Neuroprotective action of halogenated derivatives of L-phenylalanine
Neuroprotective action of halogenated derivatives of L-phenylalanine
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DOI：
10.1161/01.str.0000125722.10606.07
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发表时间：
2004-05-01
期刊：
影响因子：
8.3
通讯作者：
Martynyuk, AE
中科院分区：
文献类型：
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作者：
Kagiyama, T;Glushakov, AV;Martynyuk, AE
芳香族氨基酸L-苯丙氨酸（L-Phe）通过一套独特的突触前和突触后机制显著且可逆地抑制兴奋性突触能传递（GST）。因此，我们假设，内源性衍生物的L-苯丙氨酸，这显示出有效的抗谷氨酸能活性，可能会安全和有效地保护大脑的条件下，其特征在于过度激活的谷氨酸receptors. Methods-我们测试了这一假设在体外与组合的膜片钳和乳酸脱氢酶（LDH）的分析，在大鼠培养的神经元暴露于模拟缺血，结果L-苯丙氨酸的卤代衍生物3，5-二碘-L-酪氨酸（DIT）和3，5-二溴-L-酪氨酸（DBrT）对GST的抑制作用与L-苯丙氨酸相似，但作用更强。例如，DIT和DBrT抑制α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）/红藻氨酸受体介导的mEPSC频率的IC 50分别为104.6+/-14.1 mumol/L和127.5+/-13.3 mumol/L。在能量剥夺期间，DIT和DBrT对GST的抑制持续存在。此外，DBrT显着减少LDH释放神经元培养暴露于氧葡萄糖剥夺。在短暂MCAO大鼠中，DBrT使脑梗死体积和神经功能缺损评分分别降低至对照值的52.7+/-14.1%和57.1+/-12.0%。DBrT既不改变房室结和心室内传导在离体心脏，也没有心率和血压在vivo.Conclusion-DBrT，内源性卤代衍生物的L-苯丙氨酸，显示出作为一类新的神经保护剂的代表，通过发挥显着的神经保护作用在体外和体内模型的脑缺血的承诺。
Background and Purpose-The aromatic amino acid L-Phenylalanine (L-Phe) significantly and reversibly depresses excitatory glutamatergic synaptic transmission (GST) via a unique set of presynaptic and postsynaptic mechanisms. Therefore, we hypothesized that endogenous derivatives of L-Phe, which display potent antiglutamatergic activity, may safely and efficaciously protect the brain during conditions characterized by overactivation of glutamate receptors.Methods-We tested this hypothesis in vitro with a combination of patch-clamp and lactate dehydrogenase (LDH) analyses in rat cultured neurons exposed to simulated ischemia, and in vivo using a rat model of experimental stroke caused by transient middle cerebral artery occlusion (MCAO).Results-3,5-diiodo-L-tyrosine (DIT) and 3,5-dibromo-L-tyrosine (DBrT), endogenous halogenated derivatives of L-Phe, attenuated GST by similar mechanisms as L-Phe, but with greater potency. For example, the IC50s for DIT and DBrT to depress the frequency of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor-mediated mEPSCs were 104.6+/-14.1 mumol/L and 127.5+/-13.3 mumol/L, respectively. Depression of GST by DIT and DBrT persisted during energy deprivation. Furthermore, DBrT significantly reduced LDH release in neuronal cultures exposed to oxygen glucose deprivation. In rats subjected to transient MCAO, DBrT decreased the brain infarct volume and neurological deficit score to 52.7+/-14.1% and 57.1+/-12.0% of control values, respectively. DBrT neither altered atrioventricular nodal and intraventricular conduction in isolated heart, nor heart rate and blood pressure in vivo.Conclusion-DBrT, an endogenous halogenated derivative of L-Phe, shows promise as a representative of a novel class of neuroprotective agents by exerting significant neuroprotection in both in vitro and in vivo models of brain ischemia.