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.

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.

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).