Regulatory role of cannabinoid receptor 1 in stress-induced excitotoxicity and neuroinflammation

Silvia Zoppi (1) , Beatriz G Pérez-Nievas (1) , Jose Lm Madrigal (1) , Jorge Manzanares (1) , Juan C Leza (1) , Borja Garcia Bueno (1)

1 Pharmacology

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. In order to elucidate the possible regulatory role of 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 immobilisation/acoustic stress (2h/day for 4d), 2) to specifically activate CB1, the selective CB1 agonist ACEA (2.5 mg/kg) was i.p. 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 NMDA glutamate receptor activation. Daily ACEA pre-treatment prevented stress-induced: 1) upregulation of CB1 mRNA and protein, 2) decrease in glutamate uptake and glutamate astroglial transporter EAAT-2 expression, 3) increase in consecutive proinflammatory molecules, such as cytokines (TNF-α and MCP-1), nuclear factor kappa B (NF-κB) and enzymatic sources, such as inducible nitric oxide synthase (NOS-2) and cyclooxygenase-2 (COX-2), 4) increase in lipid peroxidation; while 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 gamma (15d-PGJ2/PPARγ). Conversely, KO animal experiments indicated that a lack of CB1 produces 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 patho-physiology.

Mots clés: Mood; Anxiety; Stress Disorders; Neurodegeneration; Neuroprotection; Cannabinoids; Neuroendocrinology; CB1; stress; neuroinflammation; excitotoxicity; ACEA

Silvia Zoppi, Beatriz G Pérez-Nievas, Jose Lm Madrigal, Jorge Manzanares, Juan C Leza, et al.. Regulatory role of cannabinoid receptor 1 in stress-induced excitotoxicity and neuroinflammation. Neuropsychopharmacology, 2010, ⟨10.1038/npp.2010.214⟩. ⟨hal-00598946⟩