Neuroprotective Effects of Noncanonical PAR1 Agonists on Cultured Neurons in Excitotoxicity

Babkina, I.; Savinkova, I.; Molchanova, T.; Sidorova, M.; Surin, A.; Gorbacheva, L.

Авторы: Babkina I., Savinkova I., Molchanova T., Sidorova M., Surin A., Gorbacheva L.
Журнал: International Journal of Molecular Sciences
Том: 25
Номер: 1221
Год издания: 2024
Издательство: MDPI
Местоположение издательства: Basel, Switzerland
Первая страница: 1
Последняя страница: 13
DOI: 10.3390/ijms25021221
Аннотация: Serine proteases regulate cell functions through G protein-coupled protease-activated receptors (PARs). Cleavage of one peptide bond of the receptor amino terminus results in the formationof a new N-terminus (“tethered ligand”) that can specifically interact with the second extracellularloop of the PAR receptor and activate it. Activation of PAR1 by thrombin (canonical agonist) and activated protein C (APC, noncanonical agonist) was described as a biased agonism. Here, we havesupposed that synthetic peptide analogs to the PAR1 tethered ligand liberated by APC could have neuroprotective effects like APC. To verify this hypothesis, a model of the ischemic brain impairment based on glutamate (Glu) excitotoxicity in primary neuronal cultures of neonatal rats has been used. It was shown that the nanopeptide NPNDKYEPF-NH2 (AP9) effectively reduced the neuronal death induced by Glu. The influence of AP9 on cell survival was comparable to that of APC. Both APC and AP9 reduced the dysregulation of intracellular calcium homeostasis in cultured neurons induced by excitotoxic Glu (100 M) or NMDA (200 M) concentrations. PAR1 agonist synthetic peptides might be noncanonical PAR1 agonists and a basis for novel neuroprotective drugs for disorders related to Glu excitotoxicity such as brain ischemia, trauma and some neurodegenerative diseases.
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Neuroprotective Effects of Noncanonical PAR1 Agonists on Cultured Neurons in Excitotoxicityстатья

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