Effects of Intranasal Dantrolene Nanoparticles on Brain Concentration and Behavior in PS19 Tau Transgenic Mice

Article type: Research Article

Authors: Vera, Robert^a | Hong, Nicholas^a | Jiang, Bailin^{a; b} | Liang, Ge^a | Eckenhoff, Maryellen F.^a | Kincaid, Halle J.^a | Browne, Veron^c | Chellaraj, Vinolia^c | Gisewhite, Douglas^c | Greenberg, Michael^c | Ranjan, Sudhir^c | Zhu, Gaozhong^c | Wei, Huafeng^{a; *}

Affiliations: [a] Department of Anesthesiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA | [b] Department of Anesthesiology, Peking University People’s Hospital, Beijing, China | [c] Eagle Pharmaceuticals, Inc., Woodcliff Lake, NJ, USA

Correspondence: [*] Correspondence to: Huafeng Wei, MD, PhD, Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, 305 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104, USA. Tel.: +1 215 7468704; Fax: +1 215 349 5078; E-mail:huafeng.wei@pennmedicine.upenn.edu.

Abstract: Background:Repurposing dantrolene to treat 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 and 9–11-month-old C57BL/6J mice. Blood and brain samples were collected 20 minutes after a single ERFR dose, and the plasma and brain concentrations were analyzed. Baseline behavior was assessed in untreated PS19 tau transgenic mice at 6 and 9 months of age. PS19 mice were treated with intranasal ERFR, with or without acrolein (to potentiate cognitive dysfunction), for 3 months, beginning at 2 months of age. Animal behavior was examined, including cognition (cued and contextual fear conditioning, y-maze), motor function (rotarod), and olfaction (buried food test). Results:The dantrolene concentration in the blood and brain decreased with age, with the decrease 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 treatment with intranasal ERFR, even with acrolein. Conclusions:Our studies suggest the intranasal administration of ERFR has higher concentrations in the brain than the blood in aged mice and has no serious systemic side effects with chronic use in PS19 mice.

Keywords: Alzheimer’s disease, blood-brain barrier, calcium, cognition, dantrolene, pharmacokinetics, PS19 mice, ryanodine receptor, tau protein, therapeutics

DOI: 10.3233/JAD-231337

Journal: Journal of Alzheimer's Disease, vol. 98, no. 2, pp. 549-562, 2024