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

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Stroke remains a significant health challenge with limited effective therapies.
• Excitotoxicity, driven by N-methyl-D-aspartate receptor (NMDAR) overactivation, is a key mechanism of neuronal death in ischemic stroke.
• Postsynaptic density protein-95 (PSD-95) is crucial for synaptic function and survival, making it a viable therapeutic target.

Purpose of the Study:

• To review advancements in PSD-95-targeted cell-penetrating peptides (CPPs) for stroke neuroprotection.
• To explore therapeutic strategies that counteract excitotoxicity and PSD-95 cleavage.
• To propose combination therapies for improved stroke treatment.

Main Methods:

• Development of CPPs to interfere with the PSD-95/NMDAR/nNOS complex (nerinetide, AVLX-144).
• Design of CPPs to inhibit PSD-95 cleavage by calpain (TP95414).
• Evaluation of CPP efficacy in preclinical stroke models, assessing neurotoxicity, infarct volume, and neurobehavioral outcomes.

Main Results:

• Nerinetide and AVLX-144 reduced NMDAR-mediated neurotoxicity, infarct size, and improved outcomes in stroke models.
• PSD-95 cleavage by calpain is a pathological consequence of excitotoxicity.
• TP95414 prevented PSD-95 cleavage, reduced neuronal death, and improved outcomes in a preclinical stroke model.

Conclusions:

• PSD-95-targeted CPPs represent a promising therapeutic avenue for stroke.
• Interfering with both PSD-95/NMDAR interactions and PSD-95 cleavage offers a dual-action strategy.
• Combination therapy with these CPPs may enhance neuroprotection and improve outcomes in stroke and other excitotoxicity-related disorders.