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Influence of Adenosine Receptor A2a Antagonist on Glutamate Transporter GLT-1 Expression in Middle Cerebral Artery Ischemia-reperfusion Injury Zone of Rats

Author: LiuBin
Tutor: ChenKangNing
School: Third Military Medical University
Course: Neurology
Keywords: Rats Middle cerebral artery occlusion (MCAO) Adenosine Adenosine A2a receptor Glutamate transporter Neuronal damage
CLC: R743.3
Type: Master's thesis
Year: 2011
Downloads: 39
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Abstract

Background: Ischemic stroke is a transient or permanent occlusion of the feeding artery of the brain, causing the blood flow of the blood supply to the area is a sharp decline in the emergence of a serious illness corresponding neurological deficits, morbidity up to 250-400/10 000, the mortality rate is about 30% of the survivors more than left with a permanent disability, serious threat to human health. Unfortunately, no effective treatment of cerebral protection measures for ischemic stroke. Theoretically calcium antagonist drugs such protective effect of ischemic brain damage, but are ineffective in clinical applications. Therefore necessary to explore new brain protective pathway. Adenosine (adenosine, ADO) is a the organism metabolic process intermediates, is also an important signaling molecules. It does this by binding to different receptors on nerve cells, regulating a number of important physiological processes. Physiological state of adenosine receptors is moderate the adenosine activation, play an important role in sleep and arousal, cognition and memory, movement, mood. Has been found that the adenosine receptor include the A ₁ R, A _2a R, A _2b R and A _{3 R four subtypes. These four receptors belong to the G protein coupled receptor family. Wherein A ₁ R, A _2a R for high expression of receptors, the lower concentration of ADO can be activated to produce a biological effect. But such as in ischemia, hypoxia, trauma, excessive neurons discharge metabolic disorder. The large releases ADO will be aggravated by activating adenosine receptors of excitatory amino acids (excitatory amino acids, EAAs) are caused by brain damage. The study also found that the reduced Glu release} R A _{1 is activated and the the Glu release of A _2a R increase. Therefore, release of Glu for its function in a certain extent, by the regulation of adenosine and its receptor. The study found that blocking A _2a R cerebral ischemia have neuroprotective effects, can reduce the volume of cerebral infarction, neurological improvement. Speculate and preliminary evidence of blocking A _2a R protective effect of ischemic neuronal injury may be related to the inhibition of Glu release. Our group preliminary study found that blocking adenosine A _2a R, in cerebral ischemia District extracellular glutamate levels significantly lower than the control group, but has not been elucidated lead extracellular glutamate accumulation The reduction mechanism and the possible link. Glutamate transporter 1 (GLT-1) in the central nervous system, is widely distributed in glial cells, and bear 90% of the glutamate transporter task. Studies have found that, A _2a R activated glial cells can inhibit the function of GLT-1 transporter glutamate. Therefore, we speculated that blocking A _2a R produced ischemic neuroprotective effect may be enhanced accelerated glutamate transporter GLT-1 functions in hand, reducing extracellular glutamate accumulation related. Objective: to middle cerebral artery occlusion model (Middle cerebral artery occlusion, MCAO) as the research object, observe the A _2a R antagonist the adenosine A _2a R on middle cerebral artery ischemia / reperfusion infarct volume and neurological score and striatum area of ??GLT-1 expression. A _2a R generated neuroprotective mechanisms to reveal blocking administration for further clinical studies to select the timing and target of the foundation. Method: to be improved according to the the longa proposed reversible MCAO suture method of focal cerebral ischemia and reperfusion model. Respectively in male SD rat brain ischemia 2h ischemia 2h / reperfusion 22h two time points adenosine receptor A _2a antagonist SCH-58261 (selective adenosine receptor A < sub> 2a} antagonist), was observed after the rats neurological deficit and infarct volume. And RT-PCR, WB the method detection striatum area of ??GLT-1 expression. Results: (1) neurological deficit scores: ischemic 2h control group score 2.33 ± 0.52, ischemia 2h intervention group, 2.67 ± 0.52, there was no significant difference between; ischemia 2h / reperfusion 22h control group score 2.50 ± 0.55, missing blood 2h / reperfusion 22h intervention group was 1.67 ± 0.52, significant differences (P lt; 0.05); ischemia 2h / reperfusion 22h intervention group scores were significantly lower than the ischemic of 2h intervention group. (2) the volume of cerebral infarction estimates: ischemic 2h / reperfusion 22h infarct volume was significantly greater than the infarct volume of ischemic 2h; infarct volume of the intervention group were less than the ischemic control group. Ischemic infarct volume (23.63 ± 3.89 mm ^{3 ) 2h intervention group than the control group (28.26 ± 2.48 mm ^{3 ) reduced by 16%, a significant difference (P lt ; 0.05). Ischemia 2h / reperfusion the 22h intervention group, infarct volume (95.12 ± 18.22 mm ^{3 ) than the control group (141.80 ± 27.64 mm ^{3 ) 33% reduction in both There were significant differences (P lt; 0.01). (3) GLT-1 immunofluorescence observed: FITC-labeled immunofluorescence method combined with laser confocal microscope the rat striatum District GLT-1 general distribution. Observed GLT-1 positive signals were located in the membrane of nerve cells. GLT-1 protein content in rat striatum (4) GLT-1 Western Blot observed: compared with ischemic control group and normal control group, the intervention group were significantly increased (p lt; 0.01). Compared with normal control, ischemia 2h control group of GLT-1 protein content decreased significantly (p lt; 0.05), and ischemic 2h / reperfusion the 22h control group GLT-1 instead somewhat elevated (p lt; 0.05) . (5) GLT-1 mRNA RT-PCR observation: compared with ischemic control group and normal control group, SCH-58261 significantly increased GLT-1 mRNA expression in ischemic rat striatum (p lt; 0.01). Compared with the normal control group, GLT-1 expression in both ischemic control group decreased (p lt; 0.05), which is particularly evident ischemia 2h. Conclusion: The results suggest that cerebral ischemia induced neuronal damage; adenosine receptor A2a antagonist SCH-58261 can reduce cerebral ischemia / reperfusion infarct volume, and improvement of ischemic rat nerve function; adenosine receptors A2a antagonist SCH-58261 may improve cerebral ischemia / reperfusion result in the expression of GLT-1 decreased; suggesting that cerebral ischemia / reperfusion adenosine receptor A2a involved in neuronal injury in may be the mechanism involved in the GTL-1 expression.}}}}

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