The gliopeptide ODN, a ligand for the benzodiazepine site of GABAA receptors, boosts functional recovery after stroke

Rhita Lamtahri, Mahmoud Hazime, Emma K. Gowing, Raghavendra Y. Nagaraja, Julie Maucotel, Michael Alasoadura, Pascale P. Quilichini, Katia Lehongre, Benjamin Lefranc, Katarzyna Gach-Janczak, Ann Britt Marcher, Susanne Mandrup, David Vaudry, Andrew N. Clarkson, Jérôme Leprince, Julien Chuquet*

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Abstrakt

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 (GABA ARs). Conversely, in the late phase, negative allosteric modulation of GABA AR can correct the suboptimal excitability and improves both sensory and motor recovery. Here, we hypothesized that octadecaneuropeptide (ODN), an endogenous allosteric modulator of the GABA AR 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.

OriginalsprogEngelsk
TidsskriftJournal of Neuroscience
Vol/bind41
Udgave nummer33
Sider (fra-til)7148-7159
ISSN0270-6474
DOI
StatusUdgivet - 18. aug. 2021

Bibliografisk note

Funding Information:
This work was supported by Institut National de la Santé et de la Recherche Médicale U1239; Fondation AVC sous égide de la Fondation pour la Recherche Médicale et ses partenaires, Grant FRAVC1180713009 to J.C., Normandy Region and the European Union; Europe gets involved in Normandy with European Regional Development Fund, a Grant Interreg TC2N to D.V.; New Zealand Neurological Foundation; Royal Society of New Zealand Project Grant; Ministry of Business, Innovation and Employment, New Zealand; Brain Research New Zealand animal costs; and New Zealand Lottery Health equipment grant. We thank Dr Arnaud Arabo who provided help and expertise that greatly assisted the research. pA.N.C., J.L., and J.C. contributed equally to this work. The authors declare no competing financial interests. Correspondence should be addressed to Julien Chuquet at julien.chuquet@univ-rouen.fr. https://doi.org/10.1523/JNEUROSCI.2255-20.2021 Copyright © 2021 the authors

Publisher Copyright:
Copyright © 2021 the authors

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