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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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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