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Activated Protein C via PAR1 Receptor Regulates Survival of Neurons under Conditions of Glutamate Excitotoxicity

L. R. Gorbacheva1, T. P. Storozhevykh2, V. G. Pinelis2, O. N. Davydova2, S. Ishiwata3, and S. M. Strukova1*

1Biology Faculty, Lomonosov Moscow State University, 119899 Moscow, Russia; E-mail: sstrukova@yahoo.com

2Research Center of Children's Health, Russian Academy of Medical Sciences, Moscow, Russia

3Department of Physics, Faculty of Science and Engineering, Waseda University, Tokyo, Japan; E-mail: ishiwata@waseda.jp

* To whom correspondence should be addressed.

Received October 1, 2007; Revision received November 12, 2007
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.
KEY WORDS: activated protein C, glutamate toxicity, apoptosis, hippocampal and cortical neurons, proteinase-activated receptor, geldanamycin

DOI: 10.1134/S0006297908060138