Alzheimer's: New Method To Protect Brain Cells From Neurodegenerative Diseases Found
Researchers at LSU Health Sciences Center New Orleans, provides evidence that one of the only naturally occurring fatty acids in the brain that has the ability to interact with the receptors originally identified as the targets of THC (the psychoactive component of marijuana) can help to protect brain cells from neurodegenerative diseases like Alzheimer's and Parkinson's. Published in the Journal of Biological Chemistry, the research focuses on the cellular and molecular mechanisms of inflammation, specifically the role these relatively recently discovered endogenous cannabinoids can play in the control of COX-2 and other cyclooxygenases. COX-2 is a key player in neuroinflammation and has been implicated in the development of neurodegenerative diseases and worsening of damage from such insults as traumatic brain injury and stroke. The researchers show that endocannabinoid 2-arachidonoylglycerol (2-AG) functions as an endogenous COX-2 inhibitor, turning off the production of COX-2 which normally goes into overdrive in response to pro-inflammatory and certain types of toxic stimuli, resulting in the injury or death of brain cells. The researchers also revealed the specific signaling pathways that regulate the 2-AG suppression of COX-2. The findings provide a basis for opening up new therapeutic approaches to protect neurons from inflammation and toxicity-induced neurodegeneration, they said.
Anti-Inflammatory Actions Of The Endocannabinoid System In A Rodent Model Of Chronic Neuroinflammation
Topic: Therapeutic strategies, others Presentation
Time:Wednesday, 1:30 p.m. - 3:45 p.m.
Yannick Marchalant1, Susanna Rosi2, Gary L. Wenk1, 1Ohio State University, Columbus, OH, USA; 2University of Arizona, Tucson, AZ, USA. Contact e-mail:
Keyword: animal model, anti-inflammatory, behavioral symptoms
Background: Neuroinflammation is associated with a variety of neurological diseases, including Alzheimers disease (AD), and is reliably detected by the presence of activated microglia. Recent evidence suggests that the activation of the endocannabinoid system may control inflammatory processes in the brain. Cannabinoids receptors are found associated with microglia in plaques; the activation of these receptors can reverse the beta-amyloid-induced activation of microglia, making them of potential therapeutic use in AD. Objective(s):We investigated the effect of a cannabinoid receptor agonist, WIN-55212-2, on microglia activation induced by a chronic intracerebroventricular lipopolysaccharide (LPS) infusion and its possible mechanisms of action. Methods:Daily injections of WIN-55212-2 (0.5 or 1.0 mg/kg, i.p.) were given to three months old male rats implanted into the 4th ventricle with a chronic indwelling cannula connected to an osmotic minipump containing LPS (250 ng/hr) or vehicle. During the third week of treatment, the rats were behaviorally tested using the Morris water pool task. Results: Animals treated with WIN demonstrated a significant anti-inflammatory effect represented by a reduction in microglia activation. LPS-infused rats treated with WIN-55212-2 did not demonstrate impaired performance in the Morris water pool task as compared to the LPS-infused rats without WIN-55212-2. We are currently investigating the endocannabinoid receptor subtype that is responsible for this anti-inflammatory action and whether specific regions of the brain are more vulnerable to the consequences of the inflammation. Conclusions: These results highlight the potential benefits of pharmacological manipulation of endocannabinoid receptor within the brain and may guide the design of more effective therapies for AD
Commercial Relationship:Y. Marchalant, None;S. Rosi, None;G.L. Wenk, None.
Alzheimer's disease: THC inhibits the enzyme acetylcholinesterase
Researchers at The Scripps Research Institute have found that the active ingredient in marijuana, tetrahydrocannabinol or THC, inhibits the formation of amyloid plaque, the primary pathological marker for Alzheimer's disease.
The study is published in the journal Molecular Pharmaceutics, a publication of the American Chemical Society.
According to the Scripps Research study, which used both computer modeling and biochemical assays, THC inhibits the enzyme acetylcholinesterase ( AchE ), which acts as a "molecular chaperone" to accelerate the formation of amyloid plaque in the brains of Alzheimer patients.
Although experts disagree on whether the presence of beta-amyloid plaques in those areas critical to memory and cognition is a symptom or cause, it remains a significant hallmark of the disease. With its strong inhibitory abilities, the study said, THC " may provide an improved therapeutic for Alzheimer's disease " that would treat " both the symptoms and progression" of the disease.
" While we are certainly not advocating the use of illegal drugs, these findings offer convincing evidence that THC possesses remarkable inhibitory qualities, especially when compared to AChE inhibitors currently available to patients," said Kim Janda, at Scripps Research.
" In a test against Propidium, one of the most effective inhibitors reported to date, THC blocked AChE-induced aggregation completely, while the Propidium did not. Although our study is far from final, it does show that there is a previously unrecognized molecular mechanism through which THC may directly affect the progression of Alzheimer's disease."
As the new study points out, any new treatment that could halt or even slow the progression of Alzheimer's disease would have a major impact on the quality of life for patients, as well as reducing the staggering health care costs associated with the disease.
Alzheimer's disease is the leading cause of dementia among the elderly, and the numbers are growing. The Alzheimer's Association estimates 4.5 million Americans have the disease, a figure that could reach as high as 16 million by 2050. A survey by the National Center for Health Statistics noted that half of all nursing home residents have Alzheimer's disease or a related disorder. The costs of caring for Alzheimer's patients are at least $100 billion annually, according to the National Institute on Aging.
Over the last two decades, the causes of Alzheimer's disease have been clarified through extensive biochemical and neurobiological studies, leading to an assortment of possible therapeutic strategies including interference with beta amyloid metabolism, the focus of the Scripps Research study.
The cholinergic system - the nerve cell system in the brain that uses acetylcholine ( Ach ) as a neurotransmitter - is the most dramatic of the neurotransmitter systems affected by Alzheimer's disease. Levels of acetylcholine, which was first identified in 1914, are abnormally low in the brains of Alzheimer's patients. Currently, there are four FDA-approved drugs that treat the symptoms of Alzheimer's disease by inhibiting the active site of acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine.
" When we investigated the power of THC to inhibit the aggregation of beta-amyloid, " Janda said, " we found that THC was a very effective inhibitor of acetylcholinesterase. In addition to Propidium, we also found that THC was considerably more effective than two of the approved drugs for Alzheimer's disease treatment, Donepezil ( Aricept ) and Tacrine ( Cognex ), which reduced amyloid aggregation by only 22 percent and 7 percent, respectively, at twice the concentration used in our studies. Our results are conclusive enough to warrant further investigation."
Source: The Scripps Research Institute, 2006