Neuroprotective potential of tranilast in streptozotocin-induced sporadic Alzheimer's disease model targeting TXNIP-NLRP3 inflammasome pathway.

Sporadic Alzheimer's disease (sAD) is a progressive neurodegenerative disorder characterised by oxidative stress, neuroinflammation, mitochondrial dysfunction and cerebral insulin resistance. Even though approximately 95 % of AD cases are reported as sporadic, the exact pathogenesis remains sparse. Tranilast, an analogue of tryptophan metabolite, was initially endowed as an anti-allergic agent and used in multiple inflammatory ailments. Still, the molecular mechanisms targeting sAD are yet to be investigated. In the present study, we investigated the neuroprotective potential of tranilast by performing biochemical, molecular and histopathological assessments using both in vivo and in vitro experimental sAD models. Streptozotocin (STZ; 3 mg/kg) was bilaterally injected on day 1 and 3 through the intracerebroventricular (ICV) route to Sprague Dawley rats for the in vivo model induction. Spontaneous alternation test, novel object recognition test, and passive avoidance test were performed to assess the altered behavioural patterns in animals. Furthermore, human neuroblastoma cells (SHSY5Y) were exposed to STZ (1 mM) and tranilast for 24 h to validate the in vivo results. Three weeks of tranilast (30 and 100 mg/kg, p.o.) treatment improved neurobehavioural anomalies in ICV-STZ-treated rats by halting neuroinflammation and NLRP3 inflammasome activation caused by enhanced reactive oxygen species (ROS) and thioredoxin interaction protein (TXNIP) overexpression. The phosphorylated tau (p-tau S416) level was also increased in the ICV-STZ rat's hippocampus and reversed upon tranilast treatment. A high dose of tranilast (100 mg/kg) treatment sensitised hippocampal insulin signalling in ICV-STZ-treated rats. Furthermore, in cell culture studies, 24-h tranilast (30 and 100 μM) treatment reduced the mitochondrial ROS production and attenuated inflammasome activation in STZ-treated SHSY5Y cells. In summary, the findings of the study proclaim the neuroprotective potential of tranilast in STZ induced model of sAD by modulating the TXNIP-NLRP3 inflammasome pathway.