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 penet...

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Main Authors: Jintao Wang, Yun Shi, Shuchun Yu, Yan Wang, Qingcheng Meng, Ge Liang, Maryellen F Eckenhoff, Huafeng Wei
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2020-01-01
Series:PLoS ONE
Online Access:https://doi.org/10.1371/journal.pone.0229156
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spelling doaj-ac377e32469a482aa897f0356c999acb2021-03-03T22:10:30ZengPublic Library of Science (PLoS)PLoS ONE1932-62032020-01-01153e022915610.1371/journal.pone.0229156Intranasal administration of dantrolene increased brain concentration and duration.Jintao WangYun ShiShuchun YuYan WangQingcheng MengGe LiangMaryellen F EckenhoffHuafeng WeiDantrolene 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.https://doi.org/10.1371/journal.pone.0229156
collection DOAJ
language English
format Article
sources DOAJ
author Jintao Wang
Yun Shi
Shuchun Yu
Yan Wang
Qingcheng Meng
Ge Liang
Maryellen F Eckenhoff
Huafeng Wei
spellingShingle Jintao Wang
Yun Shi
Shuchun Yu
Yan Wang
Qingcheng Meng
Ge Liang
Maryellen F Eckenhoff
Huafeng Wei
Intranasal administration of dantrolene increased brain concentration and duration.
PLoS ONE
author_facet Jintao Wang
Yun Shi
Shuchun Yu
Yan Wang
Qingcheng Meng
Ge Liang
Maryellen F Eckenhoff
Huafeng Wei
author_sort Jintao Wang
title Intranasal administration of dantrolene increased brain concentration and duration.
title_short Intranasal administration of dantrolene increased brain concentration and duration.
title_full Intranasal administration of dantrolene increased brain concentration and duration.
title_fullStr Intranasal administration of dantrolene increased brain concentration and duration.
title_full_unstemmed Intranasal administration of dantrolene increased brain concentration and duration.
title_sort intranasal administration of dantrolene increased brain concentration and duration.
publisher Public Library of Science (PLoS)
series PLoS ONE
issn 1932-6203
publishDate 2020-01-01
description 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.
url https://doi.org/10.1371/journal.pone.0229156
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