Targeting the AMPK/SIRT1-NLRP3 Inflammasome Axis: Simvastatin, Ezetimibe, and Their Combination Attenuate...

Striatal neurodegeneration, a prominent pathological feature of several neurological disorders, is associated with progressive behavioral decline alongside cognitive and motor dysfunction, reflecting the critical regulatory role of the striatum in coordinating multiple aspects of brain function. Neuroinflammation, particularly through NF-κB/NLRP3-pathway activation, which triggers the cleavage and subsequent secretion of IL-1β/IL-18, contributes substantially to neuronal injury, with glial activation serving as a key driver, whereas the AMPK/SIRT1-signaling cascade exerts anti-inflammatory and neuroprotective effects. Network pharmacology suggested potential interactions between AMPK/SIRT1-signaling and NF-κB/NLRP3-associated inflammatory and glial pathways. Simvastatin and Ezetimibe possess pleiotropic properties that may modulate these pathways. This research evaluated the neuroprotective potential of Simvastatin and Ezetimibe, given alone or combined, in a striatal neurodegeneration model induced by 3-nitropropionic acid(3-NP) in rats. Adult male Wistar rats were assigned by random selection into six-cohorts (n=15/group): control-cohort; 3-NP (10 mg/kg/day, administered intraperitoneally for 21 days) vehicle-cohort; and 3-NP-treated cohorts receiving Simvastatin (10 or 20 mg/kg, orally), Ezetimibe (10 mg/kg, orally), or a combination of both (10 mg/kg each). Treatments were administered 1h before 3-NP injection. Exposure to 3-NP induced marked oxidative stress, neuroinflammation, gliosis, neurotransmitter disturbances, histopathological alterations, and behavioral deficits. In comparison to the 3-NP-vehicle-cohort, Simvastatin and/or Ezetimibe enhanced AMPK/SIRT1-signaling, suppressed NF-κB/NLRP3 inflammasome activation, reduced glial reactivity, restored neurotransmitter homeostasis, and improved behavioral and histopathological outcomes. The combination regimen consistently produced the most pronounced protective effects. Collectively, Simvastatin and Ezetimibe attenuate 3-NP-induced striatal neurodegeneration, possibly through modulation of AMPK/SIRT1-associated neuroinflammatory and glial signaling pathways, warranting further evaluation in additional experimental models.