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.

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“…In this study, hippocampal pyramidal neurons had regular levels of KCC2 and did not display damage signals at 6 h post stroke, but they started to degenerate when KCC2 levels decreased at 48 h after stroke [26]. In a similar way, an acute blockage of upstream pathways inhibiting KCC2 showed an increased neuronal survival following an ischemic incident in mice [74]. Therefore, all these evidences seem to point at the upregulation of KCC2 as a therapeutic target to provide protection against stroke-induced cell death.…”

“…Contrary to what it was seen for NKCC1, the amount of KCC2 at both mRNA and protein levels was downregulated in both rat and mouse models of ischemic stroke [45,64,66,73,74]. Curiously, whereas the KCC2 levels in the plasma membrane are notably reduced 3 h post ischemia [74], there is a progressive decrease in the levels of total KCC2 given that it is significant on days 1 and 7 post stroke, but not at 2 h after injury [64].…”

“…Curiously, whereas the KCC2 levels in the plasma membrane are notably reduced 3 h post ischemia [74], there is a progressive decrease in the levels of total KCC2 given that it is significant on days 1 and 7 post stroke, but not at 2 h after injury [64]. Therefore, a relationship between a maintained expression of KCC2 overtime and the long-term survival rate of neurons has been proposed [64], which was recently supported [26,74]. In this study, hippocampal pyramidal neurons had regular levels of KCC2 and did not display damage signals at 6 h post stroke, but they started to degenerate when KCC2 levels decreased at 48 h after stroke [26].…”

Decreased spasticity of Baishaoluoshi Decoction through the BDNF/TrKB-KCC2 pathway on poststroke spasticity rats

“…chloride. Engaging GABA A R leads to an efflux of chloride into the extracellular domain, leading to neuronal excitement [28,29]. Excitatory motoneurons lead to hyper-stretch reflexes, leading to hemiplegia limb spasticity [30].…”

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“…However, whereas evidence shows a negative impact of high-dose EtOH on cellular physiology, a low dose seems to reduce the apoptotic rate. In fact, recent data suggests that a low dose of EtOH contributes to the regulation of the expression of the TNF receptor, p75NTR, and a potassium-chloride transporter (KCC2) [ 56 ]. While p75NTR is involved in the regulation of apoptosis, KCC2 regulates the cellular electrochemical gradient, and its expression is crucial to maintaining the classic hyperpolarizing GABAergic inhibition in mature adult neurons [ 56 ].…”