13, 2010
Monday, May 10, 2010
May 2010: Cannabinoids do not cause oxidative stress as previously thought. (Universidade do Porto; Porto, Portugal)
First some background: In order for human beings to survive, they must consume oxygen. This oxygen consumption drives the most basic of metabolic processes, allowing us to efficiently utilize carbohydrates, proteins, and fats as cellular sources of energy. The final conversion of these molecules to energy occurs within a cellular organelle known as the mitochondria. Within the mitochondria, oxygen is reduced and coupled with hydrogen to produce water, and a resulting hydrogen gradient drives the formation of ATP (cellular energy). However, this process is slightly inefficient, as some of the reduced oxygen fails to couple with hydrogen and become reactive oxygen species, such as superoxide. These reactive oxygen species may cause damage to a cell’s DNA, RNA, or proteins, but are normally converted by a series of enzymes (e.g. superoxide dismutase) into non-reactive molecules. Oxidative stress occurs when the balance between reactive species formation and conversion are disrupted, causing an accumulation of reactive oxygen species and an increase in cellular damage. Reactive oxygen species may also be formed as a byproduct of several other processes such as drug metabolism by cytochrome P450 enzymes. ∆9-Tetrahydrocannabinol (THC) has been previously reported to cause oxidative stress due to an increase in reactive oxygen species formation.1
The new information: In this experiment, mice were injected with either THC, vehicle (the contents of the THC injection without the actual THC), or nothing. The mice livers were then analyzed for the activity level of enzymes that interact with reactive oxygen species: superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase, and glutathione peroxidase. Additionally, the biomarkers indicating oxidative stress in the mouse liver were lipid peroxidation, protein carbonylation, and DNA oxidation. The results showed that THC caused no change in the activity levels of all 5 enzymes and no biomarkers for oxidative stress were observed. Additionally, the vehicle actually caused an increase in glutathione peroxidase activity, indicating an increase in levels of hydroperoxides, a type of reactive oxygen species. But in the THC injection, the glutathione peroxidase activity level was normal, indicating that THC actually reduced the level of oxidative stress caused by the vehicle.
What this means: This experiment shows that THC in fact does not cause oxidative stress in the liver, and disproves several theories that have been previously presented. This goes to further dispel some of the notions that cannabinoids are more harmful than beneficial for the patient. Additionally, by opposing the increase in glutathione peroxidase activity caused by the vehicle, THC may in fact be an antioxidant in the liver as it has been shown to be in the brain.2 This indicates that cannabinoids may be beneficial in treating other liver diseases besides hepatitis C.
1Sarafian, T.A., et al. “Oxidative Stress Produced by Marijuana Smoke. An Adverse Effect Enhanced by Cannabinoids.” American Journal of Respiratory Cell and Molecular Biology. 20.6(1999): 1286-93.
2Hampson, A.J., et al. “Cannabidiol and (−)Δ9-Tetrahydrocannabinol are Neuroprotective Antioxidants.” Proceedings of the National Academy of Sciences of the United States of America. 95.14(1998): 8268-73.
Pinto, C.E., et al. “Effect of (-)-Delta(9)-Tetrahydrocannabinoid on the Hepatic Redox State of Mice.” Brazilian Journal of Medical and Biological Research. 43.4(2010): 325-9.
The new information: In this experiment, mice were injected with either THC, vehicle (the contents of the THC injection without the actual THC), or nothing. The mice livers were then analyzed for the activity level of enzymes that interact with reactive oxygen species: superoxide dismutase, catalase, glutathione-S-transferase, glutathione reductase, and glutathione peroxidase. Additionally, the biomarkers indicating oxidative stress in the mouse liver were lipid peroxidation, protein carbonylation, and DNA oxidation. The results showed that THC caused no change in the activity levels of all 5 enzymes and no biomarkers for oxidative stress were observed. Additionally, the vehicle actually caused an increase in glutathione peroxidase activity, indicating an increase in levels of hydroperoxides, a type of reactive oxygen species. But in the THC injection, the glutathione peroxidase activity level was normal, indicating that THC actually reduced the level of oxidative stress caused by the vehicle.
What this means: This experiment shows that THC in fact does not cause oxidative stress in the liver, and disproves several theories that have been previously presented. This goes to further dispel some of the notions that cannabinoids are more harmful than beneficial for the patient. Additionally, by opposing the increase in glutathione peroxidase activity caused by the vehicle, THC may in fact be an antioxidant in the liver as it has been shown to be in the brain.2 This indicates that cannabinoids may be beneficial in treating other liver diseases besides hepatitis C.
1Sarafian, T.A., et al. “Oxidative Stress Produced by Marijuana Smoke. An Adverse Effect Enhanced by Cannabinoids.” American Journal of Respiratory Cell and Molecular Biology. 20.6(1999): 1286-93.
2Hampson, A.J., et al. “Cannabidiol and (−)Δ9-Tetrahydrocannabinol are Neuroprotective Antioxidants.” Proceedings of the National Academy of Sciences of the United States of America. 95.14(1998): 8268-73.
Pinto, C.E., et al. “Effect of (-)-Delta(9)-Tetrahydrocannabinoid on the Hepatic Redox State of Mice.” Brazilian Journal of Medical and Biological Research. 43.4(2010): 325-9.
Wednesday, May 5, 2010
May 2010: Cannabinoids may be used to target brain cancer cells. (University of the Basque Country; Leioa, Spain)
First some background: Brain cancer refers to the uncontrolled growth of cells in the brain, mainly neurons or glial cells. Glial cells refer to brain cells which do not actually conduct the signals that give rise to bodily function, but rather play a supportive role for neurons. When cancer arises from glial cells, such as oligodendrocytes, astrocytes, microglia, and ependyma, the tumor is referred to as a glioma. Malignant gliomas are the most prominent form of life-threatening brain cancer as well as one of the most aggressive forms of cancer known; thus although gliomas are not the most common, they are one of the most deadly cancers. Additionally, unlike lung or colon cancer, there are no known environmental factors that may cause brain cancer besides vinyl chloride or radiation, which the average person is not readily exposed to; and diagnosing brain cancer involves more expensive imaging techniques. These factors combined make gliomas one of the hardest forms of cancer to battle.
The new information: This experiment aimed to elucidate changes in cannabinoid receptor expression of gliomas. It was conducted by introducing antibodies raised against the receptors to human glial tumors and measuring the rate and levels at which the antibodies bound both cannabinoid receptor 1 and 2 (CB1 and CB2). It was found that in glioblastoma multiforme (the typical glioma), levels of CB1 were decreased by 43% and levels of CB2 were increased by 765% compared to a sample of normal, healthy brain tissue.
What this means: By altering levels of cannabinoid receptors, the brain cancer cells now differentiate themselves in terms of their response to cannabinoids. It has been widely documented that cannabinoids may induce cell apoptosis via CB2 receptors, and thus this astounding increase in CB2 receptor expression by gliomas make them far more susceptible to programmed cell death than other brain cells. Thus, levels of cannabinoids that would be safe for normal brain tissue would cause death in brain cancer cells. Therefore, cannabis may have potential therapeutic effects for those diagnosed with brain cancer, and more specifically, glioblastoma multiforme (GBM).
De Jesús, M.L., et al. “Opposite changes in cannabinoid CB1 and CB2 receptor expression in human gliomas.” Neurochemistry International. 56.6-7(2010): 829-33.
The new information: This experiment aimed to elucidate changes in cannabinoid receptor expression of gliomas. It was conducted by introducing antibodies raised against the receptors to human glial tumors and measuring the rate and levels at which the antibodies bound both cannabinoid receptor 1 and 2 (CB1 and CB2). It was found that in glioblastoma multiforme (the typical glioma), levels of CB1 were decreased by 43% and levels of CB2 were increased by 765% compared to a sample of normal, healthy brain tissue.
What this means: By altering levels of cannabinoid receptors, the brain cancer cells now differentiate themselves in terms of their response to cannabinoids. It has been widely documented that cannabinoids may induce cell apoptosis via CB2 receptors, and thus this astounding increase in CB2 receptor expression by gliomas make them far more susceptible to programmed cell death than other brain cells. Thus, levels of cannabinoids that would be safe for normal brain tissue would cause death in brain cancer cells. Therefore, cannabis may have potential therapeutic effects for those diagnosed with brain cancer, and more specifically, glioblastoma multiforme (GBM).
De Jesús, M.L., et al. “Opposite changes in cannabinoid CB1 and CB2 receptor expression in human gliomas.” Neurochemistry International. 56.6-7(2010): 829-33.
Thursday, April 22, 2010
April 2010: A Mechanism by Which Cannabinoids Act as an Antidepressant is Illustrated. (Charles University; Prague, Czech Republic)
Note: Starting in May, there will consistently be two new summaries a week.
First some background: Mood disorders effect approximately 5-13% of the United States population, with major depressive disorder (unipolar depression) reflecting 4-9%.* Although the etiology of depression is not well understood, it is associated with decreased hippocampal volume. Within the hippocampus, a region named the subgranular zone is one of only two areas in the brain where new brain cells can be produced. This area of the hippocampus contains stem cells that form new neurons and differentiate in response to brain-derived neurotrophic factor (BDNF). Antidepressants work by increasing levels of serotonin, dopamine, and norepinephrine in the brain. Increased levels of serotonin and norepinephrine cause an increase in BDNF levels, thus causing an increase in hippocampal volume. Current pharmacological mechanisms for treating depression utilize reuptake inhibitors, which increase levels of these chemicals by inhibiting their reuptake into brain cells. However, older antidepressants, less favored now because of their side effects, are targeted to inhibit the enzyme monoamine oxidase (e.g. isocarboxazid, phelezine). Monoamines refer to a class of molecules which include the aforementioned neurotransmitters serotonin, dopamine, and norepinephrine as well as several others such as histamine. The enzyme monoamine oxidase catalyzes the degradation of these monoamines, thus a monoamine oxidase inhibitor (MAOI) would cause higher levels of these chemicals in the brain. There are two types of monoamine oxidase enzymes found in the human body, MAO-A and MAO-B. MAO-A is found mainly in brain cells that utilize norepinephrine and is able to degrade norepinephrine, serotonin, and dopamine most effectively; while MAO-B is found mainly in brain cells that utilize serotonin and is able to degrade β-phenylethanolamine and dopamine most effectively.
