Postacute administration of the GABA α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats
Background: Ischemic stroke causes hypoexcitability in the peri-infarct motor neocortex that stems from increased tonic γ-amino-butyric acid (GABA) activity in neurons. This hypoexcitability, while neuroprotective in the acute phase, may impair neuroplasticity and functional recovery in the subacute...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-11-01
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| Series: | Clinical and Translational Neuroscience |
| Online Access: | https://doi.org/10.1177/2514183X20948306 |
| _version_ | 1818581762453798912 |
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| author | Marta Pace Matteo Falappa Patricia Machado Laura Facchin Dirk M Hermann Claudio L Bassetti |
| author_facet | Marta Pace Matteo Falappa Patricia Machado Laura Facchin Dirk M Hermann Claudio L Bassetti |
| author_sort | Marta Pace |
| collection | DOAJ |
| description | Background: Ischemic stroke causes hypoexcitability in the peri-infarct motor neocortex that stems from increased tonic γ-amino-butyric acid (GABA) activity in neurons. This hypoexcitability, while neuroprotective in the acute phase, may impair neuroplasticity and functional recovery in the subacute phase of stroke. The purpose of this study is to investigate the effect of delayed and prolonged administration of S44819, which is a potent and competitive selective antagonist of GABA A receptors, on the skilled reaching function in a rodent model of stroke. Methods: Male Sprague–Dawley rats ( n = 15) were subjected to permanent middle cerebral artery occlusion. Starting 3 days after stroke, a vehicle or S44819 (3 or 10 mg/kg, BID) was delivered orally twice a day for 28 days. All animals were euthanized 2 weeks later after the washout period. A single pellet reaching task (SPR) was performed before (baseline value) and after the ischemic surgery at several time points (3, 10, 17, 24, 31, 38, and 45 days) to assess the motor deficit. Infarct volume and body changes were also evaluated. Results: S44819, administered at 10 but not 3 mg/kg, significantly improves SPR results over the 45 days after the ischemic surgery. No effect was observed in the infarct size and in the body weight over time between the groups investigated. Conclusion: S44819 at 10 mg/kg significantly enhances motor recovery on a skilled reaching task after sensory-motor cortex lesion. Additionally, our study, in light of the results of the RESTORE BRAIN (Randomized Efficacy and Safety Trial of Oral GABA A α5 antagonist S44819 after Recent ischemic Event) trial, may help clinicians to design clinical studies and stratify variables and patients adequately. |
| first_indexed | 2024-12-16T07:38:39Z |
| format | Article |
| id | doaj.art-883ec7d55c3e43c285f26034f6a9df82 |
| institution | Directory Open Access Journal |
| issn | 2514-183X |
| language | English |
| last_indexed | 2024-12-16T07:38:39Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Clinical and Translational Neuroscience |
| spelling | doaj.art-883ec7d55c3e43c285f26034f6a9df822022-12-21T22:39:08ZengMDPI AGClinical and Translational Neuroscience2514-183X2020-11-01410.1177/2514183X20948306Postacute administration of the GABA α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in ratsMarta Pace0Matteo Falappa1Patricia Machado2Laura Facchin3Dirk M Hermann4Claudio L Bassetti5 Center for Experimental Neurology, Department of Neurology, , Bern, Switzerland Genetics and Epigenetics of Behaviour Laboratory, , Genoa, Italy , Suresnes, France Center for Experimental Neurology, Department of Neurology, , Bern, Switzerland Department of Neurology, , Essen, Germany Department of Neurology, , Bern, SwitzerlandBackground: Ischemic stroke causes hypoexcitability in the peri-infarct motor neocortex that stems from increased tonic γ-amino-butyric acid (GABA) activity in neurons. This hypoexcitability, while neuroprotective in the acute phase, may impair neuroplasticity and functional recovery in the subacute phase of stroke. The purpose of this study is to investigate the effect of delayed and prolonged administration of S44819, which is a potent and competitive selective antagonist of GABA A receptors, on the skilled reaching function in a rodent model of stroke. Methods: Male Sprague–Dawley rats ( n = 15) were subjected to permanent middle cerebral artery occlusion. Starting 3 days after stroke, a vehicle or S44819 (3 or 10 mg/kg, BID) was delivered orally twice a day for 28 days. All animals were euthanized 2 weeks later after the washout period. A single pellet reaching task (SPR) was performed before (baseline value) and after the ischemic surgery at several time points (3, 10, 17, 24, 31, 38, and 45 days) to assess the motor deficit. Infarct volume and body changes were also evaluated. Results: S44819, administered at 10 but not 3 mg/kg, significantly improves SPR results over the 45 days after the ischemic surgery. No effect was observed in the infarct size and in the body weight over time between the groups investigated. Conclusion: S44819 at 10 mg/kg significantly enhances motor recovery on a skilled reaching task after sensory-motor cortex lesion. Additionally, our study, in light of the results of the RESTORE BRAIN (Randomized Efficacy and Safety Trial of Oral GABA A α5 antagonist S44819 after Recent ischemic Event) trial, may help clinicians to design clinical studies and stratify variables and patients adequately.https://doi.org/10.1177/2514183X20948306 |
| spellingShingle | Marta Pace Matteo Falappa Patricia Machado Laura Facchin Dirk M Hermann Claudio L Bassetti Postacute administration of the GABA α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats Clinical and Translational Neuroscience |
| title | Postacute administration of the GABA α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats |
| title_full | Postacute administration of the GABA α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats |
| title_fullStr | Postacute administration of the GABA α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats |
| title_full_unstemmed | Postacute administration of the GABA α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats |
| title_short | Postacute administration of the GABA α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats |
| title_sort | postacute administration of the gaba α5 antagonist s44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats |
| url | https://doi.org/10.1177/2514183X20948306 |
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