Babkina, I.; Savinkova, I.; Molchanova, T.; Sidorova, M.; Surin, A.; Gorbacheva, L. Neuroprotective Effects of Noncanonical PAR1 Agonists on Cultured Neurons in Excitotoxicity. Int. J. Mol. Sci.2024, 25, 1221.
Babkina, I.; Savinkova, I.; Molchanova, T.; Sidorova, M.; Surin, A.; Gorbacheva, L. Neuroprotective Effects of Noncanonical PAR1 Agonists on Cultured Neurons in Excitotoxicity. Int. J. Mol. Sci. 2024, 25, 1221.
Babkina, I.; Savinkova, I.; Molchanova, T.; Sidorova, M.; Surin, A.; Gorbacheva, L. Neuroprotective Effects of Noncanonical PAR1 Agonists on Cultured Neurons in Excitotoxicity. Int. J. Mol. Sci.2024, 25, 1221.
Babkina, I.; Savinkova, I.; Molchanova, T.; Sidorova, M.; Surin, A.; Gorbacheva, L. Neuroprotective Effects of Noncanonical PAR1 Agonists on Cultured Neurons in Excitotoxicity. Int. J. Mol. Sci. 2024, 25, 1221.
Abstract
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 formation of a new N-terminus ("tethered ligand") that can specifically interact with the second extracellular loop of the PAR receptor and activate it. Activation of PAR1 by thrombin (canonical agonist) and activated protein C (APC, noncanonical agonist) was described as biased agonism. Here we have supposed that synthetic peptide analogues 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 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 µM) or NMDA (200 µM) concentrations. PAR1 agonist synthetic peptides might be a noncanonial PAR1-agonist and a basis of novel neuroprotective drugs for disorders related to Glu excitotoxicity such as brain ischemia, trauma and some neurodegenerative diseases.
Keywords
activated protein C; neuroprotection; protease-activated receptors; neurons; glutamate; intracellular calcium
Subject
Biology and Life Sciences, Neuroscience and Neurology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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