The role of the endocannabinoid system in the pathogenesis of degenerative diseases

The aim of this article is to present the possible role of the endocannabinoid system in the pathogenesis of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. The endocannabinoid system includes the cannabinoid receptors CB1 and CB2, as well as endogenous cannabinoids and enzymes regulating the synthesis and biodegradation of endocannabinoids. Endocannabinoids are arachidonic acid derivatives conjugated with ethanolamine or glycerol. The most important of them are arachidonylethanolamide, also known by the name anandamide, and 2-arachidonylglycerol. The most important cannabinoids are tetrahydrocannabinol and cannabidiol. The endocannabinoid system plays an important role in the mechanisms of learning and memory, emotion, behavior, pain perception, and neuroprotection. The activity of the CB1 receptor plays an important role in memory processes. CB1 receptor agonists disrupt memory processes, while CB1 receptor antagonists reverse these deficits or act as memory enhancers. In neurodegenerative diseases, microglia is activated. When activated, microglia significantly increases endocannabinoid synthesis and expression of CB2 receptors. Their expression has a protective effect by increasing the production of neuroprotective factors and reducing the production of pro-inflammatory factors. Endocannabinoids reduce the activity of the stress axis – hypothalamus-pituitary-adrenal – and regulate the stress response by influencing the noradrenergic pathways. The endocannabinoid system modulates the phenomena associated with neurodegeneration. This is due to the effects dependent on CB1 receptors’ activation, causing normalization of glutamatergic transmission and increasing autophagy, and activation of CB2 receptors, resulting in weakening of inflammatory features, and reduction of oxidative stress – independent of cannabinoid receptors.