The new information: This experiment tested the effect of three cannabinoids on the activity of both monoamine oxidase enzymes. The three cannabinoids used were ∆9-tetrahydrocannabinol (THC), anandamide (a cannabinoid that occurs naturally in our body), and the synthetic cannabinoid WIN (WIN 55,212-2). The concentrations needed to inhibit 50% of the enzyme activity were then compared with the MAOI medication iproniazid. It was found that the MAO-A enzyme was blocked at lowest concentrations by WIN, followed closely by THC, with a large gap in concentration between THC and anandamide. The MAO-B enzyme was blocked at approximately equal concentrations of THC and WIN, with a large gap in concentrations between them and anandamide. Additionally, the concentrations at which all three blocked the MAOs were much greater than the concentration of iproniazid needed for the same result. The concentrations were measured in micromoles per liter, meaning that they were measured based on number of molecules and not their size or weight.
What this means: The results of this experiment illustrate in detail the dependence of the antidepressant effect of cannabis on concentration of cannabinoids. Because the effect of THC on monoamine oxidase is not as powerful as MAOI medications, there will not be the dangerous drug and food interactions that are notorious side effects of MAOIs. However, marijuana would nonetheless increase the amount of serotonin and norepinephrine in the brain, thus leading to an expansion in the size of the hippocampus. This neurogenerative effect is part of what leads to the antidepressant properties of marijuana. Additionally, damage to the hippocampus is also seen in Alzheimer’s disease, decreases in long-term memory, post-traumatic stress disorder, schizophrenia, and epilepsy caused by hippocampal sclerosis. Thus cannabis may hypothetically be helpful in the treatment of these conditions and more through its action as an inhibitor of the enzyme monoamine oxidase.
*Nestler, E.J., Hyman, S.E., and Malenka, R.C. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. New York: McGraw-Hill, 2009.
Fišar, Z. “Inhibition of Monoamine Oxidase Activity by Cannabinoids.” Naunyn-Schmiedeberg’s Archives of Pharmacology. (2010): preprint.
First some background: Mood disorders effect approximately 5-13% of the United States population, with major depressive disorder (unipolar depression) reflecting 4-9%.* Although the etiology of depression is not well understood, it is associated with decreased hippocampal volume. Within the hippocampus, a region named the subgranular zone is one of only two areas in the brain where new brain cells can be produced. This area of the hippocampus contains stem cells that form new neurons and differentiate in response to brain-derived neurotrophic factor (BDNF). Antidepressants work by increasing levels of serotonin, dopamine, and norepinephrine in the brain. Increased levels of serotonin and norepinephrine cause an increase in BDNF levels, thus causing an increase in hippocampal volume. Current pharmacological mechanisms for treating depression utilize reuptake inhibitors, which increase levels of these chemicals by inhibiting their reuptake into brain cells. However, older antidepressants, less favored now because of their side effects, are targeted to inhibit the enzyme monoamine oxidase (e.g. isocarboxazid, phelezine). Monoamines refer to a class of molecules which include the aforementioned neurotransmitters serotonin, dopamine, and norepinephrine as well as several others such as histamine. The enzyme monoamine oxidase catalyzes the degradation of these monoamines, thus a monoamine oxidase inhibitor (MAOI) would cause higher levels of these chemicals in the brain. There are two types of monoamine oxidase enzymes found in the human body, MAO-A and MAO-B. MAO-A is found mainly in brain cells that utilize norepinephrine and is able to degrade norepinephrine, serotonin, and dopamine most effectively; while MAO-B is found mainly in brain cells that utilize serotonin and is able to degrade β-phenylethanolamine and dopamine most effectively.
The new information: This experiment tested the effect of three cannabinoids on the activity of both monoamine oxidase enzymes. The three cannabinoids used were ∆9-tetrahydrocannabinol (THC), anandamide (a cannabinoid that occurs naturally in our body), and the synthetic cannabinoid WIN (WIN 55,212-2). The concentrations needed to inhibit 50% of the enzyme activity were then compared with the MAOI medication iproniazid. It was found that the MAO-A enzyme was blocked at lowest concentrations by WIN, followed closely by THC, with a large gap in concentration between THC and anandamide. The MAO-B enzyme was blocked at approximately equal concentrations of THC and WIN, with a large gap in concentrations between them and anandamide. Additionally, the concentrations at which all three blocked the MAOs were much greater than the concentration of iproniazid needed for the same result. The concentrations were measured in micromoles per liter, meaning that they were measured based on number of molecules and not their size or weight.
What this means: The results of this experiment illustrate in detail the dependence of the antidepressant effect of cannabis on concentration of cannabinoids. Because the effect of THC on monoamine oxidase is not as powerful as MAOI medications, there will not be the dangerous drug and food interactions that are notorious side effects of MAOIs. However, marijuana would nonetheless increase the amount of serotonin and norepinephrine in the brain, thus leading to an expansion in the size of the hippocampus. This neurogenerative effect is part of what leads to the antidepressant properties of marijuana. Additionally, damage to the hippocampus is also seen in Alzheimer’s disease, decreases in long-term memory, post-traumatic stress disorder, schizophrenia, and epilepsy caused by hippocampal sclerosis. Thus cannabis may hypothetically be helpful in the treatment of these conditions and more through its action as an inhibitor of the enzyme monoamine oxidase.
*Nestler, E.J., Hyman, S.E., and Malenka, R.C. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience. New York: McGraw-Hill, 2009.
Fišar, Z. “Inhibition of Monoamine Oxidase Activity by Cannabinoids.” Naunyn-Schmiedeberg’s Archives of Pharmacology. (2010): preprint.
Sunday, April 11, 2010
June 2010: Cannabinoids inhibit a group of cancer-causing enzymes. (Hokuriku University; Kanazawa, Japan)
Note: June refers to the publication date
First some background: The human body contains an expansive number of enzymes, proteins which increase the rate of chemical reactions in our bodies. These enzymes typically facilitate the various molecular metabolic processes that are occurring at any given second within our cells, but some of their products and/or byproducts can be harmful, even carcinogenic (cause cancer). Perhaps the largest group of enzymes in our bodies is the cytochrome P450 (CYP) family, which catalyze the monooxidation (addition of one oxygen) of various organic molecules. One of the main functions of this enzyme family is the metabolism of drugs in the liver. However, some subfamilies, such as the CYP1 subfamily (enzymes CYP1A1, CYP1A2, CYP1B1), also induce the formation of carcinogenic compounds from polycyclic aromatic hydrocarbons. Polycyclic aromatic hydrocarbons are common constituents of smoke, especially cigarette smoke, and are known as procarcinogens. The label procarcinogen indicates that the molecule in and of itself will not cause cancer, but can be induced to cause cancer when altered by a metabolic process.
The new information: This experiment tested the effects of three cannabinoids found in marijuana on the catalytic effects of CYP1 enzymes. The three cannabinoids used were delta(9)-tetrahydrocannabinol (THC), cannabidiol, and cannabinol; it was found that all three cannabinoids inhibited all three CYP1 enzymes to some degree, with THC being the least potent inhibitor, cannabidiol inhibiting CYP1A1 most effectively, and cannabinol inhibiting CYP1A2 and CYP1B1 most effectively. Additionally, it was shown that all three cannabinoids were competitive inhibitors, meaning that at higher concentrations/potencies of other substrates for the CYP1 enzymes, the cannabinoids were displaced.
What this means: By illustrating that three of the major cannabinoids found in marijuana can cause potent inhibition of all three enzymes in the CYP1 subfamily, marijuana may prevent certain forms of cancer. Polycyclic aromatic hydrocarbons are common components in environmental pollution, and are usually inhaled, resulting in lung cancer. By inhibiting the enzyme that converts the procarcinogen into the cancer-causing compound, cannabis may be prophylactically used to prevent one of the main causes of lung cancer. Additionally, because CYP1 enzymes are also involved in drug metabolism, cannabis could be use to augment various pharmaceuticals for maximal effectiveness. In order for a drug to be excreted from the body, it generally first passes through at least two phases of metabolism, with cytochrome P450 enzymes representing one of the major components of the first phase. Thus if a drug is known to be metabolized by one of the CYP1 enzymes and cannabis is co-administered, it would take longer for the drug to be broken down in and removed from our bodies. Therefore, cannabis could extend the half-life of various medications, possibly reducing the cost to patients.
Yamaori, S., et al. “Characterization of Major Phytocannabinoids, Cannabidiol and Cannabinol, as Isoform-selective and Potent Inhibitors of Human CYP1 Enzymes.” Biochemical Pharmacology. 79.11(2010): 1691-8.
First some background: The human body contains an expansive number of enzymes, proteins which increase the rate of chemical reactions in our bodies. These enzymes typically facilitate the various molecular metabolic processes that are occurring at any given second within our cells, but some of their products and/or byproducts can be harmful, even carcinogenic (cause cancer). Perhaps the largest group of enzymes in our bodies is the cytochrome P450 (CYP) family, which catalyze the monooxidation (addition of one oxygen) of various organic molecules. One of the main functions of this enzyme family is the metabolism of drugs in the liver. However, some subfamilies, such as the CYP1 subfamily (enzymes CYP1A1, CYP1A2, CYP1B1), also induce the formation of carcinogenic compounds from polycyclic aromatic hydrocarbons. Polycyclic aromatic hydrocarbons are common constituents of smoke, especially cigarette smoke, and are known as procarcinogens. The label procarcinogen indicates that the molecule in and of itself will not cause cancer, but can be induced to cause cancer when altered by a metabolic process.
The new information: This experiment tested the effects of three cannabinoids found in marijuana on the catalytic effects of CYP1 enzymes. The three cannabinoids used were delta(9)-tetrahydrocannabinol (THC), cannabidiol, and cannabinol; it was found that all three cannabinoids inhibited all three CYP1 enzymes to some degree, with THC being the least potent inhibitor, cannabidiol inhibiting CYP1A1 most effectively, and cannabinol inhibiting CYP1A2 and CYP1B1 most effectively. Additionally, it was shown that all three cannabinoids were competitive inhibitors, meaning that at higher concentrations/potencies of other substrates for the CYP1 enzymes, the cannabinoids were displaced.
