The Gliopeptide ODN, a Ligand for the Benzodiazepine Site of GABA A Receptors, Boosts Functional Recovery after Stroke - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Journal of Neuroscience Année : 2021

The Gliopeptide ODN, a Ligand for the Benzodiazepine Site of GABA A Receptors, Boosts Functional Recovery after Stroke

Résumé

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

Domaines

Neurosciences
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Dates et versions

hal-03596716 , version 1 (07-03-2022)

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Rhita Lamtahri, Mahmoud Hazime, Emma Gowing, Raghavendra Nagaraja, Julie Maucotel, et al.. The Gliopeptide ODN, a Ligand for the Benzodiazepine Site of GABA A Receptors, Boosts Functional Recovery after Stroke. Journal of Neuroscience, 2021, 41 (33), pp.7148-7159. ⟨10.1523/JNEUROSCI.2255-20.2021⟩. ⟨hal-03596716⟩
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