Cannabinoid receptors and endocannabinoids: role in neuroinflammatory and neurodegenerative disorders

The cannabinoid receptors type 1 (CB1) and type 2 (CB2) play important roles in degenerative and inflammatory disorders of the central nervous system. CB1 receptors are mostly expressed in neurons, whereas CB2 receptors are mostly found in glial cells and microglia. CB2 receptors in particular become activated and are over-expressed in disorders such as Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, Huntington’s chorea and Parkinson’s disease. Both CB1 and CB2 receptors are the target for D9-tetrahydrocannabinol, the major psychoactive agent in marijuana, as well as endogenous cannabinoids (endocannabinoids) of which 2-arachidonoylglycerol and anandamide are the two best studied. The neuromodulatory actions of endocannabinoids at CB1 receptors allow them to counteract the neurochemical imbalances arising in these disorders, whereas their action at CB2 receptors regulates the activity and function of glia and microglia. The level of expression of both receptor subtypes and enzymes controlling endocannabinoid levels undergo time- and brain region-specific alterations during neurodegenerative and neuroinflammatory disorders. In this article, the authors discuss the plasticity of the endocannabinoid system in relation to the aforementioned disorders, and evaluate the suitability of either direct or indirect activators or blockers of CB1 and CB2 receptors for the treatment of symptoms or amelioration of the progression of these diseases.