How can the medicinal properties of marijuana be improved to treat neurodegenerative diseases?
The brain, being isolated from the rest of the body by the blood brain barrier, has its own specialized immune system consisting of the interplay between glial cells and small numbers of patrolling immune cells. This "brain specific immune system" is similar to the peripheral immune system in its ability to both destroy foreign agents and repair injured tissue, though it does so with much less efficacy. Indeed, while the brain's immune system can probably cope with minor insults and infections, its unable to mount effective responses against more devastating neuropathological processes, including:
- Mutated proteins that aggregate, such as huntingtin that induces Huntington's disease,
- Viruses, such as HIV that induce AIDS dementia,
- Invading autoimmune cells, such as T-cells directed against oligodendrocytes, that induce multiples sclerosis
Remarkably, these neuropathological processes are often associated with dysfunctional glial cells, limiting their ability to repair injured neurons and actually rendering them more hostile against healthy neurons. Thus, a promising therapeutic approach for the aforementioned neurodegenerative diseases is to develop pharmacological agents that target glial cells to reinstate their reparative function while tempering their hostility.
My laboratory is interested in identifying the molecular machinery controlling changes in glial cell phenotype, with the aim of developing pharmacological tools that will minimize their harmful phenotype and reinstate - or even boost - their reparative function. Our current most promising target is the endocannabinoid signaling system.
Cannabinoids, the bioactive components produced by the marijuana plant Cannabis Sativa, have immunomodulatory properties that are quite distinct from currently available immunomodulatory drugs. These compounds act through specific receptors named CB1 and CB2. CB1 receptors are expressed by neurons and mediate the drug of abuse properties of marijuana, while CB2 receptors are expressed by immune and glial cells and mediate its immunomodulatory properties. This dichotomy has tremendous therapeutic potential since it allows for the development of agents that specifically target CB2 receptors and thus regulate immune functions without inducing the drug of abuse adverse effects mediated through CB1 receptors. Cannabinoid receptors are normally activated by endogenous ligands, the endocannabinoids.
We are currently testing the hypothesis that agents acting through CB2 receptors or blocking the degradation of endocannabinoids can temper the detrimental inflammatory responses occurring in Huntington's disease, AIDS dementia and multiple sclerosis. We chose to study these pathologies because they remain without cure and thus demand regimented scientific efforts to relieve these patients. We are also using genetic and proteomics approaches to identify novel cannabinoid receptors and enzymes degrading endocannabinoids, with the hope that such proteins constitute promising targets for therapy. Our goal is to identify cannabinoid-based targets and agents devoid of drug of abuse properties that provide treatment of diverse neuropathologies.