title: 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.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Zoppi
authors.forename: Beatriz G
authors.initials: BG
authors.lastname: Pérez Nievas
authors.forename: José L M
authors.initials: JL
authors.lastname: Madrigal
authors.forename: Jorge
authors.initials: J
authors.lastname: Manzanares
authors.forename: Juan C
authors.initials: JC
authors.lastname: Leza
authors.forename: Borja
authors.initials: B
authors.lastname: García-Bueno
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D004660:Encephalitis / Q000378:metabolism* / Q000523:psychology; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000502:physiology*; D013315:Stress, Psychological / Q000378:metabolism* / Q000523:psychology
chemical_list: D001095:Arachidonic Acids; D027342:Excitatory Amino Acid Transporter 2; D043884:Receptor, Cannabinoid, CB1; C119325:arachidonyl-2-chloroethylamide