AbstractBackgroundMetabolic syndrome (MS) includes clusters of metabolic disorders and type 2 DM (T2DM) is most common MS which cause insulin resistance (IR). The IR mediated dysregulation of signaling cascades in brain increase the production and secretion of Aβ, p‐tau which prompt to Alzheimer’s (AD). Therefore, repaglinide (REP) a meglitinides drug is used, which act by targeting ATP binding cassette and evidence indicated that REP increase neuronal survival via upregulating ATF‐6 gene and blocking the DREAM. Thus, there is huge possibility that REP regulate and modulate the expression of pro‐apoptotic protein, anti‐apoptotic protein, calcium homeostasis and may eventually reduce the neuronal cell death.MethodsIn, in vitro studies, primarily cytotoxicity assay was performed on SHSY‐5Y cells and to mimic the neurodegenerative condition, the cells were treated with streptozotocin (STZ, 2.5mM). Further, to check the efficacy of REP in AD, in vivo studies were performed using HFD fed STZ induced murine model. The HFD was fed for 16 weeks followed by administration of STZ (30mg/kg; i.p) in wistar rats for induction of DM linked AD.ResultsIn vitro and in vivo studies were conducted to understand the neuroprotective potential of the REP. It was observed that the REP shows cellular viability of ∼80‐85% and no morphological changes in the cells were identified. Additionally, the results have shown that REP increase the cell viability of STZ treated SHSY‐5Y cells by ∼1.2‐fold and significantly (p<0.01) decreased the oxidative stress in H2O2 treated cells. After treatment of REP (4 mg/kg,p.o) for 4 weeks in DM linked AD wistar rats, a significant (p<0.01) decrement in Aβ, tau proteins, TNF‐α, IL‐6, MDA, NO and increment in BDNF, SOD, GSH level was observed compared to disease control rats. Further, in behavioral studies a significant improvement (p<0.01) in the retention memory and spatial memory was observed after the REP treatment. Additionally, a significant (p<0.05) increase in Bcl‐2, ATF‐6 expression, and decrement in Bax, Caspase‐3 expression indicates reduction in neuronal cell death then the disease rats.ConclusionIn summary, it concluded that REP act as a neuroprotective agent which might be used to treat MS linked AD.