Activated protein C via PAR1 receptor regulates survival of neurons under conditions of glutamate excitotoxicity.
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.
Gorbacheva
L R
LR
Biology Faculty, Lomonosov Moscow State University, Moscow, 119899, Russia.
Storozhevykh
T P
TP
Pinelis
V G
VG
Davydova
O N
ON
Ishiwata
S
S
Strukova
S M
SM
D000818:Animals; D000831:Animals, Newborn; D016227:Benzoquinones / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects; D003603:Cytotoxins / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011486:Protein C / Q000378:metabolism* / Q000494:pharmacology* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044463:Receptor, PAR-1 / Q000819:agonists / Q000502:physiology*; D013917:Thrombin / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors
D016227:Benzoquinones; D003603:Cytotoxins; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D011486:Protein C; D044463:Receptor, PAR-1; D018698:Glutamic Acid; D013917:Thrombin; C001277:geldanamycin; D010975:Platelet Aggregation Inhibitors