Effects of intranasal dantrolene nanoparticles on brain concentration and behavior in PS19 tau transgenic mice.

ABSTRACT

Background: Repurposing dantrolene as a potential disease-modifying treatment for Alzheimer's disease has been shown to be effective in amyloid transgenic mouse models but has not been examined in a model of tauopathy. Objective: The effects of a nanoparticle intranasal formulation, the Eagle Research Formulation of Ryanodex (ERFR), in young adult and aged wild type and PS19 tau transgenic mice was investigated. Methods: The bioavailability of intranasal ERFR was measured in 2 months and 9-12 month old C57BL/6J male mice. Mice received a single intranasal dose of ERFR and, after 20 min, blood and brain samples were collected. Dantrolene concentrations in the plasma and brain were analyzed by High Performance Liquid Chromatography. Animal behavior was examined in PS19 tau transgenic mice, with/without acrolein treatment to exacerbate cognitive deficits. Behavioral tests included cognition (cued and contextual fear conditioning, y-maze), motor function (rotarod), and olfaction (buried food test). Results: Dantrolene concentration in the blood and brain decreased with age, though the decrease was greater in the blood resulting in a higher brain to blood concentration ratio. The behavioral assays showed no significant changes in cognition, olfaction or motor function in the PS19 mice compared to controls after chronic ERFR treatment even with acrolein treatment. Conclusion: Our studies suggest that while we did not find PS19 mice to be a reliable Alzheimer animal model to test the therapeutic efficacy of dantrolene, the results suggest a potential for ERFR to be an effective chronic therapy for Alzheimer's disease and that further studies are indicated.