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首页> 外文期刊>The European Journal of Neuroscience >In vitro and invivo effects of a novel dimeric inhibitor of PSD-95 on excitotoxicity and functional recovery after experimental traumatic brain injury
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In vitro and invivo effects of a novel dimeric inhibitor of PSD-95 on excitotoxicity and functional recovery after experimental traumatic brain injury

机译：在实验创伤脑损伤后，PSD-95新型二聚体抑制剂对PSD-95的微细抑制剂的体外和Invivo效应

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PSD-95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury (TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a novel dimeric inhibitor of PSD-95, UCCB01-147, on histopathology and long-term cognitive outcome after controlled cortical impact (CCI) in rats. As excitotoxic cell death is thought to be a prominent part of the pathophysiology of TBI, we also investigated the neuroprotective effects of UCCB01-147 and related compounds on NMDA-induced cell death in cultured cortical neurons. Anesthetized rats were given a CCI or sham injury, and were randomized to receive an injection of either UCCB01-147 (10mg/kg), the non-competitive NMDAR-receptor antagonist MK-801 (1mg/kg) or saline immediately after injury. At 2 and 4weeks post-trauma, spatial learning and memory were assessed in a water maze, and at 3months, brains were removed for estimation of lesion volumes. Overall, neither treatment with UCCB01-147 nor MK-801 resulted in significant improvements of cognition and histopathology after CCI. Although MK-801 provided robust neuroprotection against NMDA-induced toxicity in cultured cortical neurons, UCCB01-147 failed to reduce cell death and became neurotoxic at high doses. The data suggest potential differential effects of PSD-95 inhibition in stroke and TBI that should be investigated further in future studies taking important experimental factors such as timing of treatment, dosage, and anesthesia into consideration.
机译：PSD-95抑制剂已被证明是中风的神经保护，但仅在治疗具有与中风共同的病理生理机制的创伤性脑损伤（TBI）中进行了非常有限的程度。目前研究的目的是评估PSD-95，UCCB01-147的新型二聚体抑制剂对大鼠控制皮质撞击（CCI）后的组织病理学和长期认知结果的影响。由于兴奋毒性细胞死亡被认为是TBI病理生理学的突出部分，我们还研究了UCCB01-147和相关化合物在培养的皮质神经元中对NMDA诱导的细胞死亡的神经保护作用。将麻醉的大鼠赋予CCI或假损伤，并随机地接受损伤后立即注射UCCB01-147（10mg / kg），不竞争性的NMDAR受体拮抗剂MK-801（1mg / kg）或盐水。在2和4周的后创伤后，在水迷宫中评估空间学习和记忆，并在3个月，除去脑袋以估计病变量。总的来说，UCCB01-147和MK-801的治疗既不导致CCI后认知和组织病理学的显着改善。尽管MK-801在培养的皮质神经元中提供了针对NMDA诱导的毒性的强大神经保护，但UCCB01-147未能减少细胞死亡，并且在高剂量下成为神经毒性。该数据表明PSD-95抑制在中风和TBI中的潜在差异效应，在未来的研究中应该进一步研究，以考虑到治疗，用量和麻醉时的重要实验因素。

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