Activation of Glutamate Transporter-1 (GLT-1) Confers Sex-Dependent Neuroprotection in Brain Ischemia.

Flavia A Tejeda-Bayron,Serguei N Skatchkov,Gerónimo Maldonado-Martínez,Héctor M Maldonado,David E Rivera-Aponte,Misty J Eaton,Christian J Malpica-Nieves

doi:10.3390/brainsci11010076

Flavia A Tejeda-Bayron, Serguei N Skatchkov + Show 5 more

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https://doi.org/10.3390/brainsci11010076

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Abstract

Stroke is one of the leading causes of long-term disability. During ischemic stroke, glutamate is released, reuptake processes are impaired, and glutamate promotes excitotoxic neuronal death. Astrocytic glutamate transporter 1 (GLT-1) is the major transporter responsible for removing excess glutamate from the extracellular space. A translational activator of GLT-1, LDN/OSU 0212320 (LDN) has been previously developed with beneficial outcomes in epileptic animal models but has never been tested as a potential therapeutic for ischemic strokes. The present study evaluated the effects of LDN on stroke-associated brain injury. Male and female mice received LDN or vehicle 24 h before or 2 h after focal ischemia was induced in the sensorimotor cortex. Sensorimotor performance was determined using the Rung Ladder Walk and infarct area was assessed using triphenyltetrazolium chloride staining. Males treated with LDN exhibited upregulated GLT-1 protein levels, significantly smaller infarct size, and displayed better sensorimotor performance in comparison to those treated with vehicle only. In contrast, there was no upregulation of GLT-1 protein levels and no difference in infarct size or sensorimotor performance between vehicle- and LDN-treated females. Taken together, our results indicate that the GLT-1 translational activator LDN improved stroke outcomes in young adult male, but not female mice.

Highlights

Stroke is the fifth-leading cause of death in the United States and ranks as one of the leading causes of long-term disability [1]
This study aims to evaluate the effects of upregulating glutamate transporter 1 (GLT-1) with LDN-OSU 0232120 (LDN) as a potential therapeutic for ischemic stroke
We found that post-transcriptional upregulation of GLT-1 with LDN correlates with decreases in infarct size and improvements in sensorimotor performance after focal ischemia in young adult male mice

Summary

Introduction

Stroke is the fifth-leading cause of death in the United States and ranks as one of the leading causes of long-term disability [1]. Ischemic stroke results when an arterial blockage causes interruption of the flow of nutrients and oxygen to an area of the brain. Cells fail to generate sufficient ATP, resulting in energy failure that leads to loss of ionic gradients and dysregulation of neurotransmitter release [2]. Glutamate is released, reuptake processes are impaired, and glutamate binds to its postsynaptic receptors and promotes excitotoxic neuronal death after an ischemic insult [3]. For many years, astrocytes were considered support cells with limited structural roles to the neurons. The wide range of roles astrocytes play has

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