Safety and efficacy of GABAA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial

Chabriat, Hugues; Bassetti, Claudio L.; Marx, Ute C.; Audoli-Inthavong, Marie-Laure; Sors, Aurore; Lambert, Estelle V.; Wattez, Marine; Hermann, Dirk M.; Althaus, Katharina; Amaro, Sergi; Bae, Hee‐Joon; Bąk, Zbigniew; Barbarini, Leonardo; Bassi, Pietro; Bazan, Rodrigo; Bereczki, Dániel; Berkowicz, Tomasz; Berrouschot, J.; Blacquiere, Dylan; Brola, Waldemar; Butcher, Ken; Cardona, Pere; Cha, Jae‐Kwan; Cloud, Geoffrey; Cohen, David; Cordonnier, Charlotte; Csányi, Attila; Członkowska, Anna; Davis, Stephen M.; Dawson, Jesse; Klippel, Nina De; Denier, Christian; Desfontaines, Philippe; Diener, Hans‐Christoph; Diószeghy, Péter; Dippel, Diederik W.J.; Dorado, Laura; Folyovich, András; Friedrich, Maurício; Fryze, Waldemar; Gagliardi, Rubens José; Gottschal, Marianna; Grimley, Rohan; Grond, Martin; Gröschel, Klaus; Hosseini, Hassan; Hwang, Yang‐Ha; Kallmuenzer, Bernd; Khan, Usman; Kim, Jong Sung; Kleinig, Timothy; Köves, Ágnes; Martin, Aida Lago; Lasek–Bal, Anetta; Lembo, Giuseppe; Lemmens, Robin; Lindert, Ralf; Marrone, Luiz Carlos Porcello; Zabaleta, Maite Martínez; Mas, Jean‐Louis; Vallejo, J. Masjuán; Mazighi, Mikaël; Minelli, César; Mistri, Amit; Molina, Carlos A.; Álvarez, F. Moniche; Moro, Carla Heloísa Cabral; Mulleners, Wim M.; Nabavi, Darius G.; Neau, Jean‐Philippe; O’Brien, Bill; Óváry, Csaba; Pánczél, Gyula; Park, Man‐Seok; Phan, Thanh Vân; Ragab, Suzanne; Rejdak, Konrad; Freitas, Gabriel R. de; Roffe, Christine; González, Jaume Roquer; Rover, Luisa; Silva, Gisele Sampaio; Schellinger, Peter D.; Martín, Tomás Segura; Shaw, Louise; Sibon, Igor; Škoda, Ondřej; Smadja, Didier; Sobolewski, Piotr; Soda, Hassan; Sprigg, Nikola; Świat, Maciej; Szekeres, L.; Szegedi, Norbert; Toni, Danilo; Valikovics, Attila; Vanhooren, Geert; Vécsei, László; Wein, Theodore; Wong, Andrew; Carrillo, A.

doi:10.1016/s1474-4422(20)30004-1

Cited by 37 publications

(22 citation statements)

References 17 publications

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“…However, despite the positive results of our preclinical study, 14 the findings of the RESTORE BRAIN study (Randomized Efficacy and Safety Trial of Oral GABA A α5 antagonist S44819 after Recent ischemic Event) have been recently published that did not confirm a positive effect of S44819 on clinical outcomes in patients after ischemic stroke, suggesting that S44819 cannot be recommended for stroke therapy. In light of the findings of this clinical study, the results of our preclinical study assume a relevant role in determining the variables that should be considered to stratify patients and variables in a stroke recovery trial.…”

Section: Discussioncontrasting

confidence: 61%

Postacute administration of the GABA_A α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats

Pace

Falappa

Machado

et al. 2020

Clinical and Translational Neuroscience

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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 GABAA 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 GABAA α5 antagonist S44819 after Recent ischemic Event) trial, may help clinicians to design clinical studies and stratify variables and patients adequately.

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Section: Discussioncontrasting

confidence: 61%

Postacute administration of the GABA_A α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats

Pace

Falappa

Machado

et al. 2020

Clinical and Translational Neuroscience

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“…Reducing pathologically increased tonic inhibition with S44819 during early stroke led to better motor function in mice 78 , with associated increased neuronal viability, decreased peri-infarct astrogliosis, increased brain capillary density, and higher proliferation of neural precursor cells. Despite this promising evidence from preclinical studies, a recent phase II clinical trial reported no significant difference in overall post-stroke recovery after long-term administration of S44819 in early stroke compared with placebo 79 . However, the modified Rankin Scale, the primary endpoint measure, has low sensitivity, and the absence of measurement on motor-specific scales makes it hard to detect small improvements in motor functions.…”

Section: Modulating Gabaergic Inhibition In Strokementioning

confidence: 99%

Recent advances in the role of excitation–inhibition balance in motor recovery post-stroke

Grigoras¹,

Stagg²

2021

Fac Rev

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Stroke affects millions of people worldwide each year, and stroke survivors are often left with motor deficits. Current therapies to improve these functional deficits are limited, making it a priority to better understand the pathophysiology of stroke recovery and find novel adjuvant options. The excitation–inhibition balance undergoes significant changes post-stroke, and the inhibitory neurotransmitter γ-aminobutyric acid (GABA) appears to play an important role in stroke recovery. In this review, we summarise the most recent studies investigating GABAergic inhibition at different stages of stroke. We discuss the proposed role of GABA in counteracting glutamate-mediated excitotoxicity in hyperacute stroke as well as the evidence linking decreased GABAergic inhibition to increased neuronal plasticity in early stroke. Then, we discuss two types of interventions that aim to modulate the excitation–inhibition balance to improve functional outcomes in stroke survivors: non-invasive brain stimulation (NIBS) and pharmacological interventions. Finding the optimal NIBS administration or adjuvant pharmacological therapies would represent an important contribution to the currently scarce therapy options.

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“…First clinical proof-of-concept studies using strategies that promote neuronal plasticity made promising observations (Chollet et al, 2011) and demonstrated the feasibility of plasticitypromoting treatment studies. Subsequent studies identified a number of methodological pitfalls related to the selection of therapeutic targets, the use of clinical endpoints and scales, and the size of study cohorts (FOCUS Trial Collaboration, 2019;Chabriat et al, 2020;Hermann et al, 2020). With the use of adequately designed and powered studies, chances appear favorable that plasticity-promoting treatments can be translated successfully into clinics.…”

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confidence: 99%

Hot Topics in Cellular Neuropathology II: Promoting Neuronal Plasticity in the Injured Central Nervous System

Hermann

2022

Front. Cell. Neurosci.

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Safety and efficacy of GABAA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial

Cited by 37 publications

References 17 publications

Postacute administration of the GABA_A α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats

Postacute administration of the GABA_A α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats

Recent advances in the role of excitation–inhibition balance in motor recovery post-stroke

Hot Topics in Cellular Neuropathology II: Promoting Neuronal Plasticity in the Injured Central Nervous System

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Safety and efficacy of GABAA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial

Cited by 37 publications

References 17 publications

Postacute administration of the GABAA α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats

Postacute administration of the GABAA α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats

Recent advances in the role of excitation–inhibition balance in motor recovery post-stroke

Hot Topics in Cellular Neuropathology II: Promoting Neuronal Plasticity in the Injured Central Nervous System

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Postacute administration of the GABA_A α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats

Postacute administration of the GABA_A α5 antagonist S44819 promotes recovery of peripheral limb fine motor skills after permanent distal middle cerebral artery occlusion in rats