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.

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.

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.