Carveol attenuated intracerebroventricular streptozotocin-induced memory impairment by modulating inflammasome-mediated pyroptosis and mTOR-dependent signaling

Alzheimer's disease, an accelerating neurodegenerative disorder, is distinguished by cognitive dysfunction, followed by accumulation of 𝛽-amyloid, and hyperphosphorylation of tau protein in neurons. Our study investigated that the intracerebroventricular administration of a sub-diabetogenic dose of streptozotocin (STZ) induced a state of insulin resistance that triggered oxidative stress, which ultimately contributed to the neuroinflammatory signaling cascade in the cortex and hippocampus region of the brain. The pathogenic role of neuroinflammation was further examined, and substantial contributions from both the inflammasome pathway and mammalian target of rapamycin (mTOR) signaling were demonstrated. Both these mediators significantly contributed to the release of cytokines, including interleukin (IL-6) and tumor necrosis factor alpha (TNF-α). Further, elevated levels of lipid peroxides (LPO), accompanied by reactive oxygen species (ROS), and coupled to downregulated antioxidant enzymes were observed in the STZ group. On the other hand, our results that were analyzed by nonparametric statistical methods demonstrated that treatment with carveol significantly reduced the inflammatory and oxidative responses, accompanied by improved survival and growth factors such as peroxisome proliferator-activated receptor gamma (PPARγ) and brain-derived neurotrophic factor (BDNF), all of which collectively improved behavioral responses. To further rule out the role of carveol on mTOR, we administered rapamycin alone and in combination with carveol, and our results suggested that both carveol and rapamycin upregulated the antioxidant enzyme levels and reversed neurodegeneration by downregulating the inflammatory targets. Moreover, docking analysis was performed on targets such as COX-2, NLRP3, and mTOR, which further substantiated drug-protein interactions. Our findings indicate that carveol mitigated the heightened response of STZ in this model with improved neuroprotective effects, possibly through the inhibition of the mTOR pathway, similar to the established drug rapamycin.