Neuroprotection by inhibition of the postsynaptic density protein 95 (PSD95)

自从我开始在Universitätsmedizin美因茨医院的神经外科实习以来，我一直是Keric博士神经血管研究团队的一名研究员。计划在Krembil研究所的研究奖学金为我提供了获得新经验和深化实验方法的机会，这将是在神经血管领域康复的重要一步。Tymianski博士的研究团队专注于神经保护领域，并发表了多项关于神经毒性机制和抑制导致细胞死亡的信号通路的高影响力研究。实验研究证明了高质量的研究和良好的实验室基础设施。Tymianski等人开发了一种名为Nerinetide的突触后密度蛋白95抑制剂，它可以阻断过度刺激的NMDA受体对一氧化氮（NO）合酶的激活。因此，Nerinetide阻止了NO的兴奋毒性浓度的产生和由此产生的神经毒性。该小组已经在老鼠和猕猴的体内研究中展示了令人鼓舞的结果。随后的随机、对照、多中心、双盲研究ESCAPE-NA1证明了奈利肽治疗卒中患者有更好的功能结局和更小的缺血体积。然而，当PSD95抑制剂与阿替普酶等溶解性药物同时使用时，效果有所降低。rtPA激活纤溶蛋白导致血栓溶解，但同时也导致PSD95抑制剂的快速降解。然而，溶栓是脑卒中患者治疗中必不可少的一步。这就是为什么开发耐纤溶酶的奈奈肽变种很重要。因此，抗纤溶酶PSD95抑制剂的神经保护作用结合溶栓的益处可能会改善受影响患者的临床结果。在我的研究期间，我将参与新的抗纤溶酶PSD95抑制剂的体内研究测试。将分析剂量、相互作用、相容性和药代动力学。在大鼠短暂性大脑中动脉闭塞模型中评价其神经保护能力。在此基础上，将进行进一步的研究，最终将耐纤溶酶PSD95抑制剂引入临床常规。此外，Tymianski等人的研究表明，抑制PSD95对炎症性和退行性神经系统疾病也是有益的。其他研究表明，抑制PSD95对脑出血（ICH）患者具有神经保护作用，可阻断兴奋毒性作用并减少继发性脑损伤。回国后，我计划利用我新开发的技能进一步研究神经毒性效应，并将我获得的知识转移到我们实验室建立的脑出血模型上。

Since the beginning of my residency in the neurosurgical department of the Universitätsmedizin Mainz I have been an investigator in the neurovascular research team of Dr. Keric. The planned research fellowship at Krembil Research Institute offers me the opportunity to gain new experiences and to deepen experimental methods which will be an important step towards habilitation in the neurovascular field. The research team of Dr. Tymianski is specialized in the field of neuroprotection and has published multiple high-impact studies about neurotoxic mechanisms and inhibition of signaling pathways leading to cell death. The experimental investigations are proof for a high quality of research and an excellent infrastructure of the laboratory. Tymianski et al. have developed an inhibitor of the postsynaptic density protein 95 named Nerinetide, which interrupts the activation of Nitric oxide (NO)-Synthase by overstimulated NMDA receptors. Thus, Nerinetide prevents the production of an excitotoxic concentration of NO and the resulting neurotoxicity. The group has already shown promising results in in vivo studies in rats and makaques. The subsequent randomized, controlled, multicentric, double blinded study named ESCAPE-NA1 proved a better functional outcome and smaller volumes of ischemia in stroke patients treated with Nerinetide. Though, a reduction of effect has been detected when the PSD95 inhibitor has been simultaneously provided with lytic drugs like Alteplase. The activation of plasmin by rtPA causes lysis of the thrombus but it causes a fast degradation of the PSD95 inhibitor concurrently. Nevertheless, thrombolysis is an essential step in the therapy of stroke patients. That’s why it is important to develop a plasmin resistant variant of Nerinetide. As a result the neuroprotective effect of a plasmin resistant PSD95 inhibitor combined with the benefit of thrombolysis could lead to an improvement of clinical outcome for affected patients. During my fellowship I will take part in the investigations testing the new plasmin resistant PSD95 inhibitor in vivo. Dosing, interactions, compatibility, and pharmacokinetics will be analyzed. The neuroprotective capacity will be evaluated in the transient middle cerebral artery occlusion model in rats. Based on the results further studies will be conducted leading to the introduction of the plasmin resistant PSD95 inhibitor in clinical routine.Furthermore, it has been shown by Tymianski et al. that the inhibition of PSD95 is beneficial in inflammatory and degenerative neurological diseases, as well. Other studies have indicated a neuroprotective effect of PSD95 inhibition in patients with intracerebral hemorrhage (ICH) by interruption of excitotoxic effects and reduction of secondary brain injury.After my return I plan to benefit from my newly developed skills for further investigations of neurotoxic effects and to transfer my gained knowledge on the ICH model which is established in our laboratory.