afizagabar (S44819) / Servier - LARVOL DELTA

Restoration of Extrasynaptic/Synaptic GABAAR-α5 Localization Improves Sevoflurane-Induced Early Memory Impairment in Aged Mice. (PubMed, Neurosci Bull) - "Acute treatment with the selective extrasynaptic GABAAR-α5 antagonist S44819 restored the GABAAR-α5-mediated inhibitory currents by reversing radixin phosphorylation-dependent GABAAR-α5 re-localization, then improved the sevoflurane-induced spatial memory impairment in aged mice. Our results suggest that the localization of GABAAR-α5 altered by sevoflurane is linked to unbalanced GABAergic transmission, which induces early memory impairment in aged mice. Modulating the GABAAR-α5 localization might be a novel strategy to improve memory after sevoflurane exposure."

Journal • Preclinical • Alzheimer's Disease • Anesthesia • CNS Disorders • RDX

Novel GABAAR antagonists target networked gene hubs at the leading-edge in high-grade gliomas. (PubMed, Neuro Oncol) - "Our co-expression network analysis identified key ion channels at the leading-edge in HGGs, which can be targeted by GABAAR-acting drugs to disrupt tumor progression."

Journal • Brain Cancer • Diffuse Midline Glioma • Glioblastoma • Glioma • High Grade Glioma • Oncology • Solid Tumor

Sevoflurane Induces Spatial Memory Impairment in Aged Mice via Promoting GABAAR-α5 Extrasynaptic Distribution (ASA 2024) - "Some mice were treated with selecitve extrasynaptic GABAAR-α5 antagonist S44819 (3mg/kg, i.p.), or vehicle following the sevoflurane, and 30 min before the start of the morris water maze test. Extrasynaptic GABAAR-α5 distribution enrichment was involved in the occurrence of sevoflurane-induced spatial memory deficits, which may be mediated by the increased phosphorylation of radixin."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • RDX

The Case for Clinical Trials with Novel GABAergic Drugs in Diabetes Mellitus and Obesity. (PubMed, Life (Basel)) - "Potential therapeutic benefits could be achieved (i) By resetting the hypoglycemic counter-regulatory response; (ii) Through trophic actions on pancreatic islets, (iii) By the mobilization of antioxidant defence mechanisms in the brain. Furthermore, preclinical proof-of-concept work, as well as clinical trials that apply the novel GABA compounds in eating disorders, e.g., olanzapine-induced weight-gain, also appear warranted."

Journal • Cardiovascular • CNS Disorders • Cognitive Disorders • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Psychiatry • Schizophrenia

Post-acute delivery of α5-GABAA antagonist, S 44819, improves functional recovery in juvenile rats following stroke. (PubMed, Exp Neurol) - "Grip-test data analysis reveals that rats treated with S 44819 at the dose of 3 mg/kg displayed a better recovery on day 9 and day 16. These results are in agreement with those previously observed in adult rats, demonstrating that targeting α5-GABAA receptors improves neurological recovery after stroke in juvenile rats."

Journal • Preclinical • Cardiovascular • Ischemic stroke

Safety and efficacy of GABA α5 antagonist S44819 in patients with ischaemic stroke: a multicentre, double-blind, randomised, placebo-controlled trial. (PubMed, Lancet Neurol) - P2 | "There was no evidence that S44819 improved clinical outcome in patients after ischaemic stroke, and thus S44819 cannot be recommended for stroke therapy. The concept of tonic inhibition after stroke should be re-evaluated in humans."

Clinical • Journal • Cardiovascular • Reperfusion Injury

Randomized Efficacy and Safety Trial with Oral S 44819 after Recent ischemic cerebral Event (RESTORE BRAIN study): a placebo controlled phase II study. (PubMed, Trials) - P2; "The RESTORE BRAIN study might represent the first proof of concept study of an innovative therapeutic approach that is primarily based on enhancing functional recovery after IS."

Clinical • Journal • P2 data