What this means: By illustrating that three of the major cannabinoids found in marijuana can cause potent inhibition of all three enzymes in the CYP1 subfamily, marijuana may prevent certain forms of cancer. Polycyclic aromatic hydrocarbons are common components in environmental pollution, and are usually inhaled, resulting in lung cancer. By inhibiting the enzyme that converts the procarcinogen into the cancer-causing compound, cannabis may be prophylactically used to prevent one of the main causes of lung cancer. Additionally, because CYP1 enzymes are also involved in drug metabolism, cannabis could be use to augment various pharmaceuticals for maximal effectiveness. In order for a drug to be excreted from the body, it generally first passes through at least two phases of metabolism, with cytochrome P450 enzymes representing one of the major components of the first phase. Thus if a drug is known to be metabolized by one of the CYP1 enzymes and cannabis is co-administered, it would take longer for the drug to be broken down in and removed from our bodies. Therefore, cannabis could extend the half-life of various medications, possibly reducing the cost to patients.
Yamaori, S., et al. “Characterization of Major Phytocannabinoids, Cannabidiol and Cannabinol, as Isoform-selective and Potent Inhibitors of Human CYP1 Enzymes.” Biochemical Pharmacology. 79.11(2010): 1691-8.
Tuesday, April 6, 2010
March 2010: Cannabinoids inhibit and may prevent neuropathic pain in diabetes. (University of Calgary; Alberta, Canada)
First some background: According to the World Health Organization, more than 220 million people worldwide are living with diabetes. Within the United States, the National Diabetes Fact Sheet cites 23.6 million people, or 7.6% of the population, as currently living with diabetes; and an additional 1.6 million as diagnosed each year. There are two common forms of diabetes: type I and type II. Type I diabetes usually affects an individual at birth, as they are unable to produce insulin in sufficient quantity. Type II diabetes typically occurs later in an individual's life and reflects a decreased ability of cells to utilize insulin. Insulin is a hormone secreted from Beta cells of the pancreas mainly in response to increased glucose levels in the blood. Insulin acts to allow glucose to be taken up by cells in muscle, liver, and fat, and subsequently being converted into stored forms of energy. With the accompanying lack of insulin or its function in diabetes, glucose, the simplest form of sugar, accumulates in the bloodstream, leading to a multitude of pathologies including neuropathic pain. Hyperglycemia (elevated blood glucose) causes small blood vessels to uptake higher levels of glucose, leading to thicker as well as weaker blood vessel membranes. With these thicker blood vessels comes a reciprocal decrease in blood flow, leading to decreased oxygen levels in many organs, including the brain. The decreased oxygen levels in the brain decreases the conduction velocity of neurons and may cause structural changes in brain cells. Additionally, Hyperglycemia causes the upregulation of oxygen radicals as well as the activation of microglia, both of which can damage nerve cells. Microglia are a type of brain cell that act as immune cells of the brain, they respond to infections of the brain and spinal cord. However, their activation in diabetes causes them to release cytotoxic chemicals in absence of infection, which can damage nerve cells. This damage and structural change in nerve cells is thought to be responsible for the phenomenon of diabetic peripheral neuropathy. It has been previously shown that inhibiting microglial activation leads to a dissipation of neuropathic pain in mouse models of diabetes.* It is also well known that both neurons and microglial cells express cannabinoid receptors.
The new information: This experiment involved inducing diabetes in mice in the presence and absence of cannabinoid agonists and observing the mice over a course of 8 months. There were six main experimental groups, one of which diabetes was induced without cannabinoid treatment, serving as a control. In a second group, diabetes was induced in conjunction with cannabidiol treatment. It was found that in this second group, neuropathic pain did not develop over the course of 8 months and the levels of activated microglia in the spinal cord were greatly reduced compared to the control. Additionally, when cannabidiol treatment was stopped, the mice continued to show reduced microglia as well as no signs of neuropathic pain. A third and fourth group involved the induction of diabetes and treatment with both CB1 and CB2 cannabinoid receptor agonists once symptoms of neuropathic pain started. The results indicated that both CB1 and CB2 agonists inhibited the symptoms of neuropathic pain, but the pain returned after treatment was stopped. The last two groups involved treatment with CB1 and CB2 cannabinoid receptor antagonists, which block the effect of cannabinoids, and no change was seen in the levels of pain compared to the control group.
What this means: This experiment provided more evidence that cannabinoids may be used in the treatment of neuropathic pain. However, the novel information obtained is much more surprising. When treated with cannabidiol at the onset of diabetes, the diabetic mice did not have any symptoms of neuropathic pain even when treatment was stopped. This suggests that treatment with cannabidiol at the onset of diabetes may produce permanent protective changes for nerve cells. Therefore, cannabis could hypothetically be used short-term at the onset of type II diabetes in adults for lifetime or long-term prevention of diabetic peripheral neuropathy.
*Tsuda, M., et al. “Activation of Dorsal Horn Microglia Contributes to Diabetes-induced Tactile Allodynia via Extracellular Signal-regulated Protein Kinase Signaling.” Glia. 56.4(2008): 378-86.
Toth, C., et al. “Cannabinoid-mediated Modulation of Neuropathic Pain and Microglial Accumulation in a Model of Murine Type I Diabetic Peripheral Neuropathic Pain.” Molecular Pain. 6.16(2010).
The new information: This experiment involved inducing diabetes in mice in the presence and absence of cannabinoid agonists and observing the mice over a course of 8 months. There were six main experimental groups, one of which diabetes was induced without cannabinoid treatment, serving as a control. In a second group, diabetes was induced in conjunction with cannabidiol treatment. It was found that in this second group, neuropathic pain did not develop over the course of 8 months and the levels of activated microglia in the spinal cord were greatly reduced compared to the control. Additionally, when cannabidiol treatment was stopped, the mice continued to show reduced microglia as well as no signs of neuropathic pain. A third and fourth group involved the induction of diabetes and treatment with both CB1 and CB2 cannabinoid receptor agonists once symptoms of neuropathic pain started. The results indicated that both CB1 and CB2 agonists inhibited the symptoms of neuropathic pain, but the pain returned after treatment was stopped. The last two groups involved treatment with CB1 and CB2 cannabinoid receptor antagonists, which block the effect of cannabinoids, and no change was seen in the levels of pain compared to the control group.
What this means: This experiment provided more evidence that cannabinoids may be used in the treatment of neuropathic pain. However, the novel information obtained is much more surprising. When treated with cannabidiol at the onset of diabetes, the diabetic mice did not have any symptoms of neuropathic pain even when treatment was stopped. This suggests that treatment with cannabidiol at the onset of diabetes may produce permanent protective changes for nerve cells. Therefore, cannabis could hypothetically be used short-term at the onset of type II diabetes in adults for lifetime or long-term prevention of diabetic peripheral neuropathy.
*Tsuda, M., et al. “Activation of Dorsal Horn Microglia Contributes to Diabetes-induced Tactile Allodynia via Extracellular Signal-regulated Protein Kinase Signaling.” Glia. 56.4(2008): 378-86.
Toth, C., et al. “Cannabinoid-mediated Modulation of Neuropathic Pain and Microglial Accumulation in a Model of Murine Type I Diabetic Peripheral Neuropathic Pain.” Molecular Pain. 6.16(2010).
Monday, March 29, 2010
March 2010: A novel process by which cannabinoids alleviate pain has been determined molecularly (Medizinische Hochschule Hannover; Hannover, Germany)
First some background: Chronic pain is often a difficult condition to treat and sometimes even diagnose. Originating as a protective mechanism, pain notifies us when an external stimulus may cause us harm or when something internal start to go awry. However, in certain types of chronic pain and what is referred to as neuropathic pain, this once protective mechanism exhibits functional degeneracy, where its function in the human body is not established. What has been well established however, is the process by which we feel this pain. When peripheral cells are damaged, an inflammatory response ensues, leading to the release of chemicals such as bradykinin, histamine, prostanoids, and tachykinins. These chemicals as well as physical pressure and severe temperatures act on dendritic terminals of nociceptive neurons, mostly activating TRP (transient receptor potential) channels. These TRP channels are a family of stimulus-sensitive non-selective cation channels, thus permeable to sodium, calcium, magnesium, and other positively charged ions. Activation of TRP channels causes a signal to be sent along this nociceptive (pain) neuron, whose cell body resides in the dorsal root ganglion. These cell bodies then relay their signal to a different neuron in the spinal cord. This spinal cord neuron, located in the dorsal horn, also receives input from several other neurons, dictating the level of pain felt and are usually inhibitory. It is well documented that cannabinoids can act in a retrograde fashion at these synapses utilizing CB1 (cannabinoid receptor 1) in order to inhibit the signal coming from the primary afferent neuron (the one that originally sensed the pain). Additionally, it has been established that cannabinoids may act at TRP channels directly, desensitizing them to painful stimuli. However, in recent years, it has emerged that cannabinoids may also act on other parts of the pain pathway.
The new information: Although it has been previously noted that cannabinoids act on different parts of the pain pathway, including glycine receptors, the exact molecular mechanism has not been established. The modulatory inhibitory neurons utilize one of two neurotransmitters to decrease the painful signal coming from the primary afferent neuron: GABA (gamma-aminobutyric acid) and glycine. It is known that cannabinoids somehow act on glycine receptors in order to decrease the sensation of pain. This experiment involved mutating the glycine receptor in specific regions to determine how cannabinoids, specifically cannabidiol, interact with the receptor. By mutating an amino acid in the second transmembrane domain from serine (polar) to isoleucine (nonpolar), cannabidiol had no effect on the receptor. However, in absence of the mutation, cannabidiol caused both co-activation and direct activation of the glycine receptor. Co-activation is also referred to as positive allosteric modulation, where the cannabinoid by itself will not activate the receptor, but in presence of glycine (the receptor agonist), there is an increased intracellular response. Additionally, cannabidiol was shown to directly activate this receptor, causing inhibition of the noxious (painful) signal.
What this means: As mentioned in previous entries, THC (∆9-tetrahydrocannabinol) is not the only cannabinoid found in plants of the Cannabis genus. The remaining cannabinoids all have differing structures, properties, and functions. However, the current pharmaceutical market utilizes only THC containing medication, which cannot fully utilize the benefits of Marijuana. By showing the exact molecular mechanism by which cannabidiol interacts with glycine receptors, another means by which cannabis lead to analgesia has been established.
Foadi, N., et al. “Lack of Positive Allosteric Modulation of Mutated Alpha(1)S267I Glycine Receptors by Cannabinoids.” Naunyn-Schmiedeberg's Archives of Pharmacology. (2010): preprint.
