Novel diketopiperazine enhances motor and cognitive recovery after traumatic brain injury in rats and shows neuroprotection in vitro and in vivo
Novel diketopiperazine enhances motor and cognitive recovery after traumatic brain injury in rats and shows neuroprotection in vitro and in vivo
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DOI：
10.1097/01.wcb.0000046143.31247.fd
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发表时间：
2003-03-01
影响因子：
6.3
通讯作者：
Kozikowski, AP
中科院分区：
文献类型：
--
作者：
Faden, AI;Knoblach, SM;Kozikowski, AP
作者开发了一种新型二酮哌嗪，在多种体外模型以及大鼠创伤性脑损伤 (TBI) 的临床相关实验模型中显示出神经保护活性。 1-ARA-35b (35b)（一种衍生自改良促甲状腺激素释放激素 (TRH) 类似物的环化二肽）治疗可显着减少神经胶质细胞共培养物中与坏死（麦毒毒素）、细胞凋亡（十字孢菌素）或机械损伤相关的细胞死亡。与媒介物处理的对照组相比，遭受侧向液体冲击诱导的 TBI 并随后在创伤后 35 分钟静脉注射 1 mg/kg 35b 的大鼠显示运动恢复和空间学习显着改善。磁共振成像显示，治疗还显着减少了病变体积，并减少了同侧海马中观察到的 TUNEL 阳性神经元的数量。与TRH或传统TRH类似物不同，35b治疗不会改变平均动脉压、体温或促甲状腺激素释放，并且没有兴奋活性。此外，与 TRH 或典型的 TRH 类似物相比，TBI 后施用 35b 不会改变游离镁浓度或细胞生物能状态。受体结合研究表明，35b 对 50 种经典受体、通道或转运蛋白不具有高亲和力。因此，35b没有表现出与TRH相关的任何典型生理作用，但在体内和体外具有神经保护作用，并且似乎可以减弱坏死性和凋亡性细胞死亡。
The authors developed a novel diketopiperazine that shows neuroprotective activity in a variety of in vitro models, as well as in a clinically relevant experimental model of traumatic brain injury (TBI) in rats. Treatment with 1-ARA-35b (35b), a cyclized dipeptide derived from a modified thyrotropin-releasing hormone (TRH) analog, significantly reduced cell death associated with necrosis (maitotoxin), apoptosis (staurosporine), or mechanical injury in neuronalglial cocultures. Rats subjected to lateral fluid percussion-induced TBI and then treated with 1 mg/kg intravenous 35b thirty minutes after trauma showed significantly improved motor recovery and spatial learning compared with vehicle-treated controls. Treatment also significantly reduced lesion volumes as shown by magnetic resonance imaging, and decreased the number of TUNEL-positive neurons observed in ipsilateral hippocampus. Unlike TRH or traditional TRH analogs, 35b treatment did not change mean arterial pressure, body temperature, or thyroid- stimulating hormone release, and did not have analeptic activity. Moreover, in contrast to TRH or typical TRH analogs, 35b administration after TBI did not alter free-magnesium concentration or cellular bioenergetic state. Receptor-binding studies showed that 35b did not act with high affinity at 50 classical receptors, channels, or transporters. Thus, 35b shows none of the typical physiologic actions associated with TRH, but possesses neuroprotective actions in vivo and in vitro, and appears to attenuate both necrotic and apoptotic cell death.