Activated protein C via PAR1 receptor regulates survival of neurons under conditions of glutamate excitotoxicity |
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Authors: | L. R. Gorbacheva T. P. Storozhevykh V. G. Pinelis O. N. Davydova S. Ishiwata S. M. Strukova |
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Affiliation: | Biology Faculty, Lomonosov Moscow State University, Moscow, 119899, Russia. |
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Abstract: | The effect of an anticoagulant and cytoprotector blood serine proteinase--activated protein C (APC)--on survival of cultured hippocampal and cortical neurons under conditions of glutamate-induced excitotoxicity has been studied. Low concentrations of APC (0.01-10 nM) did not cause neuron death, but in the narrow range of low concentrations APC twofold and stronger decreased cell death caused by glutamate toxicity. High concentrations of APC (>50 nM) induced the death of hippocampal neurons similarly to the toxic action of glutamate. The neuroprotective effect of APC on the neurons was mediated by type 1 proteinase-activated receptor (PAR1), because the inactivation of the enzyme with phenylmethylsulfonyl fluoride or PAR1 blockade by a PAR1 peptide antagonist ((Tyr1)-TRAP-7) prevented the protective effect of APC. Moreover, APC inhibited the proapoptotic effect of 10 nM thrombin on the neurons. Geldanamycin, a specific inhibitor of heat shock protein Hsp90, completely abolished the antiapoptotic effect of 0.1 nM APC on glutamate-induced cytotoxicity in the hippocampal neurons. Thus, APC at low concentrations, activating PAR1, prevents the death of hippocampal and cortical neurons under conditions of glutamate excitotoxicity. |
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Keywords: | activated protein C glutamate toxicity apoptosis hippocampal and cortical neurons proteinase-activated receptor geldanamycin |
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