The new information: Although it has been previously noted that cannabinoids act on different parts of the pain pathway, including glycine receptors, the exact molecular mechanism has not been established. The modulatory inhibitory neurons utilize one of two neurotransmitters to decrease the painful signal coming from the primary afferent neuron: GABA (gamma-aminobutyric acid) and glycine. It is known that cannabinoids somehow act on glycine receptors in order to decrease the sensation of pain. This experiment involved mutating the glycine receptor in specific regions to determine how cannabinoids, specifically cannabidiol, interact with the receptor. By mutating an amino acid in the second transmembrane domain from serine (polar) to isoleucine (nonpolar), cannabidiol had no effect on the receptor. However, in absence of the mutation, cannabidiol caused both co-activation and direct activation of the glycine receptor. Co-activation is also referred to as positive allosteric modulation, where the cannabinoid by itself will not activate the receptor, but in presence of glycine (the receptor agonist), there is an increased intracellular response. Additionally, cannabidiol was shown to directly activate this receptor, causing inhibition of the noxious (painful) signal.
What this means: As mentioned in previous entries, THC (∆9-tetrahydrocannabinol) is not the only cannabinoid found in plants of the Cannabis genus. The remaining cannabinoids all have differing structures, properties, and functions. However, the current pharmaceutical market utilizes only THC containing medication, which cannot fully utilize the benefits of Marijuana. By showing the exact molecular mechanism by which cannabidiol interacts with glycine receptors, another means by which cannabis lead to analgesia has been established.
Foadi, N., et al. “Lack of Positive Allosteric Modulation of Mutated Alpha(1)S267I Glycine Receptors by Cannabinoids.” Naunyn-Schmiedeberg's Archives of Pharmacology. (2010): preprint.
Wednesday, March 24, 2010
March 2010: Cannabinoids have a role in reducing heart disease. (Shanghai Jiaotong University; Shanghai, China)
First some background: According to the World Health Organization (WHO), heart disease accounts for approximately 12 million deaths worldwide per year; and within the United States, about 2,600 people die per day from its complications. Although heart disease can manifest itself in several forms, the most common and most lethal is coronary artery disease, or atherosclerosis of the heart arteries. Atherosclerosis refers to the thickening of artery walls due to deposits of cholesterol shuttles such as LDL (low-density lipoprotein). Atherosclerosis develops when LDL molecules become oxidized by free oxygen radicals such as superoxide, a by-product of cellular reactions. Oxidized species such as the newly formed LDL cause damage upon contact with the endothelial cells lining arteries. When these cells are damaged, the body’s immune system tries to repair the damage and break down the oxidized LDL, but are unable to, and instead release more reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-α). This starts a vicious cycle leading to greater and greater levels of inflammation, causing the artery to harden, narrow, and eventually be completely blocked. It is known that subtypes of immune system cells such as macrophages and T cells contain cannabinoid receptor 2 (CB2).
The new information: In this experiment, macrophages were isolated from model mice and rats and exposed to oxidized LDL in the presence and absence of a cannabinoid agonist. The levels of reactive oxygen species (ROS) and TNF-α as well as intracellular signaling molecules were then measured. It was found that in the absence of the cannabinoid, the oxidized LDL strongly induced the generation of ROS and TNF-α. However, in the presence of the cannabinoid, the levels of ROS and TNF-α were greatly reduced, which was shown to occur via a mechanism of inhibiting intracellular signaling pathways within the macrophage. When the macrophage was exposed to both cannabinoid and a cannabinoid receptor blocker, the oxidized LDL once again strongly induced the generation of ROS and TNF-α, suggesting that the reduction was a direct product of the cannabinoid.
What this means: By illustrating that cannabinoids effectively reduce the inflammatory response of macrophages to oxidized LDL, this study shows that cannabinoids may be used as a prophylactic measure in preventing coronary artery disease. Additionally, cannabinoids may have therapeutic benefits in the treatment of atherosclerosis, as it would greatly decrease further inflammation and the appearance of plaques. Therefore use of cannabis in patients with coronary artery disease may reduce their risk of heart attack.
Hao, M.X., et al. “The Cannabinoid WIN55, 212-2 Protects Against Oxidized LDL-induced Inflammatory Response in Murine Macrophages.” Journal of Lipid Research. (2010): preprint.
The new information: In this experiment, macrophages were isolated from model mice and rats and exposed to oxidized LDL in the presence and absence of a cannabinoid agonist. The levels of reactive oxygen species (ROS) and TNF-α as well as intracellular signaling molecules were then measured. It was found that in the absence of the cannabinoid, the oxidized LDL strongly induced the generation of ROS and TNF-α. However, in the presence of the cannabinoid, the levels of ROS and TNF-α were greatly reduced, which was shown to occur via a mechanism of inhibiting intracellular signaling pathways within the macrophage. When the macrophage was exposed to both cannabinoid and a cannabinoid receptor blocker, the oxidized LDL once again strongly induced the generation of ROS and TNF-α, suggesting that the reduction was a direct product of the cannabinoid.
What this means: By illustrating that cannabinoids effectively reduce the inflammatory response of macrophages to oxidized LDL, this study shows that cannabinoids may be used as a prophylactic measure in preventing coronary artery disease. Additionally, cannabinoids may have therapeutic benefits in the treatment of atherosclerosis, as it would greatly decrease further inflammation and the appearance of plaques. Therefore use of cannabis in patients with coronary artery disease may reduce their risk of heart attack.
Hao, M.X., et al. “The Cannabinoid WIN55, 212-2 Protects Against Oxidized LDL-induced Inflammatory Response in Murine Macrophages.” Journal of Lipid Research. (2010): preprint.
Saturday, March 13, 2010
April 2010: Cannabinoids inhibit highly invasive cancer metastasis. (University of Rostock; Rostock, Germany)
Note: April refers to publication date, which is April 1; the actual study was conducted in November 2009. Additionally, to all the avid readers, I apologize for the wait, it's been a busy couple of weeks.
First some background: Most of the research summaries featured within this blog involve the effects of synthetic cannabinoid receptor agonists rather than the actual substances found within plants of the Cannabis genus. Although the ∆9-Tetrahydrocannabinol (THC) found in Cannabis is a CB1 and CB2 cannabinoid receptor agonist, it is still rarely used experimentally. Rarer still, is experimentation with one of the several other cannabinoids found within Cannabis plants. There are four other known cannabinoids that have been derived from Cannabis: Cannabidiol (CBD), Cannabinol (CBN), Tetrahydrocannabivarin (THCV), and Cannabichromene (CBC). When a patient considers the alternatives to medical marijuana, there is only one that supposedly is comparable, Dronabinol, marketed by Abbott (formally Solvay) pharmaceuticals as Marinol. Dronabinol is essentially synthetically produced THC, and thus contains only one of the substances in Cannabis that has shown therapeutic potential. Additionally, not all cannabinoids found in Cannabis act on the primary cannabis receptors CB1 and CB2; therefore in order to achieve the full medical benefits of marijuana, the other substances must be consumed as well. One of the other cannabinoids found in Cannabis plants is cannabidiol. Although it has not been researched as extensively as THC, it has been shown to generally make up 40% of extracts from the Cannabis plant.1 Cannabidiol’s exact physiological functions have not been fully understood, but it has been previously shown to interact with TRPV1 (transient receptor potential cation channel, subfamily V, member 1) receptors and have anti-cancer properties.
The new information: In this experiment, two different cancer cell lines were treated with cannabidiol, and both showed impaired invasion. The cell lines were of highly invasive human cervical cancer (HeLa, C33A) and human lung cancer (A549). The cannabidiol-driven impaired invasion was shown to be reversed by both an antagonist to CB1 and CB2 cannabinoid receptors as well as an antagonist to TRPV1 receptors. Although this did not represent particularly novel information, it was also found that the decrease in invasion occurred concurrently with an increase in TIMP-1 (tissue inhibitor of matrix metalloprotease-1). When the cell lines were genetically altered to be unable to produce TIMP-1, cannabidiol showed no effect in impairing cancer invasion. Additionally, the human lung cancer cell line was induced in thymic-aplastic nude mice, which lack a functioning immune system that could possibly defend against the cancer, where it was found that treatment with cannabidiol caused significant inhibition of lung metastasis.
What this means: The results of this study indicate that current pharmaceutical capabilities to utilize the substances found in the Cannabis plant are severely underdeveloped. In order to utilize the full therapeutic potential of marijuana, it must be ingested along with other substances naturally occurring in the plant. This particular experiment elucidated the molecular mechanism of cannabidiol-induced inhibition of cancer metastasis, which along with studies pertaining to anti-cancer effects of strictly cannabinoid receptor agonists, start to form a complete picture of the cancer-inhibiting capabilities of Cannabis.
1Grlie, L. "A Comparative Study on Chemical and Biological Characteristics of Various Samples of Cannabis Resin." Bulletin on Narcotics. 14(1976): 37–46.
Ramer, R., et al. “Cannabidiol Inhibits Cancer Cell Invasion via Upregulation of Tissue Inhibitor of Matrix Metalloproteinases-1.” Biochemical Pharmacology. 79.7(2010): 955-66.
First some background: Most of the research summaries featured within this blog involve the effects of synthetic cannabinoid receptor agonists rather than the actual substances found within plants of the Cannabis genus. Although the ∆9-Tetrahydrocannabinol (THC) found in Cannabis is a CB1 and CB2 cannabinoid receptor agonist, it is still rarely used experimentally. Rarer still, is experimentation with one of the several other cannabinoids found within Cannabis plants. There are four other known cannabinoids that have been derived from Cannabis: Cannabidiol (CBD), Cannabinol (CBN), Tetrahydrocannabivarin (THCV), and Cannabichromene (CBC). When a patient considers the alternatives to medical marijuana, there is only one that supposedly is comparable, Dronabinol, marketed by Abbott (formally Solvay) pharmaceuticals as Marinol. Dronabinol is essentially synthetically produced THC, and thus contains only one of the substances in Cannabis that has shown therapeutic potential. Additionally, not all cannabinoids found in Cannabis act on the primary cannabis receptors CB1 and CB2; therefore in order to achieve the full medical benefits of marijuana, the other substances must be consumed as well. One of the other cannabinoids found in Cannabis plants is cannabidiol. Although it has not been researched as extensively as THC, it has been shown to generally make up 40% of extracts from the Cannabis plant.1 Cannabidiol’s exact physiological functions have not been fully understood, but it has been previously shown to interact with TRPV1 (transient receptor potential cation channel, subfamily V, member 1) receptors and have anti-cancer properties.
