Intranasal liposomal minocycline mitigates aluminum-induced cognitive and structural deficits by targeting redox-NF-κB/NLRP3 axis

Chronic neurodegeneration is increasingly linked to redox imbalance and persistent activation of inflammatory pathways, particularly the NF-κB/NLRP3 inflammasome axis. Aluminum exposure induces oxidative stress, hippocampal inflammation, and cognitive decline. While minocycline exhibits anti-inflammatory and antioxidant properties, its therapeutic translation is often limited by systemic delivery constraints and off-target effects, necessitating novel delivery strategies.

Adult rats were subjected to chronic AlCl₃ exposure to induce neurodegeneration. They were then treated with intranasal Lip@min. A preliminary pilot study optimized the dose, identifying 1 mg/kg as the optimal therapeutic balance. Researchers assessed oxidative stress markers (MDA, NO, SOD, CAT, GPx, GSH), pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, MCP-1), iNOS expression, NF-κB nuclear immunoreactivity, and NLRP3 levels. Histopathological analysis of CA1 neuronal density and behavioral evaluation using Y-maze and novel object recognition (NOR) tests were performed.

Chronic AlCl₃ exposure induced marked redox collapse, activation of NF-κB/NLRP3 signaling, and elevated cytokine production. This was accompanied by significant CA1 neuronal degeneration and cognitive impairment in behavioral tests. Intranasal Lip@min treatment significantly reduced oxidative stress markers and suppressed NF-κB nuclear translocation and NLRP3 expression. It also attenuated pro-inflammatory mediator levels, reversing the inflammatory cascade. > Structural preservation of CA1 neurons was observed, accompanied by significant improvement in both working and recognition memory, demonstrating functional recovery. The dose optimization identified 1 mg/kg as the optimal balance between efficacy and pulmonary safety.