Engineering a chitosan-based nanoemulsion for non-invasive CNS-targeting approach: dual neuroprotection against epileptic and depressive disorders.

The frequent comorbidity of epilepsy and depression presents a major therapeutic challenge, with current therapies limited by systemic side effects and poor blood-brain barrier penetration. This study aimed to develop a non-invasive, dual-therapy topical nanoemulsion for combined (additive), rather than formally demonstrated synergistic, neuroprotection. A Quality-by-Design optimized chitosan-lipid nanoemulsion co-encapsulating ashwagandha extract and citicoline was engineered. The formulation exhibited favorable characteristics: nanoscale size (~ 145 nm), positive zeta potential (+ 35.9 mV), and sustained in vitro drug release. Its efficacy was evaluated in rat models of acute strychnine-induced seizures and forced swimming test-induced depression following topical application to the shaved head region. The treatment significantly attenuated seizure severity and latency in the acute seizure model. Concurrently, it reversed depressive-like behaviors across multiple tests (Forced Swim Test, FST; Tail Suspension Test, TST; and Sucrose Preference Test, SPT), with efficacy surpassing oral fluoxetine. Histopathological analysis of brain tissue confirmed pronounced neuroprotection in both models. This chitosan-based topical nanoemulsion presents a promising, patient-compliant strategy for dual neuroprotection against interconnected neurological disorders, offering a proof-of-concept for a novel combinatorial therapeutic approach. Although direct pharmacokinetic confirmation of brain drug distribution remains to be established, the observed pharmacodynamic and histopathological outcomes are consistent with CNS engagement following topical application, supporting further investigation of this delivery platform.