The new information: In this experiment, two different cancer cell lines were treated with cannabidiol, and both showed impaired invasion. The cell lines were of highly invasive human cervical cancer (HeLa, C33A) and human lung cancer (A549). The cannabidiol-driven impaired invasion was shown to be reversed by both an antagonist to CB1 and CB2 cannabinoid receptors as well as an antagonist to TRPV1 receptors. Although this did not represent particularly novel information, it was also found that the decrease in invasion occurred concurrently with an increase in TIMP-1 (tissue inhibitor of matrix metalloprotease-1). When the cell lines were genetically altered to be unable to produce TIMP-1, cannabidiol showed no effect in impairing cancer invasion. Additionally, the human lung cancer cell line was induced in thymic-aplastic nude mice, which lack a functioning immune system that could possibly defend against the cancer, where it was found that treatment with cannabidiol caused significant inhibition of lung metastasis.
What this means: The results of this study indicate that current pharmaceutical capabilities to utilize the substances found in the Cannabis plant are severely underdeveloped. In order to utilize the full therapeutic potential of marijuana, it must be ingested along with other substances naturally occurring in the plant. This particular experiment elucidated the molecular mechanism of cannabidiol-induced inhibition of cancer metastasis, which along with studies pertaining to anti-cancer effects of strictly cannabinoid receptor agonists, start to form a complete picture of the cancer-inhibiting capabilities of Cannabis.
1Grlie, L. "A Comparative Study on Chemical and Biological Characteristics of Various Samples of Cannabis Resin." Bulletin on Narcotics. 14(1976): 37–46.
Ramer, R., et al. “Cannabidiol Inhibits Cancer Cell Invasion via Upregulation of Tissue Inhibitor of Matrix Metalloproteinases-1.” Biochemical Pharmacology. 79.7(2010): 955-66.
Wednesday, March 3, 2010
February 2010: Cannabinoids inhibit pain and bone loss induced by bone cancer (The University of Arizona; Tucson, Arizona)
First some background: Malignant bone cancer refers to a number of diverse tumor types, including osteosarcoma, chondrosarcoma, fibrosarcoma, cordoma, and Erwig’s sarcoma. Although the physiological mechanisms leading to tumor formation and malignancy may differ, the main symptoms of most forms of bone cancer are severe pain and bone loss. Thus, in standard treatment regiments for bone cancer, opiates are used in addition to chemotherapy and radiotherapy to abate the pain. However, use of opiates for analgesia has several downsides: physical addiction, high abuse potential, and rapid tolerance to name a few. Additionally, two side effects of chronic opiate use lead to an exacerbation of bone cancer symptoms. The first is pain hypersensitization. When the body is exposed to constant levels of any drug that acts as a receptor agonist, it induces a protective response to maintain its original state. Therefore when exposed to chronic opiate medications, the body reduces expression of opioid receptors, leading to decreased pain inhibition and thus increased sensitivity to pain. The second is hypogonadism. Opiates act on what is known as the hypothalamic-pituitary axis, causing decreased levels of hormone release. One of these hormones is GnRH (gonadotropin releasing hormone). GnRH causes release of two hormones from the anterior pituitary: LH (luteinizing hormone) and FSH (follicle stimulating hormone). These two hormones are responsible for regulating the amount of testosterone in both males and females. Although testosterone is widely known for being the main sex hormone in males, it is also present in lesser amounts in females with a common protective function of maintaining bone density. Thus chronic use of opiate medications will lead to an increased level of bone loss.
The new information: Cannabinoids have been shown to be a more valid alternative for treating bone cancer-mediated pain. The experiment was carried out by inducing bone cancer in mice and performing both behavioral and radiologic image interpretation of symptoms. After confirming the development of cancer, the mice were shown to have experienced both spontaneous and touch-evoked behavioral signs of pain. By administrating cannabinoids to the mice, both the spontaneous and stimulated pain was inhibited. Additionally, a sustained treatment regimen of cannabinoids led to significant reductions in bone loss, manifesting as a decreased likelihood of cancer-induced bone fractures.
What this means: By showing the benefits of utilizing cannabinoids as an alternative analgesic for bone cancer patients, cannabis may be a healthier alternative than opiates in treating pain associated with the cancer. Chronic use of opiates can cause more harm than good, as they often exacerbate the symptoms of bone cancer via patient hypersensitivity to pain and decreased bone mineral density. Cannabinoids on the other hand not only provide a non-physically addictive alternative, but also have been shown to attenuate the bone loss seen in cancer patients.
Lozano, A., et al. “A Cannabinoid 2 Receptor Agonist Attenuates Bone Cancer-induced Pain and Bone Loss.” Life Sciences. 2010: (preprint)
The new information: Cannabinoids have been shown to be a more valid alternative for treating bone cancer-mediated pain. The experiment was carried out by inducing bone cancer in mice and performing both behavioral and radiologic image interpretation of symptoms. After confirming the development of cancer, the mice were shown to have experienced both spontaneous and touch-evoked behavioral signs of pain. By administrating cannabinoids to the mice, both the spontaneous and stimulated pain was inhibited. Additionally, a sustained treatment regimen of cannabinoids led to significant reductions in bone loss, manifesting as a decreased likelihood of cancer-induced bone fractures.
What this means: By showing the benefits of utilizing cannabinoids as an alternative analgesic for bone cancer patients, cannabis may be a healthier alternative than opiates in treating pain associated with the cancer. Chronic use of opiates can cause more harm than good, as they often exacerbate the symptoms of bone cancer via patient hypersensitivity to pain and decreased bone mineral density. Cannabinoids on the other hand not only provide a non-physically addictive alternative, but also have been shown to attenuate the bone loss seen in cancer patients.
Lozano, A., et al. “A Cannabinoid 2 Receptor Agonist Attenuates Bone Cancer-induced Pain and Bone Loss.” Life Sciences. 2010: (preprint)
Sunday, February 28, 2010
February 2010: Cannabinoids reduce the spread of damage following spinal cord injuries. (Hospital Nacional de Paraplejicos; Toledo, Spain)
First some background: The spinal cord is a bundle of nerve axons that descend from the brain down the back, to around the area of the waist. It is responsible for delivering and relaying messages traveling to and from the brain. The spinal cord is surrounded by bones known as vertebrae, which function to protect the spinal cord from damage or injury. However, it is still possible for damage to occur as a result of severe trauma, which tends to affect bodily functions below the area of injury. However, the initial trauma is not usually the major cause of cell death in the spinal cord. Necrosis occurs after a nerve cell axon is compressed, leading to swelling and eventually bursting. Additionally, a different process occurs known as apoptosis, or programmed cell death, in which neurons surrounding the initial area of damage receive a signal to essentially kill themselves. In spinal cord injuries this normally occurs in two waves: one wave eight hours after the initial injury that affects a specific cell type known as glial cells. The second wave occurs about seven days later in a different cell type known as oligodendrocytes, which can occur at areas distant from the epicenter of injury. This exacerbates initial damage and leads to increased loss of bodily functions.
The new information: It was found that by activating cannabinoid CB1 and CB2 receptors, neuronal axons were preserved at the immediate region of injury. Axons are long extensions of brain cells that form the actual spinal cord. These axons, also known as white matter, are coated with a fatty insulating material known as the myelin sheath, which is formed in the periphery by oligodendrocytes. It was shown that by activating these cannabinoid receptors, there was preservation of white matter and a decreased level of oligodendrocyte death at the epicenter. Additionally, the cannabinoid also inhibited myelin damage and oligodendrocyte loss at areas distant from the injury epicenter due to delayed apoptosis.
What this means: Currently, there are only two possible treatments for spinal cord injury that may help to halt the progression of neuronal damage: anti-inflammatory medication, and cold saline. Both of these work by decreasing the amount of signals that can be received by the cell processes in the spinal cord. However, anti-inflammatory medications may lead to an increased risk of infection, and administration of cold saline lacks empirical evidence to prove its effectiveness. This experiment showed that cannabis can possibly be used immediately following acute spinal cord injuries to decrease the amount of damage, and thus decrease the loss of function in patients.
Arevalo-Martin, A., et al. “The endocannabinoid 2-arachidonoylglycerol reduces lesion expansion and white matter damage after spinal cord injury.” Neurobiology of Disease. (2010): preprint.
The new information: It was found that by activating cannabinoid CB1 and CB2 receptors, neuronal axons were preserved at the immediate region of injury. Axons are long extensions of brain cells that form the actual spinal cord. These axons, also known as white matter, are coated with a fatty insulating material known as the myelin sheath, which is formed in the periphery by oligodendrocytes. It was shown that by activating these cannabinoid receptors, there was preservation of white matter and a decreased level of oligodendrocyte death at the epicenter. Additionally, the cannabinoid also inhibited myelin damage and oligodendrocyte loss at areas distant from the injury epicenter due to delayed apoptosis.
What this means: Currently, there are only two possible treatments for spinal cord injury that may help to halt the progression of neuronal damage: anti-inflammatory medication, and cold saline. Both of these work by decreasing the amount of signals that can be received by the cell processes in the spinal cord. However, anti-inflammatory medications may lead to an increased risk of infection, and administration of cold saline lacks empirical evidence to prove its effectiveness. This experiment showed that cannabis can possibly be used immediately following acute spinal cord injuries to decrease the amount of damage, and thus decrease the loss of function in patients.
Arevalo-Martin, A., et al. “The endocannabinoid 2-arachidonoylglycerol reduces lesion expansion and white matter damage after spinal cord injury.” Neurobiology of Disease. (2010): preprint.
