PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides

Autor: Margarita Díaz-Guerra, Lola Ugalde-Triviño
Přispěvatelé: Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), European Commission
Rok vydání: 2021
Předmět:
Zdroj: Digital.CSIC. Repositorio Institucional del CSIC
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International Journal of Molecular Sciences
International Journal of Molecular Sciences, Vol 22, Iss 12585, p 12585 (2021)
ISSN: 1422-0067
2019-1057
DOI: 10.3390/ijms222212585
Popis: © 2021 by the authors.
Therapies for stroke have remained elusive in the past despite the great relevance of this pathology. However, recent results have provided strong evidence that postsynaptic density protein-95 (PSD-95) can be exploited as an efficient target for stroke neuroprotection by strategies able to counteract excitotoxicity, a major mechanism of neuronal death after ischemic stroke. This scaffold protein is key to the maintenance of a complex framework of protein interactions established at the postsynaptic density (PSD) of excitatory neurons, relevant to neuronal function and survival. Using cell penetrating peptides (CPPs) as therapeutic tools, two different approaches have been devised and advanced to different levels of clinical development. First, nerinetide (Phase 3) and AVLX-144 (Phase 1) were designed to interfere with the coupling of the ternary complex formed by PSD-95 with GluN2B subunits of the N-methyl-D-aspartate type of glutamate receptors (NMDARs) and neuronal nitric oxide synthase (nNOS). These peptides reduced neurotoxicity derived from NMDAR overactivation, decreased infarct volume and improved neurobehavioral results in different models of ischemic stroke. However, an important caveat to this approach was PSD-95 processing by calpain, a pathological mechanism specifically induced by excitotoxicity that results in a profound alteration of survival signaling. Thus, a third peptide (TP95) has been recently developed to interfere with PSD-95 cleavage and reduce neuronal death, which also improves neurological outcome in a preclinical mouse model of permanent ischemia. Here, we review recent advancements in the development and characterization of PSD-95-targeted CPPs and propose the combination of these two approaches to improve treatment of stroke and other excitotoxicity-associated disorders.
This research was funded by Agencia Estatal de Investigación (PID2019-105784RB-100/AEI/ 10.13039/501100011033). The cost of publication has been paid in part by FEDER funds.
Databáze: OpenAIRE
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