Netrin-3 rectifies diabetes-induced cognitive impairment by counteracting hippocampal oxidative stress and NLRP3...

Diabetes frequently causes substantial cognitive decline, yet available treatments offer minimal benefit. Netrin-3, a laminin-like protein, regulates nervous system development and inflammatory responses. However, its involvement in diabetes-associated cognitive impairment remains poorly understood. The escalating global diabetes burden, combined with the absence of disease-modifying therapies for cognitive complications, creates an urgent need to identify novel molecular targets. Our research evaluated whether Netrin-3 could counter cognitive deterioration using db/db mice as a type 2 diabetes model. We employed adenovirus-mediated gene delivery to restore Netrin-3 expression, then assessed spatial learning and memory using Morris water maze and Y-maze paradigms. Hippocampal tissue was analyzed by Western blot, quantitative PCR, ELISA, and oxidative stress assays to examine NF-κB/NLRP3 signaling and antioxidant enzyme activity. Initial analysis showed a considerable decrease in Netrin-3 expression within the cortex of diabetic mice. Introducing Netrin-3 via an adenoviral vector resulted in substantial improvements in systemic glucose control and insulin levels. Behavioral assessments further revealed that Netrin-3 reversed cognitive deficits, evidenced by superior performance in both Morris water maze and Y-maze paradigms, confirming enhanced spatial learning and working memory. At the mechanistic level, Netrin-3 counteracted hippocampal oxidative damage through lowering reactive oxygen species and NOX-4 expression, in parallel with reviving SOD and GSH-PX antioxidant enzyme function. Additionally, it curtailed the induction of the pro-inflammatory mediators IL-1β and IL-18 and blocked the triggering of the NF-κB/NLRP3 cascade. These findings indicate that Netrin-3 lessens cognitive dysfunction in diabetes by reducing oxidative damage and brain inflammation, highlighting its novel potential as a therapeutic target for a condition with limited treatment options.