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

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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.