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

从我在美因茨大学神经外科实习开始，我就一直在凯尔博士的神经血管研究团队中担任研究员。计划在克伦比勒研究所设立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实现康复的重要一步。季米安斯基博士的研究团队专门从事神经保护领域的研究，已经发表了多篇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。已经开发出一种突触后密度蛋白95的抑制剂，名为Nerinetie，它通过过度刺激NMDA受体来中断一氧化氮合酶(NO)的激活。因此，去甲肾上腺素可以防止兴奋毒性浓度的NO的产生和由此产生的神经毒性。该小组已经在大鼠和猕猴的体内研究中展示了令人振奋的结果。随后的名为EASH-NA1的随机对照、多中心、双盲研究证明，使用奈瑞肽治疗的中风患者具有更好的功能结果和更小的缺血体积。然而，当PSD95抑制剂与Alteplase等裂解药物同时提供时，效果已被检测到降低。RtPA激活纤溶酶导致血栓溶解，但同时也导致PSD95抑制物的快速降解。然而，在中风患者的治疗中，溶栓是必不可少的一步。这就是为什么开发一种具有纤溶酶抗性的奈瑞肽变种是很重要的。因此，抗纤溶酶的PSD95抑制剂的神经保护作用与溶栓治疗的益处相结合，可能会改善受影响患者的临床结局。在我的研究员期间，我将参与体内测试新型纤溶酶抗性PSD95抑制剂的研究。将对剂量、相互作用、配伍和药代动力学进行分析。在大鼠短暂性大脑中动脉闭塞模型上评价其神经保护作用。基于这些结果，将进行进一步的研究，从而将纤溶酶抗性PSD95抑制剂引入临床程序。此外，Tymianski等人已经证明了这一点。抑制PSD95在炎症性和退行性神经系统疾病中也是有益的。其他研究表明，抑制PSD95对脑出血(ICH)患者具有神经保护作用，阻断兴奋毒性效应，减少继发性脑损伤。回国后，我计划利用我新发展的技能，进一步研究神经毒性效应，并将我所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.