Regulatory Role of Cannabinoid Receptor 1 in Stress-Induced Excitotoxicity and Neuroinflammation

Abstract

Exposure to stress elicits excitoxicity and neuroinflammation in the brain, contributing to cell death and damage in stress-related neurological and neuropsychiatric diseases. The endocannabinoid system is present in stress-responsive neural circuits and has been proposed as an endogenous neuroprotective system activated in some neuropathological scenarios to restore homeostasis. To elucidate the possible regulatory role of cannabinoid receptor 1 (CB1) in stress-induced excitotoxicity and neuroinflammation, both genetic and pharmacological approaches were used alternatively: (1) wild-type (WT) and CB1 knockout mice (CB1-KO) were exposed to immobilization/acoustic stress (2 h/day for 4 days) and (2) to specifically activate CB1, the selective CB1 agonist Arachidonyl-2'-chloroethylamide (ACEA) (2.5 mg/kg) was intraperitoneally administered daily to some groups of animals. Stress exposure increased CB1 mRNA and protein expression in the prefrontal cortex of WT mice in a mechanism related to N-methyl-D-aspartate glutamate receptor activation. Daily ACEA pretreatment prevented stress-induced: (1) upregulation of CB1 mRNA and protein, (2) decrease in glutamate uptake and glutamate astroglial transporter excitatory amino acid transporter 2 expression, (3) increase in consecutive proinflammatory molecules, such as cytokines (tumor necrosis factor-α and MCP-1), nuclear factor kappa B, and enzymatic sources, such as inducible nitric oxide synthase (NOS-2) and cyclooxygenase-2 (COX-2), (4) increase in lipid peroxidation; although having no effect on plasma corticosterone. Interestingly, a possible related mechanism could be the positive ACEA modulation of the antiinflammatory pathway deoxyprostaglandin/peroxisome proliferator-activated receptor γ (15d-PGJ(2)/PPARγ). Conversely, KO animal experiments indicated that a lack of CB1 produces hypothalamic/pituitary/adrenal (HPA) axis dysregulation and exacerbates stress-induced excitotoxic/neuroinflammatory responses. These multifaceted neuroprotective effects suggest that CB1 activation could be a new therapeutic strategy against neurological/neuropsychiatric pathologies with HPA axis dysregulation and an excitotoxic/neuroinflammatory component in their pathophysiology.