Intranasal administration of dantrolene increased brain concentration and duration.

Dantrolene has been demonstrated to be neuroprotective for multiple neurodegenerative diseases. However, dantrolene's limited penetration into the CNS hampers its effectiveness as a neuroprotective agent. Here, we studied whether the intranasal administration of dantrolene provided better penetration into the brain than the commonly used oral approach. C57BL/6 mice, aged 2-4 months, received a single dose of either intranasal or oral dantrolene (5mg/kg). Inhibition of dantrolene clearance from the brain was examined by co-administration with P-gp/BCRP inhibitors, nimodipine or elacridar. The concentration of dantrolene in the brain and plasma was measured at 10, 20, 30, 50, 70, 120, 150 and 180 minutes after administration. Separate cohorts of mice were given intranasal dantrolene (5mg/kg) or vehicle, 3 times/ week, for either 3 weeks or 4 months, to examine potential adverse side effects on olfaction and motor coordination, respectively. We found that Dantrolene concentrations were sustained in the brain after intranasal administration for 180 min, while concentrations fell to zero at 120 min for oral administration. Chronic use of intranasal dantrolene did not impair olfaction or motor function in these mice. Blood brain barrier pump inhibitors did not further increase dantrolene peak concentrations in the brain. Our results suggested that Intranasal administration of dantrolene is an effective route to increase its concentration and duration in the brain compared to the oral approach, without any obvious side effects on olfaction or motor function.

Déclaration de conflit d'intérêts

This study was supported by research grant from National Institute of General Medical Science (NIGMS R01GM084979) and National Institute of Aging (NIA R01AG061447). The results of this manuscript have been included in a US provisional patent application titled “Intranasal Administration of Dantrolene for Treatment of Alzheimer’s Disease” filed on June 28, 2019 (Serial number 62/868,820) by the University of Pennsylvania Trustee. Four of the co-authors, all employees of the University of Pennsylvania, Drs. Huafeng Wei, Qingcheng Meng, Ge Liang and Maryellen Eckenhoff, are listed as inventors of the provisional patent application. The patent application is also part of the research collaboration agreement between the University of Pennsylvania and Eagle Pharmaceutical Company, which produces and sells a formulation of dantrolene (Ryanodex) for the treatment of malignant hyperthermia. The dantrolene used in this study was purchased from Sigma Company. This does not alter our adherence to PLOS ONE policies on sharing data and materials.