Abstract

Microglial activation is an invariant feature of Alzheimer′s disease (AD). Interestingly cannabinoids are neuroprotective by preventing β-amyloid (Aβ) induced microglial activation both in vitro and in vivo. On the other hand, the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms. In the present study we compared the effects of CBD with those of other cannabinoids on microglial cell functions in vitro and on learning behaviour and cytokine expression following Aβ intraventricular administration to mice. CBD, WIN 55,212-2 (WIN), a mixed CB₁/CB₂ agonist, and JWH-133 (JWH), a CB₂ selective agonist, concentration-dependently decreased ATP-induced (400 [micro]M) increase in intracellular calcium ([Ca²⁺]_i) in cultured N13 microglial cells and in rat primary microglia. In contrast HU-308 (HU), another CB₂ agonist, was without effect. Cannabinoid and adenosine A_2A receptors may be involved in the CBD action. CBD and WIN-promoted primary microglia migration was blocked by CB₁ and/or CB₂ antagonists. JWH and HU-induced migration was blocked by a CB₂ antagonist only. All the cannabinoids decreased LPS-induced nitrite generation, which was insensitive to cannabinoid antagonism. Finally both CBD and WIN, following subchronic administration for three weeks, were able to prevent learning of a spatial navigation task and cytokine gene expression in β-amyloid injected mice. In summary, CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD. Given that CBD lacks psychoactivity it may represent a novel therapeutic approach for this neurologic disease.