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Regulatory role of the cannabinoid CB 2 receptor in stress‐induced neuroinflammation in mice

2014; Wiley; Volume: 171; Issue: 11 Linguagem: Inglês

10.1111/bph.12607

1476-5381

Silvia Zoppi, José L. M. Madrigal, Javier R. Caso, María S. García‐Gutiérrez, Jorge Manzanares, Juan C. Leza, Borja García‐Bueno,

Biochemical effects in animals

Background and Purpose Stress exposure produces excitotoxicity and neuroinflammation, contributing to the cellular damage observed in stress‐related neuropathologies. The endocannabinoids provide a homeostatic system, present in stress‐responsive neural circuits. Here, we have assessed the possible regulatory role of cannabinoid CB 2 receptors in stress‐induced excitotoxicity and neuroinflammation. Experimental Approach We used wild type ( WT ), transgenic overexpressing CB 2 receptors ( CB 2x P ) and CB 2 receptor knockout ( CB 2‐ KO ) mice exposed to immobilization and acoustic stress (2 h·day −1 for 4 days). The CB 2 receptor agonist JWH ‐133 was administered daily (2 mg·kg −1 , i.p.) to WT and CB 2‐ KO animals. Glutamate uptake was measured in synaptosomes from frontal cortex; Western blots and RT‐PCR were used to measure proinflammatory cytokines, enzymes and mediators in homogenates of frontal cortex. Key Results Increased plasma corticosterone induced by stress was not modified by manipulating CB 2 receptors. JWH ‐133 treatment or overexpression of CB 2 receptors increased control levels of glutamate uptake, which were reduced by stress back to control levels. JWH ‐133 prevented the stress‐induced increase in proinflammatory cytokines ( TNF ‐α and CCL2), in NF‐κB , and in NOS ‐2 and COX ‐2 and in the consequent cellular oxidative and nitrosative damage (lipid peroxidation). CB 2x P mice exhibited anti‐inflammatory or neuroprotective actions similar to those in JWH ‐133 pretreated animals. Conversely, lack of CB 2 receptors ( CB 2‐ KO mice) exacerbated stress‐induced neuroinflammatory responses and confirmed that effects of JWH ‐133 were mediated through CB 2 receptors. Conclusions and Implications Pharmacological manipulation of CB 2 receptors is a potential therapeutic strategy for the treatment of stress‐related pathologies with a neuroinflammatory component, such as depression.