Cannabinoid Receptor 2 Signaling in Neurodegenerative Disorders: From Pathogenesis to a Promising Therapeutic Target

Abstract

As a consequence of an increasingly aging population, the number of people affected by neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease, is rapidly increasing. Although the etiology of these diseases has not been completely defined, common molecular mechanisms including neuroinflammation, excitotoxicity and mitochondrial dysfunction have been confirmed and can be targeted therapeutically. Moreover, recent studies have shown that endogenous cannabinoid signaling plays a number of modulatory roles throughout the central nervous system (CNS), including the neuroinflammation and neurogenesis. In particular, the up-regulation of type-2 cannabinoid (CB2) receptors has been found in a number of neurodegenerative disorders. Thus, the modulation of CB2 receptor signaling may represent a promising therapeutic target with minimal psychotropic effects that can be used to modulate endocannabinoid-based therapeutic approaches and to reduce neuronal degeneration. For these reasons this review will focus on the CB2 receptor as a promising pharmacological target in a number of neurodegenerative diseases.

Keywords: Alzheimer's disease; Parkinson's disease; astrocytes; microglia; neuroinflammation; neuroprotection.

Figure 1

Schematic representation of anti-inflammatory and neuroprotective actions of CB2 agonists in AD and PD. AD and PD are characterized respectively by the deposition of Aβ and α-synuclein proteins which in turn are directly or indirectly involved in microglial and astrocytic activation. This activation of microglia and astrocytes triggers a neuroinflammatory and immune response which contributes to the progression of AD and PD. The pharmacological activation of microglial and astrocytic CB2 cannabinoid receptors with CB2 agonists is a promising therapeutic approach because it promotes anti-inflammatory and neuroprotective effects such as the suppression of pro-inflammatory cytokine release and an increases in anti-inflammatory molecules.