Endocannabinoid Receptors in the CNS: Potential Drug Targets for the Prevention and Treatment of Neurologic and Psychiatric Disorders

Abstract

The endocannabinoid system participates in the regulation of CNS homeostasis and functions, including neurotransmission, cell signaling, inflammation and oxidative stress, as well as neuronal and glial cell proliferation, differentiation, migration and survival. Endocannabinoids are produced by multiple cell types within the CNS and their main receptors, CB1 and CB2, are expressed in both neurons and glia. Signaling through these receptors is implicated in the modulation of neuronal and glial alterations in neuroinflammatory, neurodegenerative and psychiatric conditions, including Alzheimer's, Parkinson's and Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, stroke, epilepsy, anxiety and depression. The therapeutic potential of endocannabinoid receptors in neurological disease has been hindered by unwelcome side effects of current drugs used to target them; however, due to their extensive expression within the CNS and their involvement in physiological and pathological process in nervous tissue, they are attractive targets for drug development. The present review highlights the potential applications of the endocannabinoid system for the prevention and treatment of neurologic and psychiatric disorders.

Keywords: Endocannabinoids; drug targets; endocannabinoid receptors; neurodegeneration; neuroinflammation; psychiatric disease.

Fig. (1)

Effects of eCB receptor activation on the blood-brain barrier and glial inflammatory response. Activation of CB1 and CB2 receptors by their endogenous ligands or exogenous agonists at the BBB decreases endothelial permeability and leukocyte infiltration into the CNS by reducing the expression of intercellular adhesion molecules both at the endothelial layer and on leukocytes, while also increasing the expression of tight junction proteins. On glial cells, signaling through CB2 decreases production of pro-inflammatory cytokines and nitric oxide by microglia, while increasing the production of inhibitory molecules. In astrocytes, a similar effect is achieved by activation of CB1. (Figure created by the authors). (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (2)

Beneficial effects of eCB receptor activation in experimental models of neurological disease. A. In neurological pathologies such as Alzheimer’s and Parkinson’s disease, pathologic accumulation of misfolded or aggregated proteins (Amyloid β, α-synuclein, hyperphosphorylated Tau) promotes neuronal damage and development of inflammatory responses. In multiple sclerosis, aberrant recognition of self-antigens promotes demyelination and neuronal damage, causing CNS inflammation. Inflammatory responses in the CNS lead to activation of glial cells that produce proinflammatory mediators, promoting leukocyte recruitment and in some cases inducing differentiation of Th1 and Th17 cells that cause neuronal cell death. B. Activation of CB1 and CB2 receptors in leukocytes, glia and neurons prevent neuronal damage by decreasing classical microglial activation, improving the removal of myelin, decreasing the differentiation of Th1 and Th17 cells and promoting the differentiation of oligodendrocyte precursor cells (OPCs) to mature oligodendrocytes, improving remyelination and decreasing excitotoxic neuronal death. (Figure created by the authors). (A higher resolution / colour version of this figure is available in the electronic copy of the article).