Attenuation of Vascular Dementia Associated Neuroinflammation by Inhibition of the JNK Pathway in HFD/STZ-Induced Diabetic Rat Model

Diabetes-associated cognitive impairment represents a major global health burden and is driven by metabolic dysregulation, neuroinflammation, oxidative stress and vascular dysfunction. High-fat diet (HFD)-induced metabolic stress is known to exacerbate insulin resistance, cerebrovascular injury while activation of stress-responsive pathways, including c-Jun N-terminal 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-associated cognitive and neuroinflammatory changes using a HFD and streptozotocin (STZ) rat model. Male Sprague Dawley rats were allocated to control (HFD-fed), disease (HFD + STZ), control+treatment (HFD + SP600125) and treatment (HFD + STZ + SP600125) groups. The treatment groups were administered JNK inhibitor (SP600125) for 2 weeks, and cognitive performance was assessed using the Y-Maze 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-linked immunosorbent assay and modulated immunohistochemical markers by increasing TREM-2 while reducing P53 and TNF-α levels. Collectively, these results demonstrated JNK activation contributes to diabetes-associated 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.