Monday, February 22, 2010
January 2010: Cannabinoids inhibit a form of immunodeficiency due to HIV (Virginia Commonwealth University; Richmond, Virginia)
First some background: Immunodeficiency can be aptly described as the inability for the body's defense system to mount an effective response against invading pathogens, and is usually the result of a decreased number of white blood cells or a loss in ability to recognize the pathogen as foreign. HIV (Human Immunodeficiency Virus) leads to immunodeficiency via two main mechanisms: the direct killing of, or an increased rate of apoptosis (programmed cell death) in white blood cells. One of the cells that are targeted by HIV is the macrophage. Macrophages are involved in the initial response to an infection; foreign pathogens (i.e. bacteria) bind to surface receptors, causing the macrophage to envelop the bacterium and digest it. The macrophage then presents proteins of the digested pathogen to other cells, while also secreting chemical factors that attract other white blood cells. When macrophages are infected with HIV, they stop producing their own proteins and begin to produce and secrete viral toxic factors uncontrollably. One of these toxic factors is the protein Tat (transactivator), which serves as an attractant for monocytes, the precursor to macrophages. Once monocytes leave the blood stream and enter local tissues, they can develop into macrophages. By attracting other macrophages, HIV starts a vicious cycle leading to higher and higher levels of Tat in the human body. Additionally, Tat acts as a toxin by inducing apoptosis in T cells, one of the white blood cells responsible for mediating adaptive immunity. Adaptive immunity refers to the ability of the body to rapidly fight a pathogen upon re-infection. The death of the T cells leads to a loss in this adaptive immunity, which is a factor in the infection hypersensitization seen in HIV patients, especially those in which its progression has lead to the development of AIDS (Acquired Immune Deficiency Syndrome).
The new information: Administration of cannabinoids lead to an inhibition in the migration of monocytes due to Tat. By activating the CB2 cannabinoid receptor, it was shown that monocytes and macrophages did not respond to this attractive factor. The experiment proved this using three separate mechanisms. First, a cannabinoid receptor agonist was administered, which lead to the activation of the CB2 receptor on macrophages and inhibition of migration in response to Tat. Secondly, a cannabinoid receptor antagonist was administered, which blocks the CB2 receptor on macrophages and lead to migration. Lastly, the DNA of the macrophage was altered so that the CB2 receptor was not produced, and this lead to migration even in the presence of cannabinoid.
What this means: By halting one of the vicious cycles that lead to AIDS, cannabinoids can potentially stop the progression of HIV (AIDS is defined by a CD4+ (helper) T cell count below 200 cells per microliter). By decreasing the levels of HIV-induced release of Tat by macrophages, the level of T cell death due to Tat would decline. Thus, cannabis could potentially slow the progression of HIV and AIDS by disallowing widespread cellular infection. Currently, the standard treatment for HIV/AIDS is HAART (Highly Active Antiretroviral Therapy), which utilizes several of what are known as anti-retroviral drugs, which inhibit an enzyme responsible for converting the HIV genes into a format that can be read by human cells. While this form of treatment is effective in preventing cellular infection, it cannot target cells already infected with the virus. Therefore, macrophages already producing Tat will continue to produce it, attracting other macrophages for infection, and causing the continued death of white blood cells. By administering cannabis concurrently, it would add an additional level of protection by reducing the spread of HIV to attracted macrophages. Additionally, HAART is very expensive, with an approximate average cost of $1,500 per month. By utilizing cannabis in conjunction with more cost-effective anti-retroviral medications, the cost of treatment could be reduced to as little as $100 a month.
Raborn, E. and G. Cabral. “Cannabinoid Inhibition of Macrophage Migration to the Tat Protein of HIV-1 is Linked to the CB2 Cannabinoid Receptor.” The Journal of Pharmacology and Experimental Therapeutics. (2010): preprint.
The new information: Administration of cannabinoids lead to an inhibition in the migration of monocytes due to Tat. By activating the CB2 cannabinoid receptor, it was shown that monocytes and macrophages did not respond to this attractive factor. The experiment proved this using three separate mechanisms. First, a cannabinoid receptor agonist was administered, which lead to the activation of the CB2 receptor on macrophages and inhibition of migration in response to Tat. Secondly, a cannabinoid receptor antagonist was administered, which blocks the CB2 receptor on macrophages and lead to migration. Lastly, the DNA of the macrophage was altered so that the CB2 receptor was not produced, and this lead to migration even in the presence of cannabinoid.
What this means: By halting one of the vicious cycles that lead to AIDS, cannabinoids can potentially stop the progression of HIV (AIDS is defined by a CD4+ (helper) T cell count below 200 cells per microliter). By decreasing the levels of HIV-induced release of Tat by macrophages, the level of T cell death due to Tat would decline. Thus, cannabis could potentially slow the progression of HIV and AIDS by disallowing widespread cellular infection. Currently, the standard treatment for HIV/AIDS is HAART (Highly Active Antiretroviral Therapy), which utilizes several of what are known as anti-retroviral drugs, which inhibit an enzyme responsible for converting the HIV genes into a format that can be read by human cells. While this form of treatment is effective in preventing cellular infection, it cannot target cells already infected with the virus. Therefore, macrophages already producing Tat will continue to produce it, attracting other macrophages for infection, and causing the continued death of white blood cells. By administering cannabis concurrently, it would add an additional level of protection by reducing the spread of HIV to attracted macrophages. Additionally, HAART is very expensive, with an approximate average cost of $1,500 per month. By utilizing cannabis in conjunction with more cost-effective anti-retroviral medications, the cost of treatment could be reduced to as little as $100 a month.
Raborn, E. and G. Cabral. “Cannabinoid Inhibition of Macrophage Migration to the Tat Protein of HIV-1 is Linked to the CB2 Cannabinoid Receptor.” The Journal of Pharmacology and Experimental Therapeutics. (2010): preprint.
Thursday, February 18, 2010
February 2010: Cannabinoids sensitize cancer cells to lethal signals. (Universita di Palermo; Palermo, Italy)
First some background: According to the American Cancer Society, in 2009, approximately 22,620 cases of hepatic (liver) cancer were diagnosed, with an approximate 82% mortality rate. Although this is a relatively rare form of cancer, it can be caused by hepatitis or excessive alcohol consumption, and has one of the highest mortality rates. Hepatic cancer is one of the hardest cancers to diagnose, and according to the National Cancer Institute, approximately only 10-20% of liver tumors can be fully removed during surgery. If not removed, liver cancer it is usually deadly within three to six months. One of the molecular causes of cancer is known to be decreased apoptotic ability. Apoptosis refers to programmed cell death, in which a cell receives a specific signal, activating “suicidal” pathways that eventually terminate in the cell’s death. This process is used to control the proliferation of cells in our bodies, allowing us to keep a relatively constant numbers of each cell type. If a cell undergoes a mutation that leads to an inability to perform apoptosis, cell growth can no longer be controlled and a tumor is formed. If the cells within this tumor are capable of recruiting blood vessels and traveling to other parts of the body, they are referred to as malignant tumors, causing what is commonly known as cancer.
The new information: When cannabinoids were administered to human hepatocellular carcinoma (HHC) cells, it caused an up-regulation of a receptor known as DR5 (Death Receptor 5). This receptor allows binding of molecules known as TNFs (Tumor Necrosis Factors), and leads to the activation of an apoptotic pathway. When the DR5 receptors are up-regulated, there are more binding sites for TNFs, which leads to higher levels of cell death. Additionally, administration of the cannabinoid lead to a significant decrease in survival factors, which have the ability to halt the process of apoptosis. The cannabinoid in this study was co-administered with TRAIL (TNF-related apoptosis inducing ligand), leading to a significantly higher level of apoptosis than administration with TRAIL alone.
What this means: This illustrates a novel treatment for liver cancer; because it is one of the hardest carcinomas to remove surgically and its high mortality rate, liver cancer remains one of the deadliest forms. This study proved that administration of cannabinoids lead to an increased sensitivity of hepatic cancer cells to factors that lead to their death. Therefore, co-administration of cannabis with current cancer treatments can lead to an increase in their effectiveness.
Pellerito, O., et al. “The synthetic cannabinoid WIN sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis by activating p8/CHOP/DR5 axis.” Molecular Pharmacology. (2010): preprint.
The new information: When cannabinoids were administered to human hepatocellular carcinoma (HHC) cells, it caused an up-regulation of a receptor known as DR5 (Death Receptor 5). This receptor allows binding of molecules known as TNFs (Tumor Necrosis Factors), and leads to the activation of an apoptotic pathway. When the DR5 receptors are up-regulated, there are more binding sites for TNFs, which leads to higher levels of cell death. Additionally, administration of the cannabinoid lead to a significant decrease in survival factors, which have the ability to halt the process of apoptosis. The cannabinoid in this study was co-administered with TRAIL (TNF-related apoptosis inducing ligand), leading to a significantly higher level of apoptosis than administration with TRAIL alone.
What this means: This illustrates a novel treatment for liver cancer; because it is one of the hardest carcinomas to remove surgically and its high mortality rate, liver cancer remains one of the deadliest forms. This study proved that administration of cannabinoids lead to an increased sensitivity of hepatic cancer cells to factors that lead to their death. Therefore, co-administration of cannabis with current cancer treatments can lead to an increase in their effectiveness.
Pellerito, O., et al. “The synthetic cannabinoid WIN sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis by activating p8/CHOP/DR5 axis.” Molecular Pharmacology. (2010): preprint.
Saturday, February 13, 2010
February 2010: Cannabinoids affect level of hormone release from the brain. (Universidad de Buenos Aires; Buenos Aires, Argentina)
First some background: Most of the major hormones found in the body are regulated by and released from what is known as the hypothalamic-pituitary axis, involving two distinct but connected areas of the brain, the hypothalamus and pituitary gland. The hypothalamus is responsible for the production and release of hormones such as thyrotropin-releasing hormone, dopamine, growth hormone-releasing hormone, somatostatin, gonadotropin-releasing hormone, and corticotropin-releasing hormone. All of these hormones in turn act on the anterior pituitary gland causing release or inhibiting release at their respective sites of action. The other half of the pituitary gland, the posterior pituitary is responsible for the release of other hormones produced in the hypothalamus, oxytocin and vasopressin. Vasopressin, also known as anti-diuretic hormone, controls the level of hydration in the body. When released, vasopressin acts on the kidneys to increase re-absorption of water, thus decreasing the amount of urine produced. Oxytocin is known for its role in uterine contraction when giving birth and in stimulating the let-down of breast milk. Oxytocin levels also increase in both men and women during sexual arousal and especially during orgasm, which may play a role in mate selection by invoking feelings of contentment and repressing anxiety. Mutations in the gene coding for oxytocin have also been implicated as a cause of Autism.*
The new information: It was found that in hypothalamic magnocellular neurons, which are responsible for the production and release of oxytocin and vasopressin, there were significant numbers of cannabinoid receptors. This indicates that cannabinoids can modulate the production and release of these hormones. Additionally, when the brain was directly exposed to stressors, cannabinoids induced the secretion of oxytocin. The experiment was carried out by injecting lipopolysaccharide (LPS), a component of gram-negative bacterial membranes, into the brain. The LPS invokes an immune response that creates a level of stress in the brain by increasing inflammation. When the LPS was injected, there were increased levels of cannabinoids found in the brain, which lead to enhanced secretion of oxytocin.
