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High\u2010fat diet (HFD)\u2010induced metabolic stress is known to exacerbate insulin resistance, cerebrovascular injury while activation of stress\u2010responsive pathways, including c\u2010Jun N\u2010terminal kinase (JNK), thereby contributing to neuroinflammatory and cognitive alterations relevant to vascular cognitive impairment. The present study evaluated the therapeutic potential of JNK inhibition in ameliorating diabetes\u2010associated cognitive and neuroinflammatory changes using a HFD and streptozotocin (STZ) rat model. Male Sprague Dawley rats were allocated to control (HFD\u2010fed), disease (HFD\u2009+\u2009STZ), control+treatment (HFD\u2009+\u2009SP600125) and treatment (HFD\u2009+\u2009STZ\u2009+\u2009SP600125) groups. The treatment groups were administered JNK inhibitor (SP600125) for 2\u2009weeks, and cognitive performance was assessed using the Y\u2010Maze and Morris water maze tests. Disease rats exhibited significant impairments in learning and memory, accompanied by neuronal damage and elevated neuroinflammatory markers in the hippocampus and cortex. Treatment with the JNK inhibitor SP600125 significantly improved cognitive performance, attenuated neuronal injury and reduced inflammatory signalling. Notably, SP600125 decreased brain levels of NLRP3 and inducible nitric oxide synthase, as measured by enzyme\u2010linked immunosorbent assay and modulated immunohistochemical markers by increasing TREM\u20102 while reducing P53 and TNF\u2010\u03b1 levels. Collectively, these results demonstrated JNK activation contributes to diabetes\u2010associated cognitive and neuroinflammatory alterations and that pharmacological JNK inhibition may mitigate pathological features relevant to vascular cognitive impairment without implying exclusive causality. This study supports JNK signalling as a mechanistically relevant target for addressing cognitive complications associated with diabetes.<\/jats:p>","DOI":"10.1111\/1440-1681.70120","type":"journal-article","created":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T08:36:52Z","timestamp":1775291812000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Attenuation of Vascular Dementia Associated Neuroinflammation by Inhibition of the\n                    <scp>JNK<\/scp>\n                    Pathway in\n                    <scp>HFD<\/scp>\n                    \/\n                    <scp>STZ<\/scp>\n                    \u2010Induced Diabetic Rat Model"],"prefix":"10.1111","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3119-5805","authenticated-orcid":false,"given":"Sundas","family":"Firdoos","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceutical Beijing Institute of Technology (BIT)  Beijing People's Republic of China"},{"name":"Riphah Institute of Pharmaceutical Sciences Riphah International University  Islamabad Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongji","family":"Dai","sequence":"additional","affiliation":[{"name":"Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceutical Beijing Institute of Technology (BIT)  Beijing People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fawad Ali","family":"Shah","sequence":"additional","affiliation":[{"name":"Riphah Institute of Pharmaceutical Sciences Riphah International University  Islamabad Pakistan"},{"name":"Department of Pharmacology and Toxicology College of Pharmacy, Prince Sattam Bin Abdulaziz University Al\u2010Kharj  Al\u2010Kharj Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zahid","family":"Younas","sequence":"additional","affiliation":[{"name":"Department of CS &amp; IT The University of Azad Jammu &amp; Kashmir  Muzaffarabad 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