A specific inhibitor of calcium/calmodulin-dependent protein kinase-II provides neuroprotection against NMDA- and hypoxia/hypoglycemia-induced cell death.
Calcium/calmodulin-dependent protein kinase-II (CamK-II) is a major neuronal protein which plays a significant role in the cellular process of long-term potentiation (LTP), and vesicular release of neurotransmitters. Here, we show that KN-62, 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4- phenylpiperazine, a specific cell-permeable inhibitor of CamK-II substantially protected neurons from (1) acute NMDA toxicity and (2) hypoxia/hypoglycemia-induced neuronal injury in fetal rat cortical cultures. KN-62 did not directly inhibit glutamate, kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), glycine, or [piperidyl-3,4-(N)]-(N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine) (TCP) binding to rat brain membranes. Finally, KN-62 significantly reduced cellular calcium accumulation following either NMDA challenge or hypoxia/hypoglycemia insult. Our results show that CamK-II plays a key role in mediating some of the biochemical events leading to cell death following an acute excitotoxic insult.
Hajimohammadreza
I
I
Department of Neuroscience Pharmacology, Parke-Davis Pharmaceutical Research, Ann Arbor, MI 48105, USA.
Probert
A W
AW
Coughenour
L L
LL
Borosky
S A
SA
Marcoux
F W
FW
Boxer
P A
PA
Wang
K K
KK
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D002227:Carbazoles / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D019833:Genistein; D007093:Imidazoles / Q000494:pharmacology; D026121:Indole Alkaloids; D007529:Isoflavones / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D007700:Kinetics; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity*; D009281:Naphthalenes; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011083:Polycyclic Compounds / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013049:Spectrin / Q000302:isolation & purification / Q000378:metabolism
D002227:Carbazoles; D004791:Enzyme Inhibitors; D007093:Imidazoles; D026121:Indole Alkaloids; D007529:Isoflavones; D007546:Isoquinolines; D009281:Naphthalenes; D010879:Piperazines; D011083:Polycyclic Compounds; D047428:Protein Kinase Inhibitors; D013049:Spectrin; C031938:calmidazolium; D016202:N-Methylaspartate; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C049985:staurosporine aglycone; D019833:Genistein; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C058819:calphostin C; D002118:Calcium