Abstract
Voltage-dependent anion channel (VDAC) is the main protein in mitochondria-mediated apoptosis, and the modulation of VDAC may be induced by the excessive release of extracellular glutamate. This study examined the role of glutamate release on VDAC-mediated apoptosis in an eleven vessel occlusion model in rats. Male Sprague-Dawley rats (250–350 g) were used for the 11 vessel occlusion ischemic model, which were induced for a 10-min transient occlusion. During the ischemic and initial reperfusion episode, the real-time monitoring of the extracellular glutamate concentration was measured using an amperometric microdialysis biosensor and the cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry. To confirm neuronal apoptosis, the brains were removed 72 h after ischemia to detect the neuron-specific nuclear protein and pro-apoptotic proteins (cleaved caspase-3, VDAC, p53 and BAX). The changes in the mitochondrial morphology were measured by atomic force microscopy. A decrease in the % of CBF was observed, and an increase in glutamate release was detected after the onset of ischemia, which continued to increase during the ischemic period. A significantly higher level of glutamate release was observed in the ischemia group. The increased glutamate levels in the ischemia group resulted in the activation of VDAC and pro-apoptotic proteins in the hippocampus with morphological alterations to the mitochondria. This study suggests that an increase in glutamate release promotes VDAC-mediated apoptosis in an 11 vessel occlusion ischemic model.
Highlights
Brain ischemia is a condition where there is insufficient cerebral blood flow (CBF), leading to a poor oxygen supply or cerebral hypoxia, which can cause the death of brain tissue, a cerebral infarction and a loss of brain function [1]
Since the CBF is an important factor in the activation of glutamate release for cerebral brain ischemia, this study examined whether a consistently decreased CBF stimulates the release of glutamate to induce brain ischemia in an 11VO model
An increase in the level of glutamate release was observed from 114.9620.2 s after the onset of ischemia with a dramatic increase occurring throughout the entire ischemic period in both groups (Table 1)
Summary
Brain ischemia is a condition where there is insufficient cerebral blood flow (CBF), leading to a poor oxygen supply or cerebral hypoxia, which can cause the death of brain tissue, a cerebral infarction and a loss of brain function [1]. Glutamate is the principal excitatory neurotransmitter in the brain and the excessive release of extracellular glutamate is a key factor that promotes neuronal cell death [3,4]. An understanding of the excitotoxic process is needed through accurate real-time measurements of the changes in the extracellular glutamate concentration during and after a range of insults that might initiate neuronal damage [5]. Measurements of neurotransmitters, the release of glutamate, using microdialysis have been developed for in vivo analysis with continuous monitoring. Due to the successful application of real time in vivo monitoring of glutamate using amperometirc biosensor technology [6], a previous study reported the real-time electronic detection of the extracellular glutamate levels in a global ischemia model using either microdialysis [7] or enzyme-immobilized carbon nanotube-field effect transistor (CNT-FET) [8]
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