Sulfur dioxide(SO_2) pollution in the atmospheric environment causes brain inflammatory insult and inflammatory-related microvasculature dysfunction.However,there are currently no effective medications targeting the harmful outcomes from chemical inhalation.Endocannabinoids(eCBs) are involved in neuronal protection against inflammation-induced neuronal injury.The 2-arachidonoylglycerol(2-AG),the most abundant eCBs and a full agonist for cannabinoid receptors(CB1 and CB2),is also capable of suppressing proinflammatory stimuli and improving microvasculature dysfunction.Here,we indicated that endogenous 2-AG protected against neuroinflammation in response to SO_2 inhalation by inhibiting the activation of microglia and astrocytes and attenuating the overexpression of inflammatory cytokines,including tumor necrosis factor alpha(TNF-a),interleukin(IL)-1β,and inducible nitric oxide synthase(iNOS).In addition,endogenous 2-AG prevented cerebral vasculature dysfunction following SO_2 inhalation by inhibiting endothelin 1(ET-1),vascular cell adhesion molecule-1(VCAM-1) and intercellular adhesion molecule 1(ICAM-1) expression,elevating endothelial nitric oxide synthase(eNOS) level,and restoring the imbalance between thromboxane A2(TXA2) and prostaglandin 12(PGI2).In addition,the action of endogenous 2-AG on the suppression of inflammatory insult and inflammatory-related microvasculature dysfunction appeared to be mainly mediated by CB1 and CB2 receptors.Our results provided a mechanistic basis for the development of new therapeutic approaches for protecting brain injuries from SO_2 inhalation. Sulfur dioxide (SO 2) pollution in the atmospheric environment causes brain inflammatory insult and inflammatory-related microvasculature dysfunction. Despite, there are currently no effective medications targeting the harmful outcomes from chemical inhalation. Endocannabinoids (eCBs) are involved in neuronal protection against inflammation-induced neuronal injury. The 2-arachidonoylglycerol (2-AG), the most abundant eCBs and a full agonist for cannabinoid receptors (CB1 and CB2), is also capable of suppressing proinflammatory stimuli and improving microvasculature dysfunction. Here, we indicated that endogenous 2- AG protected against neuroinflammation in response to SO 2 inhalation by inhibiting the activation of microglia and astrocytes and attenuating the overexpression of inflammatory cytokines, including tumor necrosis factor alpha (TNF-a), interleukin (IL) -1β, and inducible nitric oxide synthase (iNOS ) Addition, endogenous 2-AG prevented cerebral vasculature dysfunction following SO_2 inhalation n by inhibiting endothelin 1 (ET-1), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) expression, elevating endothelial nitric oxide synthase (eNOS) level, and restoring the imbalance between thromboxane A2 (TXA2) and prostaglandin 12 (PGI2). In addition, the action of endogenous 2-AG on the suppression of inflammatory insult and inflammatory-related microvasculature dysfunction appeared to be primarily mediated by CB1 and CB2 receptors. Our results provided a mechanistic basis for the development of new therapeutic approaches for protecting brain injuries from SO_2 inhalation.