Targeting Neuroinflammation and Tau/APP Pathology via Intranasal Delivery of Azilsartan Medoxomil Nanoemulgel in AlCl₃-induced Alzheimer’s Dementia Model

Background: Cognitive impairment and dementia have become a global burden, distressing millions of elderlies, accounting for progressive loss of neurons in the brain affecting higher multiple cortical centers, and impacting social life. The renin-angiotensin system and its receptors, widely distributed within the brain, offer potential to treat dementia via diminishing oxidative stress, neuronal inflammation, and increasing blood-brain barrier (BBB) integrity. The present study delves into the formulation and optimization of thermoresponsive azilsartan medoxomil (AZL-M) loaded in situ nanoemulgel for targeted nose-to-brain delivery to the brain due to low BBB permeability and validated through in vivo models.

Methods: A Box-Behnken design was used to optimize formulation parameters such as droplet size, gelation temperature, and drug release. The optimized nanoemulgel was characterized for physicochemical properties and evaluated for ex-vivo nasal mucosal toxicity, in-vitro cytotoxicity, and ROS reduction. In-vivo efficacy of intranasal application of the optimized formulation was assessed in an AlCl₃-induced Alzheimer's model.

Results: Formulation-F20 showed optimal gelation at 33.4°C, pH-6.21, droplet size of 160nm, 60.4% drug release in 8h, high permeation, and flux, with confirmed safety and cell viability. TEER studies confirmed the integrity of RPMI-2650 monolayers, and while apparent permeability values of AZL-M solution and nanoemulgel were comparable, the nanoemulgel exhibited significantly higher cumulative permeation across the nasal epithelial barrier. In-vivo studies showed that nanoemulgel significantly improved cognitive performance and neuronal survival. At the molecular level, AZL-M treatment led to a marked reduction in brain inflammatory cytokines TNF-α and IL-1β, along with downregulation of Alzheimer’s-specific markers including phosphorylated tau, amyloid precursor protein, and NF-κB. Simultaneously, a significant upregulation of brain-derived neurotrophic factors indicated enhanced neurotrophic support and synaptic plasticity.

Conclusion: The intranasally delivered AZL-M-loaded nanoemulgel showed potential as a safe and effective therapy for Alzheimer’s dementia by attenuating neuroinflammation and Alzheimer’s pathology markers.