Off-Label Use of Bumetanide for Brain Disorders: An Overview
Bumetanide (BTN or BUM) is a FDA-approved potent loop diuretic (LD) that acts by antagonizing sodium-potassium-chloride (Na-K-Cl) cotransporters, NKCC1 (SLc12a2) and NKCC2. While NKCC1 is expressed both in the CNS and in systemic organs, NKCC2 is kidney-specific. The off-label use of BTN to modulate...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-04-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2019.00310/full |
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| author | Shivani C. Kharod Seok Kyu Kang Shilpa D. Kadam Shilpa D. Kadam |
| author_facet | Shivani C. Kharod Seok Kyu Kang Shilpa D. Kadam Shilpa D. Kadam |
| author_sort | Shivani C. Kharod |
| collection | DOAJ |
| description | Bumetanide (BTN or BUM) is a FDA-approved potent loop diuretic (LD) that acts by antagonizing sodium-potassium-chloride (Na-K-Cl) cotransporters, NKCC1 (SLc12a2) and NKCC2. While NKCC1 is expressed both in the CNS and in systemic organs, NKCC2 is kidney-specific. The off-label use of BTN to modulate neuronal transmembrane Cl− gradients by blocking NKCC1 in the CNS has now been tested as an anti-seizure agent and as an intervention for neurological disorders in pre-clinical studies with varying results. BTN safety and efficacy for its off-label use has also been tested in several clinical trials for neonates, children, adolescents, and adults. It failed to meet efficacy criteria for hypoxic-ischemic encephalopathy (HIE) neonatal seizures. In contrast, positive outcomes in temporal lobe epilepsy (TLE), autism, and schizophrenia trials have been attributed to BTN in studies evaluating its off-label use. NKCC1 is an electroneutral neuronal Cl− importer and the dominance of NKCC1 function has been proposed as the common pathology for HIE seizures, TLE, autism, and schizophrenia. Therefore, the use of BTN to antagonize neuronal NKCC1 with the goal to lower internal Cl− levels and promote GABAergic mediated hyperpolarization has been proposed. In this review, we summarize the data and results for pre-clinical and clinical studies that have tested off-label BTN interventions and report variable outcomes. We also compare the data underlying the developmental expression profile of NKCC1 and KCC2, highlight the limitations of BTN’s brain-availability and consider its actions on non-neuronal cells. |
| first_indexed | 2024-12-19T07:27:06Z |
| format | Article |
| id | doaj.art-b20ad0f5689546d5a6366db8f16233c4 |
| institution | Directory Open Access Journal |
| issn | 1662-453X |
| language | English |
| last_indexed | 2024-12-19T07:27:06Z |
| publishDate | 2019-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neuroscience |
| spelling | doaj.art-b20ad0f5689546d5a6366db8f16233c42022-12-21T20:30:49ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2019-04-011310.3389/fnins.2019.00310449965Off-Label Use of Bumetanide for Brain Disorders: An OverviewShivani C. Kharod0Seok Kyu Kang1Shilpa D. Kadam2Shilpa D. Kadam3Neuroscience Laboratory, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, United StatesNeuroscience Laboratory, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, United StatesNeuroscience Laboratory, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, United StatesDepartment of Neurology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United StatesBumetanide (BTN or BUM) is a FDA-approved potent loop diuretic (LD) that acts by antagonizing sodium-potassium-chloride (Na-K-Cl) cotransporters, NKCC1 (SLc12a2) and NKCC2. While NKCC1 is expressed both in the CNS and in systemic organs, NKCC2 is kidney-specific. The off-label use of BTN to modulate neuronal transmembrane Cl− gradients by blocking NKCC1 in the CNS has now been tested as an anti-seizure agent and as an intervention for neurological disorders in pre-clinical studies with varying results. BTN safety and efficacy for its off-label use has also been tested in several clinical trials for neonates, children, adolescents, and adults. It failed to meet efficacy criteria for hypoxic-ischemic encephalopathy (HIE) neonatal seizures. In contrast, positive outcomes in temporal lobe epilepsy (TLE), autism, and schizophrenia trials have been attributed to BTN in studies evaluating its off-label use. NKCC1 is an electroneutral neuronal Cl− importer and the dominance of NKCC1 function has been proposed as the common pathology for HIE seizures, TLE, autism, and schizophrenia. Therefore, the use of BTN to antagonize neuronal NKCC1 with the goal to lower internal Cl− levels and promote GABAergic mediated hyperpolarization has been proposed. In this review, we summarize the data and results for pre-clinical and clinical studies that have tested off-label BTN interventions and report variable outcomes. We also compare the data underlying the developmental expression profile of NKCC1 and KCC2, highlight the limitations of BTN’s brain-availability and consider its actions on non-neuronal cells.https://www.frontiersin.org/article/10.3389/fnins.2019.00310/fullbumetanide (BTN)Na-K-Cl cotransporter 1 (NKCC1)neonatal seizuresautismschizophreniatemporal lobe epilepsy (TLE) |
| spellingShingle | Shivani C. Kharod Seok Kyu Kang Shilpa D. Kadam Shilpa D. Kadam Off-Label Use of Bumetanide for Brain Disorders: An Overview Frontiers in Neuroscience bumetanide (BTN) Na-K-Cl cotransporter 1 (NKCC1) neonatal seizures autism schizophrenia temporal lobe epilepsy (TLE) |
| title | Off-Label Use of Bumetanide for Brain Disorders: An Overview |
| title_full | Off-Label Use of Bumetanide for Brain Disorders: An Overview |
| title_fullStr | Off-Label Use of Bumetanide for Brain Disorders: An Overview |
| title_full_unstemmed | Off-Label Use of Bumetanide for Brain Disorders: An Overview |
| title_short | Off-Label Use of Bumetanide for Brain Disorders: An Overview |
| title_sort | off label use of bumetanide for brain disorders an overview |
| topic | bumetanide (BTN) Na-K-Cl cotransporter 1 (NKCC1) neonatal seizures autism schizophrenia temporal lobe epilepsy (TLE) |
| url | https://www.frontiersin.org/article/10.3389/fnins.2019.00310/full |
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