1. The Gliopeptide ODN, a Ligand for the Benzodiazepine Site of GABA A Receptors, Boosts Functional Recovery after Stroke.
- Author
-
Lamtahri R, Hazime M, Gowing EK, Nagaraja RY, Maucotel J, Alasoadura M, Quilichini PP, Lehongre K, Lefranc B, Gach-Janczak K, Marcher AB, Mandrup S, Vaudry D, Clarkson AN, Leprince J, and Chuquet J
- Subjects
- Adult, Animals, Astrocytes metabolism, Cortical Spreading Depression physiology, Diazepam Binding Inhibitor deficiency, Diazepam Binding Inhibitor physiology, Drug Implants, Evoked Potentials, Somatosensory, Female, GABA-A Receptor Agonists pharmacology, Humans, Hydrogels, Infarction, Middle Cerebral Artery drug therapy, Intracranial Thrombosis drug therapy, Intracranial Thrombosis etiology, Light, Mice, Mice, Inbred C57BL, N-Methylaspartate toxicity, Neurons physiology, Neuropeptides deficiency, Neuropeptides physiology, Patch-Clamp Techniques, Peptide Fragments deficiency, Peptide Fragments physiology, Rats, Rose Bengal radiation effects, Rose Bengal toxicity, Single-Blind Method, Stroke etiology, Diazepam Binding Inhibitor therapeutic use, GABA-A Receptor Agonists therapeutic use, Neurons drug effects, Neuropeptides therapeutic use, Peptide Fragments therapeutic use, Receptors, GABA-A drug effects, Stroke drug therapy
- Abstract
Following stroke, the survival of neurons and their ability to reestablish connections is critical to functional recovery. This is strongly influenced by the balance between neuronal excitation and inhibition. In the acute phase of experimental stroke, lethal hyperexcitability can be attenuated by positive allosteric modulation of GABA
A receptors (GABAA Rs). Conversely, in the late phase, negative allosteric modulation of GABAA R can correct the suboptimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABAA R synthesized by astrocytes, influences the outcome of ischemic brain tissue and subsequent functional recovery. We show that ODN boosts the excitability of cortical neurons, which makes it deleterious in the acute phase of stroke. However, if delivered after day 3, ODN is safe and improves motor recovery over the following month in two different paradigms of experimental stroke in mice. Furthermore, we bring evidence that, during the subacute period after stroke, the repairing cortex can be treated with ODN by means of a single hydrogel deposit into the stroke cavity. SIGNIFICANCE STATEMENT Stroke remains a devastating clinical challenge because there is no efficient therapy to either minimize neuronal death with neuroprotective drugs or to enhance spontaneous recovery with neurorepair drugs. Around the brain damage, the peri-infarct cortex can be viewed as a reservoir of plasticity. However, the potential of wiring new circuits in these areas is restrained by a chronic excess of GABAergic inhibition. Here we show that an astrocyte-derived peptide, can be used as a delayed treatment, to safely correct cortical excitability and facilitate sensorimotor recovery after stroke., (Copyright © 2021 the authors.)- Published
- 2021
- Full Text
- View/download PDF