Protective Role of Low Ethanol Administration Following Ischemic Stroke via Recovery of KCC2 and p75NTR Expression

Author:

Khirug Stanislav,Soni Shetal,Saez Garcia Marta,Tessier Marine,Zhou Liang,Kulesskaya Natalia,Rauvala Heikki,Lindholm Dan,Ludwig Anastasia,Molinari Florence,Rivera ClaudioORCID

Abstract

AbstractA striking result from epidemiological studies show a correlation between low alcohol intake and lower incidence for ischemic stroke and severity of derived brain injury. Although reduced apoptosis and inflammation has been suggested to be involved, little is known about the mechanism mediating this effect in vivo. Increase in intracellular chloride concentration and derived depolarizing GABAAR-mediated transmission are common consequences following various brain injuries and are caused by the abnormal expression levels of the chloride cotransporters NKCC1 and KCC2. Downstream pro-apoptotic signaling through p75NTR may link GABAA depolarization with post-injury neuronal apoptosis. Here, we show that changes in GABAergic signaling, Cl homeostasis, and expression of chloride cotransporters in the post-traumatic mouse brain can be significantly reduced by administration of 3% ethanol to the drinking water. Ethanol-induced upregulation of KCC2 has a positive impact on neuronal survival, preserving a large part of the cortical peri-infarct zone, as well as preventing the massive post-ischemic upregulation of the pro-apoptotic protein p75NTR. Importantly, intracortical multisite in vivo recordings showed that ethanol treatment could significantly ameliorate stroke-induced reduction in cortical activity. This surprising finding discloses a pathway triggered by low concentration of ethanol as a novel therapeutically relevant target.

Funder

Academy of Finland

Agence Nationale de la Recherche

Doctoral Program in Biomedicine

Fondation des Gueules Casées

Publisher

Springer Science and Business Media LLC

Subject

Neuroscience (miscellaneous),Cellular and Molecular Neuroscience,Neurology

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