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

Abstract

A 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.

• Authors: Stanislav Khirug, Shetal Soni, Marta Saez Garcia, Marine Tessier, Liang Zhou, Natalia Kulesskaya, Heikki Rauvala, Dan Lindholm, Anastasia Ludwig, Florence Molinari, Claudio Rivera
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 58 Issue 3 Pg. 1145-1161 (Mar 2021) ISSN: 1559-1182 [Electronic] United States
• PMID: 33099743 (Publication Type: Journal Article)

Chemical References

• Biomarkers
• Chlorides
• Neuroprotective Agents
• Receptors, Nerve Growth Factor
• Symporters
• Ethanol
• gamma-Aminobutyric Acid

Topics

• Animals
• Apoptosis (drug effects)
• Biological Transport (drug effects)
• Biomarkers (metabolism)
• Brain Infarction (complications, pathology, physiopathology)
• Cell Survival (drug effects)
• Chlorides (metabolism)
• Diet
• Electrophysiological Phenomena (drug effects)
• Ethanol (administration & dosage)
• Inflammation (complications, pathology, physiopathology)
• Ischemic Stroke (drug therapy, metabolism)
• Male
• Mice, Inbred C57BL
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Receptors, Nerve Growth Factor (metabolism)
• Recovery of Function (drug effects)
• Symporters (metabolism)
• Time Factors
• gamma-Aminobutyric Acid (metabolism)
• K Cl- Cotransporters
• Mice