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Notably, the NLRP3 inflammasome is highly expressed in the hippocampus of diabetic individuals. Nerolidol, a naturally occurring compound with anti\u2010inflammatory and antioxidant properties, has been identified as a potential therapeutic option for metabolic disorders. However, the ameliorative capacity of nerolidol on diabetic hippocampal injury and its underlying mechanism remain unclear. Network pharmacology and molecular docking was used to predict the signaling pathways and therapeutic targets of nerolidol for the treatment of diabetes. Then established a diabetic rat model using streptozotocin (STZ) combined with a high\u2010fat diet and nerolidol was administered. Morris water maze to assess spatial learning memory capacity. Hematoxylin and eosin and Nissl staining was used to detect neuronal damage in the diabetic hippocampus. Transmission electron microscopy was used to detect the extent of damage to mitochondria, endoplasmic reticulum (ER) and synapses. Immunofluorescence was used to detect GFAP, IBA1, and NLRP3 expression in the hippocampus. Western blot was used to detect apoptosis (Bcl\u20102, BAX, and Cleaved\u2010Caspase\u20103); synapses (postsynaptic densifying protein 95, SYN1, and Synaptophysin); mitochondria (DRP1, OPA1, MFN1, and MFN2); ER (GRP78, ATF6, CHOP, and caspase\u201012); NLRP3 inflammasome (NLRP3, ASC, and caspase\u20101); inflammatory cytokines (IL\u201018, IL\u20101\u03b2, and TNF\u2010\u03b1); AKT (P\u2010AKT); and mitogen\u2010activated protein kinase (MAPK) pathway (P\u2010ERK, P\u2010p38, and P\u2010JNK) related protein expression. Network pharmacology showed that nerolidol's possible mechanisms for treating diabetes are the MAPK\/AKT pathway and anti\u2010inflammatory effects. Animal experiments demonstrated that nerolidol could improve blood glucose, blood lipids, and hippocampal neuronal damage in diabetic rats. Furthermore, nerolidol could improve synaptic, mitochondrial, and ER damage in the hippocampal ultrastructure of diabetic rats by potentially affecting synaptic, mitochondrial, and ER\u2010related proteins. Further studies revealed that nerolidol decreased neuroinflammation, NLRP3 and inflammatory factor expression in hippocampal tissue while also decreasing MAPK pathway expression and enhancing AKT pathway expression. However, nerolidol improves hippocampal damage in diabetic rats cannot be shown to improve cognitive function. In conclusion, our study reveals for the first time that nerolidol can ameliorate hippocampal damage, neuroinflammation, synaptic, ER, and mitochondrial damage in diabetic rats. Furthermore, we suggest that nerolidol may inhibit NLRP3 inflammasome and affected the expression of MAPK and AKT. These findings provide a new experimental basis for the use of nerolidol to ameliorate diabetes\u2010induced brain tissue damage and the associated disease.<\/jats:p>","DOI":"10.1002\/biof.2058","type":"journal-article","created":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T09:32:29Z","timestamp":1713259949000},"page":"1076-1100","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Nerolidol rescues hippocampal injury of diabetic rats through inhibiting\n                    <scp>NLRP3<\/scp>\n                    inflammasome and regulation of\n                    <scp>MAPK<\/scp>\n                    \/\n                    <scp>AKT<\/scp>\n                    pathway"],"prefix":"10.1002","volume":"50","author":[{"given":"Yining","family":"Lei","sequence":"first","affiliation":[{"name":"School of Pharmacy, Xianning Medical College Hubei University of Science and Technology  China"},{"name":"Hubei Key Laboratory 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