What this means: This experiment illustrated one of the mechanisms of cannabis’ well-known anxiolytic effects. By stimulating the synthesis and release of oxytocin, cannabis can be effectively used to treat both general and specific anxiety disorders, mood disorders, as well as some symptoms of Autism. Additionally, because it was shown that cannabinoids have modulatory effects in the pituitary, it may be possible to treat certain forms of hypopituitarism using cannabis.
De Laurentiis, A., et al. “Endocannabinoid System Participates in Neuroendocrine Control of Homeostasis.” Neuroimmunomodulation. 17.3 (2010): 153-156.
*Jacob, S., et al. "Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism." Neuroscience Letters. 417.1 (2007): 6–9.
The new information: It was found that in hypothalamic magnocellular neurons, which are responsible for the production and release of oxytocin and vasopressin, there were significant numbers of cannabinoid receptors. This indicates that cannabinoids can modulate the production and release of these hormones. Additionally, when the brain was directly exposed to stressors, cannabinoids induced the secretion of oxytocin. The experiment was carried out by injecting lipopolysaccharide (LPS), a component of gram-negative bacterial membranes, into the brain. The LPS invokes an immune response that creates a level of stress in the brain by increasing inflammation. When the LPS was injected, there were increased levels of cannabinoids found in the brain, which lead to enhanced secretion of oxytocin.
What this means: This experiment illustrated one of the mechanisms of cannabis’ well-known anxiolytic effects. By stimulating the synthesis and release of oxytocin, cannabis can be effectively used to treat both general and specific anxiety disorders, mood disorders, as well as some symptoms of Autism. Additionally, because it was shown that cannabinoids have modulatory effects in the pituitary, it may be possible to treat certain forms of hypopituitarism using cannabis.
De Laurentiis, A., et al. “Endocannabinoid System Participates in Neuroendocrine Control of Homeostasis.” Neuroimmunomodulation. 17.3 (2010): 153-156.
*Jacob, S., et al. "Association of the oxytocin receptor gene (OXTR) in Caucasian children and adolescents with autism." Neuroscience Letters. 417.1 (2007): 6–9.
Tuesday, February 9, 2010
February 2010: The beneficial effects of cannabinoids in one portion of the brain is fully understood (Goethe Universität Frankfurt am Main; Germany)
First some background: The portion of the brain used in this experiment is called the dentate gyrus. The dentate gyrus is part of the temporal lobe of the cortex, which, in layman’s terms, is the portion of the brain that exists directly on both sides of the head. The temporal lobe is involved in the processing of sounds, as well as the semantics of vision and the formation of memories. Additionally, cell damage and death in the dentate gyrus is known to be one of the etiological causes of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. It has also been well documented that cannabinoids reduce inflammation and have a protective effect in the dentate gyrus.
The new information: Although the end biological effect of cannabinoids in this area of the brain has been known for some time, the molecular events have now been determined. The experiment examined the effects of cannabinoid receptor-mediated activation of ion channels in the brain cells at varying concentrations of cannabinoids. It was found that at lower concentrations (0.01 muM), the cannabinoid most effectively mediated neuroprotection and anti-inflammatory effects, and with higher doses, the cannabinoids were less effective. It was also shown through channel blocking and activation that cannabinoids led to the inhibition of TRPV1 channels, which allow passage of calcium, magnesium, and sodium, as well as the activation of Ca(v)2.2, a voltage-gated N-type calcium channel.
What this means: This study allowed a look at the dosage-dependent effects of cannabinoids. As more is learned about how the concentration of cannabinoids affects their benefits, it will be possible to determine more effective dosages of cannabis itself. Additionally, by elucidating the molecular mechanisms of neuroprotection and anti-inflammation, it could be possible to accentuate these specific actions of cannabinoids by the use of drugs that affect the ion channels whose permeability was shown to be altered. This could lead to more effective treatment of neurodegenerative diseases such as Alzheimer’s of Parkinson’s.
Kock, M., et al. “The cannabinoid WIN 55,212-2-mediated protection of dentate gyrus granule cells is driven by CB(1) receptors and modulated by TRPA1 and Ca(v)2.2 channels.” Hippocampus. (2010): preprint.
The new information: Although the end biological effect of cannabinoids in this area of the brain has been known for some time, the molecular events have now been determined. The experiment examined the effects of cannabinoid receptor-mediated activation of ion channels in the brain cells at varying concentrations of cannabinoids. It was found that at lower concentrations (0.01 muM), the cannabinoid most effectively mediated neuroprotection and anti-inflammatory effects, and with higher doses, the cannabinoids were less effective. It was also shown through channel blocking and activation that cannabinoids led to the inhibition of TRPV1 channels, which allow passage of calcium, magnesium, and sodium, as well as the activation of Ca(v)2.2, a voltage-gated N-type calcium channel.
What this means: This study allowed a look at the dosage-dependent effects of cannabinoids. As more is learned about how the concentration of cannabinoids affects their benefits, it will be possible to determine more effective dosages of cannabis itself. Additionally, by elucidating the molecular mechanisms of neuroprotection and anti-inflammation, it could be possible to accentuate these specific actions of cannabinoids by the use of drugs that affect the ion channels whose permeability was shown to be altered. This could lead to more effective treatment of neurodegenerative diseases such as Alzheimer’s of Parkinson’s.
Kock, M., et al. “The cannabinoid WIN 55,212-2-mediated protection of dentate gyrus granule cells is driven by CB(1) receptors and modulated by TRPA1 and Ca(v)2.2 channels.” Hippocampus. (2010): preprint.
Sunday, February 7, 2010
November 2009: Cannabinoids Protects against Colitis (University Calgary; Calgary, Alberta, Canada)
First some background: Colitis specifically refers to the inflammation of the colon, the most posterior portion of the large intestine, and encompasses a broad group of medical conditions. Some of these conditions include inflammatory bowel disease (IBD), ulcerative colitis, Crohn’s disease, and pseudomembranous colitis. In addition to colonic inflammation, colitis is also usually seen with symptoms such as fever, anemia, and diarrhea; and although acute cases of colitis such as those due to bacterial infection can be easily treated, the more chronic cases of colitis may last the rest of a patient’s lifetime. It has been shown in previous studies that activation of cannabinoid receptor 1 can lead to a gradual dissipation of symptom intensity in cases of colitis.
The new information: The activation of cannabinoid receptor 2 actually protected against colitis in model organisms. The actual procedure of the experiment was to induce colitis in mice using TNBS (trinitrobenzene sulfonic acid). By studying the colons of the experimental organisms, it was also shown that mice which developed colitis showed an increase in expression of cannabinoid receptor 2 in their colons, meaning that their bodies are trying to rid themselves of colitis by increasing the effects of cannabinoids in the colon. The mice which developed colitis were then given a three-day treatment of cannabinoid agonists, which caused a large reduction in the clinical manifestations of colitis, limiting the progression of the condition.
What this means: Not only can cannabinoids lead to decreased intensity of symptoms in cases of colitis, but they can also actually protect against it, and stop the condition in its early stages. Additionally, one of the body’s natural mechanisms for protecting against the effects of colitis is to allow a greater level of access for cannabinoids to effect the colon.
Storr, M.A., et al. “Activation of cannabinoid 2 receptor (CB2) protects against experimental colitis.” Inflammatory bowel diseases. 15.11 (2009): 1678-85.
The new information: The activation of cannabinoid receptor 2 actually protected against colitis in model organisms. The actual procedure of the experiment was to induce colitis in mice using TNBS (trinitrobenzene sulfonic acid). By studying the colons of the experimental organisms, it was also shown that mice which developed colitis showed an increase in expression of cannabinoid receptor 2 in their colons, meaning that their bodies are trying to rid themselves of colitis by increasing the effects of cannabinoids in the colon. The mice which developed colitis were then given a three-day treatment of cannabinoid agonists, which caused a large reduction in the clinical manifestations of colitis, limiting the progression of the condition.
What this means: Not only can cannabinoids lead to decreased intensity of symptoms in cases of colitis, but they can also actually protect against it, and stop the condition in its early stages. Additionally, one of the body’s natural mechanisms for protecting against the effects of colitis is to allow a greater level of access for cannabinoids to effect the colon.
Storr, M.A., et al. “Activation of cannabinoid 2 receptor (CB2) protects against experimental colitis.” Inflammatory bowel diseases. 15.11 (2009): 1678-85.
Thursday, February 4, 2010
October 2009:Genetic disorders involving nonfunctional cannabinoid receptors may cause a predisposition to eating disorders(University of Naples;Italy
First some background: According to the National Institute of Mental Health (NIMH), an estimated 0.5 to 3.7 percent of females in the United States suffer from anorexia nervosa in their lifetime, and an additional 1.1 to 4.2 percent of females suffer from bulimia nervosa in their lifetime. When figured into the US Census Bureau’s most recent population statistics, this means that as many as 5.7 million females will suffer from anorexia and as many as 6.5 million females will suffer from bulimia at some point in their lifetime. Now some people may dismiss anorexia or bulimia nervosa as simply a mental disorder that has no real effect on a person’s life other than how they view themselves and food, but according to the NIMH, the mortality rate among those with anorexia nervosa is approximately 5.6% per decade, which is 12 times higher than the death rate among females ages 15-24.
The new information: The study looked at 134 patients with anorexia nervosa, 180 patients with bulimia nervosa, and 148 healthy individuals, and was looking for two specific mutations in endocannabinoid genes, a mutation in the gene coding for cannabinoid receptor 1, and a mutation in the gene coding for FAAH (fatty acid amide hydrolase), which is the enzyme in our bodies that degrades cannabinoids. It was found that compared to the healthy individuals, anorexic and bulimic patients were significantly more likely to have mutations in cannabinoid receptor 1 gene or mutations in the FAAH gene. Additionally, compared to the healthy individuals, it was much more likely that anorexic patients had mutations in both genes.
What this means: This experiment tells us that there may in fact be a genetic predisposition to anorexia nervosa and bulimia nervosa. Additionally, cannabinoids may be used in the treatment of these two eating disorders as the genetic mutations cause a decreased sensitivity to them.
