A Novel 4-Methyl-2-(5-Phenyl-Thioxo-1, 3, 5-Thiadiazinan-3-yl) Pentanoic Acid Reverses Cognitive Decline via Dual Modulation of PI3K/NLRP3 Signaling in a Brain Aging Mouse Model

Background: Aging is closely associated with cognitive decline and neuroinflammation, often driven by oxidative stress and dysregulation of immune signaling pathways such as NLRP3 inflammasome activation. Aim: This study presents the first comprehensive investigation of the neuroprotective effects of a novel pentanoic acid derivative (PAD), i.e., 4-Methyl-2-(5-Phenyl-Thioxo-1,3,5-Thiadiazinan-3-yl), in a D-galactose (D-Gal)-induced mouse model of brain aging. Methodology: Male albino mice (8 weeks; 30 g) were evenly divided into eight groups. Y-Maze and Morris Water Maze tests, antioxidant analyses, and western blotting were conducted. Results: Chronic D-Gal exposure induced oxidative damage, synaptic dysfunction, acetylcholinesterase (AChE) hyperactivity, and upregulation of the NLRP3 inflammasome complex, leading to impaired memory and learning. PAD treatment, particularly at 25 mg/kg, significantly improved behavioral outcomes via restoration of both long-term spatial and short-term working memory. At the molecular level, PAD reversed D-Gal-induced reductions in antioxidant enzyme activities (POD, SOD, CAT, and GSH) and restored synaptic protein expression (SYP, PSD-95). Notably, PAD suppressed NLRP3, ASC, IL-1β, and caspase-1 expression while enhancing phosphorylated PI3K levels, suggesting dual modulation of inflammation and pro-survival pathways. The neuroprotective effects of PAD were abrogated by the PI3K inhibitor LY294002, confirming the PI3K-dependency of its mechanism. Comparisons with MCC950, a selective NLRP3 inhibitor, revealed that PAD not only matched its anti-inflammatory efficacy but also outperformed it in PI3K activation. Conclusion: Collectively, these findings demonstrate that PAD mitigates D-Gal-induced neuroinflammation and cognitive dysfunction via PI3K-dependent inhibition of the NLRP3 inflammasome and restoration of redox balance. Furthermore, PAD represents a promising dual-action therapeutic candidate for combating age-related neurodegenerative disorders. Future studies are warranted to further define its molecular targets and evaluate its long-term safety in preclinical models.