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Following the initial mechanical injury caused by hematoma expansion, a secondary injury occurs, characterized by the production of reactive oxygen species (ROS) generated by NOX\u20102 and neuroinflammation, which is exacerbated by the upregulation of the NLRP3 inflammasome. These conditions collectively aggravate brain damage. The endocannabinoid system (ECS), through the activation of the cannabinoid receptors, has demonstrated neuroprotective properties in various models of brain injury. However, the role of the ECS during ICH remains poorly understood, particularly regarding the action of the CB1 receptor in the activation of NOX\u20102 and the inflammasome. The present study investigates the neuroprotective effects of the cannabinoid receptor agonist WIN55,212\u20102 in an ICH animal model, specifically examining the roles of NLRP3 and NOX\u20102.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Male C57BL\/6 mice were subjected to ICH through an intracerebral injection of collagenase, followed by intraperitoneal administration of WIN55,212\u20102 and\/or MCC950, a selective NLRP3 inhibitor. Various outcome measures were employed, including assessments of motor activity, hematoma volume, brain water content, and blood\u2013brain barrier (BBB) permeability, which was evaluated using Evans blue assay. Additionally, the activity of NOX and the protein levels of crucial markers such as CB1, gp91phox, NLRP3, AQP4, and caspase\u20101 were measured via western blot analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Result<\/jats:title>\n                    <jats:p>The findings demonstrate that ICH induced a significant brain lesion characterized by hematoma formation, edema, BBB disruption, and subsequent motor impairments in the affected mice. Notably, these detrimental effects were markedly reduced in animals treated with WIN55,212\u20102. The study also revealed an activation of both NOX\u20102 and NLRP3 in response to ICH, which was reduced by cannabinoid receptor activation. Furthermore, the pharmacological inhibition of NLRP3 using MCC950 also led to a reduction in hematoma size, edema, and motor impairment secondary to ICH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results support a neuroprotective role of the cannabinoid receptor activation during ICH and suggest the involvement of NOX\u20102 and NLRP3.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.70385","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T03:00:10Z","timestamp":1745982010000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cannabinoid Receptors Reduced Early Brain Damage by Regulating NOX\u20102 and the NLRP3 Inflammasome in an Animal Model of Intracerebral Hemorrhage"],"prefix":"10.1111","volume":"31","author":[{"given":"Ari Misael","family":"Mart\u00ednez\u2010Torres","sequence":"first","affiliation":[{"name":"Divisi\u00f3n de Neurociencias, Instituto de Fisiolog\u00eda Celular Universidad Nacional Aut\u00f3noma de M\u00e9xico  Ciudad de M\u00e9xico M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crisalde","family":"Ram\u00edrez\u2010Celis","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Neurociencias, Instituto de Fisiolog\u00eda Celular Universidad Nacional Aut\u00f3noma de M\u00e9xico  Ciudad de M\u00e9xico M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4880-8597","authenticated-orcid":false,"given":"Julio","family":"Mor\u00e1n","sequence":"additional","affiliation":[{"name":"Divisi\u00f3n de Neurociencias, Instituto de Fisiolog\u00eda Celular Universidad Nacional Aut\u00f3noma de M\u00e9xico  Ciudad de M\u00e9xico 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