Talampanel, a novel noncompetitive AMPA antagonist, is neuroprotective after traumatic brain injury in rats
Talampanel, a novel noncompetitive AMPA antagonist, is neuroprotective after traumatic brain injury in rats
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DOI：
10.1089/08977150152693728
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发表时间：
2001-10-01
影响因子：
4.2
通讯作者：
Busto, R
中科院分区：
文献类型：
--
作者：
Belayev, L;Alonso, OF;Busto, R
Talampanel {(R)-7-乙酰基-5-(4-氨基苯基)-8,9-二氢-8-甲基-7H-1,3-二氧杂环[4,5-h][2,3]苯二氮卓}是一种口服活性的谷氨酸兴奋性氨基酸受体 AMPA 亚型的非竞争性拮抗剂。本研究的目的是确定用他仑帕奈治疗是否能对大鼠创伤性脑损伤（TBI）模型起到保护作用。 TBI 前 24 小时，将流体冲击界面置于右侧大脑皮层旁矢状面。第二天，将禁食的大鼠用3%氟烷、70%一氧化二氮和平衡氧气麻醉；机械通气和生理调节；并遭受右顶枕部矢状旁液体撞击损伤（1.5-2.0 atm）。静脉内施用药剂（他仑帕奈，推注 4 mg/kg，然后在 72 小时内以 4 mg/kg/h 的速度输注）或载体。从创伤后 30 分钟或 3 小时开始。 TBI 后 7 天，对大脑进行灌注固定，将各个层面的冠状切片数字化，并测量挫伤面积。与媒介物治疗的大鼠相比，在创伤后30分钟开始使用talampanel治疗时，总挫伤面积显着减少（分别为0.54 +/- 0.25 vs. 1.79 +/- 0.42 mm(2)）。当 3 小时开始 talampanel 治疗时，药物的神经保护作用消失。此外，与媒介物治疗的大鼠相比，从 30 分钟开始使用 talampanel 治疗可显着减轻海马 CAI 部分所有三个亚区的神经元损伤（正常神经元计数，右侧（同侧）内侧 CAI：80.3 +/- 2.0 [talampanel] 对比 66.3 +/- 2.1 [媒介物]（平均 SEM）；中间 CAI：71.5 +/- 2.0 与 60.3 +/- 2.2；横向 CAI：分别为 74.5 +/- 3.0 与 63.0 +/- 3.2。相比之下，当 3 小时开始 talampanel 治疗时，两组的正常锥体神经元计数几乎相同。我们的研究结果证明，创伤后 30 分钟开始进行的 talampanel 疗法可显着减少组织学损伤。
Talampanel {(R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo[4,5-h][2,3] benzodiazepine} is an orally active noncompetitive antagonist of the AMPA subtype of glutamate excitatory amino acid receptors. The purpose of this study was to determine whether treatment with talampanel would protect in a rat model of traumatic brain injury (TBI). Twenty-four hours prior to TBI, a fluid-percussion interface was positioned parasagittally over the right cerebral cortex. On the following day, fasted rats were anesthetized with 3% halothane, 70% nitrous oxide, and a balance of oxygen; mechanically ventilated and physiologically regulated; and subjected to right parieto-occipital parasagittal fluid-percussion injury (1.5-2.0 atm). The agent (talampanel, bolus infusion of 4 mg/kg followed by infusion of 4 mg/kg/h over 72 h) or vehicle was administered i.v. starting at either 30 min or 3 h after trauma. Seven days after TBI, brains were perfusion-fixed, coronal sections at various levels were digitized, and contusion areas were measured. Treatment with talampanel, when instituted 30 min after trauma, significantly reduced total contusion area compared to vehicle-treated rats (0.54 +/- 0.25 vs. 1.79 +/- 0.42 mm(2), respectively). When talampanel treatment was begun at 3 h, the neuroprotective effect of the drug was lost. In addition, treatment with talampanel starting at 30 min significantly attenuated neuronal damage in all three subsectors of the hippocampal CAI sector compared to vehicle-treated rats (normal-neuron counts, right (ipsilateral) medial CAI: 80.3 +/- 2.0 [talampanel] vs. 66.3 +/- 2.1 [vehicle] (mean SEM); middle CAI: 71.5 +/- 2.0 vs. 60.3 +/- 2.2; lateral CAI: 74.5 +/- 3.0 vs. 63.0 +/- 3.2, respectively). By contrast, when talampanel treatment was begun at 3 h, normal pyramidal-neuron counts were almost identical in both groups. Our findings document that talampanel therapy instituted 30 min after trauma significantly reduces histological damage.