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

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 counterac...

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Autores principales:	Lola Ugalde-Triviño, Margarita Díaz-Guerra
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	AVLV-144 calpain cell-penetrating peptides excitotoxicity ischemia NA-1 Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/7821f650645049799143b0c0a2e508cf
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spelling	oai:doaj.org-article:7821f650645049799143b0c0a2e508cf2021-11-25T17:58:14ZPSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides10.3390/ijms2222125851422-00671661-6596https://doaj.org/article/7821f650645049799143b0c0a2e508cf2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12585https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Therapies 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<sub>414</sub>) 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.Lola Ugalde-TriviñoMargarita Díaz-GuerraMDPI AGarticleAVLV-144calpaincell-penetrating peptidesexcitotoxicityischemiaNA-1Biology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12585, p 12585 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	AVLV-144 calpain cell-penetrating peptides excitotoxicity ischemia NA-1 Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	AVLV-144 calpain cell-penetrating peptides excitotoxicity ischemia NA-1 Biology (General) QH301-705.5 Chemistry QD1-999 Lola Ugalde-Triviño Margarita Díaz-Guerra PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides
description	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<sub>414</sub>) 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.
format	article
author	Lola Ugalde-Triviño Margarita Díaz-Guerra
author_facet	Lola Ugalde-Triviño Margarita Díaz-Guerra
author_sort	Lola Ugalde-Triviño
title	PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides
title_short	PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides
title_full	PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides
title_fullStr	PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides
title_full_unstemmed	PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides
title_sort	psd-95: an effective target for stroke therapy using neuroprotective peptides
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/7821f650645049799143b0c0a2e508cf
work_keys_str_mv	AT lolaugaldetrivino psd95aneffectivetargetforstroketherapyusingneuroprotectivepeptides AT margaritadiazguerra psd95aneffectivetargetforstroketherapyusingneuroprotectivepeptides
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PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides

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