Targeting the Redox-NF-κB/NLRP3 axis with intranasal liposomal minocycline mitigates aluminum-induced cognitive and structural deficits.

backgroundChronic 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. Minocycline exhibits anti-inflammatory and antioxidant properties; however, its therapeutic translation is limited by systemic delivery constraints. METHODS AND

resultsAdult rats were exposed to chronic AlCl₃ and treated with intranasal Lip@min. A preliminary pilot study defined the optimal therapeutic dose. 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 were assessed. Histopathological analysis of CA1 neuronal density and behavioral evaluation using Y-maze and novel object recognition (NOR) tests were performed. AlCl₃ exposure induced marked redox collapse, activation of NF-κB/NLRP3 signaling, elevated cytokine production, CA1 neuronal degeneration, and cognitive impairment. Intranasal Lip@min significantly reduced oxidative stress, suppressed NF-κB nuclear translocation and NLRP3 expression, and attenuated pro-inflammatory mediator levels. Structural preservation of CA1 neurons was accompanied by significant improvement in working and recognition memory. Dose optimization identified 1 mg/kg as the optimal balance between efficacy and pulmonary safety.

conclusionIntranasal liposomal minocycline mitigates aluminum-induced neurodegeneration by modulating the redox-NF-κB/NLRP3 inflammatory axis, leading to structural and functional recovery. These findings support nose-to-brain nano-delivery as a promising strategy for targeting inflammasome-driven neuroinflammatory pathology.