Monteleone, P., et al. “Association of CNR1 and FAAH endocannabinoid gene polymorphisms with anorexia nervosa and bulimia nervosa: evidence for synergistic effects.” Genes, brain, and behavior. 8.7 (2009): 728-32.
The new information: The study looked at 134 patients with anorexia nervosa, 180 patients with bulimia nervosa, and 148 healthy individuals, and was looking for two specific mutations in endocannabinoid genes, a mutation in the gene coding for cannabinoid receptor 1, and a mutation in the gene coding for FAAH (fatty acid amide hydrolase), which is the enzyme in our bodies that degrades cannabinoids. It was found that compared to the healthy individuals, anorexic and bulimic patients were significantly more likely to have mutations in cannabinoid receptor 1 gene or mutations in the FAAH gene. Additionally, compared to the healthy individuals, it was much more likely that anorexic patients had mutations in both genes.
What this means: This experiment tells us that there may in fact be a genetic predisposition to anorexia nervosa and bulimia nervosa. Additionally, cannabinoids may be used in the treatment of these two eating disorders as the genetic mutations cause a decreased sensitivity to them.
Monteleone, P., et al. “Association of CNR1 and FAAH endocannabinoid gene polymorphisms with anorexia nervosa and bulimia nervosa: evidence for synergistic effects.” Genes, brain, and behavior. 8.7 (2009): 728-32.
Friday, January 29, 2010
November 2009: Cannabinoids inhibit tumor growth and metastasis of breast cancer. (Ohio State University, Columbus, Ohio)
First some background:
Cancer refers to the uncontrolled growth of cells within the human body. This uncontrolled growth leads to what is known as tumors, of which there are two types, benign and malignant. While benign tumors pose no serious threat, malignant tumors are capable of invading and eventually destroying nearby tissue as well as what is known as metastasis, which is the spread of cancer cells to other parts of the body. In breast cancer cells, the receptors for cannabinoids tend to be overexpressed compared to normal breast tissue
The new information:
When the cannabinoid receptors on breast cancer cells are activated, cell growth, division, and migration were inhibited. In this specific experiment, mouse breast cancer models showed a 40-50% reduction in tumor growth and a 65-80% reduction in lung metastasis (spread of cancer to the lungs). Also, in PyMT mouse models, which are analogous to human invasive ductal carcinoma, cannabinoid receptor activation led to a reduction in tumor size and not just growth. This reduction was shown to be the result of programmed cell death, or apoptosis, which the cannabinoids induced.
What this means:
This research shows that cannabinoids could potentially be used to protect against the growth and spread of breast cancer.
Qamri, Z, et al. “Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer.” Molecular cancer therapeutics. 8.11 (2009): 3117-29.
Cancer refers to the uncontrolled growth of cells within the human body. This uncontrolled growth leads to what is known as tumors, of which there are two types, benign and malignant. While benign tumors pose no serious threat, malignant tumors are capable of invading and eventually destroying nearby tissue as well as what is known as metastasis, which is the spread of cancer cells to other parts of the body. In breast cancer cells, the receptors for cannabinoids tend to be overexpressed compared to normal breast tissue
The new information:
When the cannabinoid receptors on breast cancer cells are activated, cell growth, division, and migration were inhibited. In this specific experiment, mouse breast cancer models showed a 40-50% reduction in tumor growth and a 65-80% reduction in lung metastasis (spread of cancer to the lungs). Also, in PyMT mouse models, which are analogous to human invasive ductal carcinoma, cannabinoid receptor activation led to a reduction in tumor size and not just growth. This reduction was shown to be the result of programmed cell death, or apoptosis, which the cannabinoids induced.
What this means:
This research shows that cannabinoids could potentially be used to protect against the growth and spread of breast cancer.
Qamri, Z, et al. “Synthetic cannabinoid receptor agonists inhibit tumor growth and metastasis of breast cancer.” Molecular cancer therapeutics. 8.11 (2009): 3117-29.
December 2009: Cannabinoid receptor-1 activation in the spinal cord leads to an inhibition of nerve cell damage and death. (Cleveland Clinic, Clevelan
First some background:
in conditions known as neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Lou Gehrig’s disease (ALS, amylotrophic lateral sclerosis), one of the major problems is what is
referred to as excitotoxicity. Excitotoxicity is when cells in our brain are overexcited by natural signals, leading to cell damage and eventually death. A well-known mechanism for the development of the aforementioned neurodegenerative diseases is the excitotoxicity of glutamate receptors on brain cells (glutamate is one of our body’s natural signals). These glutamate receptors have two main subtypes, NMDA and AMPA, with their names referring to an artificial substance that can perform the same role as the natural signal, glutamate.
The new information:
Within the spinal cord, nerve cells that send signals to the brain can be prevented from damage and death due to excitotoxicity. Within these nerve cells, excitotoxicity is mediated through NMDA glutamate receptors. This new research involved exposing the spinal cord nerve cells to NMDA (N-methyl-D-aspartic acid) in the presence of cannabinoids. It was found that the toxic effects of NMDA (and therefore the natural signal, glutamate) were blocked when the cannabinoids were present.
What this means:
This research simply provides more evidence for what is already generally known, that cannabinoids can slow down and even potentially stop the progression of neurodegenerative diseases. Bhat, M, WD Bowen, J Cheng, and Q Liu.
“Signaling pathways from cannabinoid receptor-1 activation to inhibition of N-methyl-D-aspartic acid mediated calcium influx and neurotoxicity in dorsal root ganglion neurons.” The Journal of pharmacology and experimental therapeutics. 331.3 (2009): 1062-70.
in conditions known as neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Lou Gehrig’s disease (ALS, amylotrophic lateral sclerosis), one of the major problems is what is
referred to as excitotoxicity. Excitotoxicity is when cells in our brain are overexcited by natural signals, leading to cell damage and eventually death. A well-known mechanism for the development of the aforementioned neurodegenerative diseases is the excitotoxicity of glutamate receptors on brain cells (glutamate is one of our body’s natural signals). These glutamate receptors have two main subtypes, NMDA and AMPA, with their names referring to an artificial substance that can perform the same role as the natural signal, glutamate.
The new information:
Within the spinal cord, nerve cells that send signals to the brain can be prevented from damage and death due to excitotoxicity. Within these nerve cells, excitotoxicity is mediated through NMDA glutamate receptors. This new research involved exposing the spinal cord nerve cells to NMDA (N-methyl-D-aspartic acid) in the presence of cannabinoids. It was found that the toxic effects of NMDA (and therefore the natural signal, glutamate) were blocked when the cannabinoids were present.
What this means:
This research simply provides more evidence for what is already generally known, that cannabinoids can slow down and even potentially stop the progression of neurodegenerative diseases. Bhat, M, WD Bowen, J Cheng, and Q Liu.
“Signaling pathways from cannabinoid receptor-1 activation to inhibition of N-methyl-D-aspartic acid mediated calcium influx and neurotoxicity in dorsal root ganglion neurons.” The Journal of pharmacology and experimental therapeutics. 331.3 (2009): 1062-70.
January 2010: Cannabinoids prevent and may aid in healing cell damage in multiple sclerosis. (Instituto Cajal, Madrid, Spain)
Cannabinoids prevent and may aid in healing cell damage in multiple sclerosis. (Instituto Cajal, Madrid, Spain)
First some background:
Multiple sclerosis is caused by cell damage in the brain and spinal cord, leading to a decreased ability of the body to communicate effectively with itself. One of the possible causes of multiple sclerosis is excitotoxicity mediated by AMPA glutamate receptors (see December 2009), but the root cause is the gradual damage and loss of the fatty myelin sheath surrounding specific areas of nerve cells. The myelin sheath is basically a layer of insulation which allows fast and precise electrical communication between cells within the brain and spinal cord.
The new information:
In mouse models of TMEV-IDD (Theiler’s murine encephalomyelitis virus-induced demyelinating disease) multiple sclerosis, increased cannabinoid levels led to protection against excitotoxicity, and thus protection against cell damage. In the experiment performed, an uptake blocker was introduced in order to increase the levels of cannabinoids at the junction between two cells. The increased level of cannabinoids led not only to the inhibition of excitotoxicity, but also activation of a factor within the cells which causes genetic changes. This factor is known as PPAR-gamma (peroxisome proliferator-activated receptor gamma), and it causes our DNA to tell the cell to produce more fat (recall that multiple sclerosis is caused by the destruction of the fatty insulation surrounding part of the nerve cell).
What this means:
Not only did this research provide more evidence that cannabinoids protect against neurodegenerative diseases, but that they may also aid in healing the cause of multiple sclerosis at a molecular level.
Loria, F, et al. “An endocannabinoid tone limits excitotoxicity in vitro and in a model of multiple sclerosis.” Neurobiology of disease. 37.1 (2010): 166-76.
First some background:
Multiple sclerosis is caused by cell damage in the brain and spinal cord, leading to a decreased ability of the body to communicate effectively with itself. One of the possible causes of multiple sclerosis is excitotoxicity mediated by AMPA glutamate receptors (see December 2009), but the root cause is the gradual damage and loss of the fatty myelin sheath surrounding specific areas of nerve cells. The myelin sheath is basically a layer of insulation which allows fast and precise electrical communication between cells within the brain and spinal cord.
The new information:
In mouse models of TMEV-IDD (Theiler’s murine encephalomyelitis virus-induced demyelinating disease) multiple sclerosis, increased cannabinoid levels led to protection against excitotoxicity, and thus protection against cell damage. In the experiment performed, an uptake blocker was introduced in order to increase the levels of cannabinoids at the junction between two cells. The increased level of cannabinoids led not only to the inhibition of excitotoxicity, but also activation of a factor within the cells which causes genetic changes. This factor is known as PPAR-gamma (peroxisome proliferator-activated receptor gamma), and it causes our DNA to tell the cell to produce more fat (recall that multiple sclerosis is caused by the destruction of the fatty insulation surrounding part of the nerve cell).
What this means:
Not only did this research provide more evidence that cannabinoids protect against neurodegenerative diseases, but that they may also aid in healing the cause of multiple sclerosis at a molecular level.
Loria, F, et al. “An endocannabinoid tone limits excitotoxicity in vitro and in a model of multiple sclerosis.” Neurobiology of disease. 37.1 (2010): 166-76.
Sunday, January 24, 2010
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