<scp>CB1</scp> Receptor Activation Provides Neuroprotection in an Animal Model of Glutamate‐Induced Excitotoxicity Through a Reduction of <scp>NOX</scp>‐2 Activity and Oxidative Stress

Abstract

ABSTRACT Background Excitotoxicity is a process in which NADPH oxidase‐2 (NOX‐2) plays a pivotal role in the generation of reactive oxygen species (ROS). Oxidative stress influences the expression of Aquaporin 4 (AQP4), a water channel implicated in blood–brain barrier (BBB) permeability and edema formation. The endocannabinoid system is widely distributed in the brain, particularly through the cannabinoid receptor type 1 (CB1) and type 2 (CB2), which have been shown to have a neuroprotective function in brain injury. Given the significant involvement of NOX‐2 in ROS production during excitotoxicity, our research aims to assess the participation of NOX‐2 in the neuroprotective effect of the cannabinoid receptor agonist WIN55,212‐2 against glutamate‐induced excitotoxicity damage in the striatum using in vivo model. Methods Wild‐type mice (C57BL/6) and NOX‐2 KO (gp91 Cybbtm1Din/J ) were stereotactically injected in the striatum with monosodium glutamate or vehicle. Subsequently, a group of mice was administered an intraperitoneal dose of WIN55,212‐2, AM251, or AM251/WIN55,212‐2 following the intracerebral injection. Motor activity was assessed, and the lesion was examined through histological sections stained with cresyl violet. Additionally, brain water content and Evans blue assay were conducted. The activity of NOX was quantified, and the protein expression of CB1, gp91 phox , AQP4, Iba‐1, TNF‐α, and NF‐κB was analyzed using Western blot. Furthermore, ROS formation was measured through the DHE assay. Results The activation of the endocannabinoid receptors demonstrated a neuroprotective response during excitotoxicity, meditated by NOX‐2. The reduction in ROS production led to a decrease in neuroinflammation, and AQP4 expression, resulting in reduced edema formation, and BBB permeability. Conclusions During excitotoxic damage, WIN55,212‐2 inhibits NOX‐2‐induced ROS production, reducing brain injury.

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