Intranasal Delivery of Metabolically Resilient Glutathione: Pharmacokinetic, Permeation, and Efficacy Studies.

Nose-to-brain delivery is an attractive drug delivery strategy for the treatment of Alzheimer's disease (AD) as it offers direct penetration of drugs into the brain by surpassing the blood-brain barrier, while reducing the potential systemic side effects. We developed a glutathione analogue, ψ-GSH, that resists catabolism and reduces AD-related behavioral and pathological abnormalities . Although ψ-GSH is effective via intraperitoneal administration, limited oral availability hinders the clinical translation of ψ-GSH. In this study, we sought to evaluate if intranasal ψ-GSH administration can provide neuroprotection in an acute mouse model of AD-related pathology. The pharmacokinetic analysis confirmed brain delivery of the compound to levels 4-fold higher than those achieved by an efficacious systemic dose of ψ-GSH. Unaffected stability in simulated nasal fluid and mucosa further displayed the feasibility of this delivery method. Repeated intranasal administration of ψ-GSH prevented cognitive impairment induced by the intracerebroventricular injection of Aβ without significant adverse effects. Biochemical and immunohistochemical analyses displayed the beneficial effect of the treatment on oxidative stress and inflammatory markers by engaging GSH-dependent mechanisms, mirroring the pharmacological effects of intraperitoneal ψ-GSH. Additionally, directional transport studies using a human nasal epithelial cell line showed directional brain transport of ψ-GSH, without compromising the integrity of tight junction proteins. Collectively, our results demonstrate intranasal delivery as a safe and effective alternative for brain delivery of ψ-GSH at pharmacologically relevant concentrations for the treatment of neurological conditions. The study supports future formulation studies for intranasal ψ-GSH administration and its efficacy evaluation in transgenic AD mouse models for preclinical advancement.