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AMPK activators such as metformin (MET), quercetin (QUE), resveratrol (RES), cinnamaldehyde (CIN), and berberine (BER) exhibit anti\u2010inflammatory and neuroprotective properties. However, their role in modulating the nucleotide\u2010binding oligomerization domain, leucine\u2010rich repeat, and pyrin domain\u2010containing protein 3 (NLRP3) inflammasome in TBI\u2010induced neuroinflammation remains unclear. This study investigated the neuroprotective effects of AMPK activators in the weight\u2010drop model of TBI, focusing on suppression of the NLRP3 inflammasome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Rats received an intraperitoneal administration of AMPK activators\u2014MET (100\u2009mg\/kg), QUE (15\u2009mg\/kg), RES (25\u2009mg\/kg), CIN (25\u2009mg\/kg), or BER (50\u2009mg\/kg)\u2014from days \u22123 to 17. TBI was induced on day 1 using the weight\u2010drop method (240\u2009g from 1.5\u2009m). Cognitive performance was evaluated using the novel object recognition test and Morris water maze. Neuroinflammatory markers, including nuclear factor kappa B (NF\u2010\u03baB), NLRP3, pro\u2010caspase\u20101, interleukin\u20101\u03b2 (IL\u20101\u03b2), tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1), and microglial polarization markers (CD86 and CD206), were assessed using Western blotting and enzyme\u2010linked immunosorbent assay (ELISA). Oxidative stress and histopathological changes were also examined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>TBI resulted in cognitive impairment, oxidative stress, and neuronal damage; reduced p\u2010AMPK\/AMPK ratio; decreased CD206 levels; and elevated the levels of NF\u2010\u03baB, CD86, TNF\u2010\u03b1, and NLRP3 inflammasome components (NLRP3, pro\u2010caspase\u20101, and IL\u20101\u03b2). Pretreatment with AMPK activators significantly improved cognitive deficits, attenuated oxidative stress and neuroinflammation, restored p\u2010AMPK\/AMPK ratio, promoted anti\u2010inflammatory effects, and suppressed NLRP3 inflammasome activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>AMPK activators exhibited neuroprotection in TBI by improving cognition and regulating oxidative stress, microglial activation, and NLRP3\u2010mediated neuroinflammation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ame2.70288","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:41:44Z","timestamp":1789713704000},"page":"1849-1868","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adenosine monophosphate\u2013activated protein kinase activation is associated with suppression of\n                    <scp>NLRP3<\/scp>\n                    inflammasome\u2013mediated neuroinflammation in a weight\u2010drop model of traumatic brain injury in Sprague\u2013Dawley rats"],"prefix":"10.1002","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7051-809X","authenticated-orcid":false,"given":"Triveni","family":"Kodi","sequence":"first","affiliation":[{"name":"Department of Pharmacology Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education  Manipal India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1198-5875","authenticated-orcid":false,"given":"Paka Sravan","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education  Manipal 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