SPECIFIC INHIBITOR OF CALCIUM CALMODULIN-DEPENDENT PROTEIN-KINASE-II PROVIDES NEUROPROTECTION AGAINST NMDA-INDUCED AND HYPOXIA HYPOGLYCEMIA-INDUCED CELL-DEATH

Calcium/calmodulin-dependent protein kinase-II (CamK-II) is a major ne uronal protein which plays a significant role in the cellular process of long-term potentiation (LTP), and vesicular release of neurotransmi tters. Here, we show that KN-62, esulfonyl)-N-methyl-L-tyrosyl]-4-phen ylpiperazine, a specific cell-permeable inhibitor of CamK-II substanti ally protected neurons from (1) acute NMDA toxicity and (2) hypoxia/hy poglycemia-induced neuronal injury in fetal rat cortical cultures, KN- 62 did not directly inhibit glutamate, kainate, pha-amino-3-hydroxy-5- methyl-4-isoxazolepropionate (AMPA), glycine, or -(N)]-(N-[1-(2-thieny l)cyclohexyl]-3,4-piperidine) (TCP) binding to rat brain membranes, Fi nally, KN-62 significantly reduced cellular calcium accumulation follo wing either NMDA challenge or hypoxia/hypoglycemia insult. Our results show that CamK-II plays a key role in mediating some of the biochemic al events leading to cell death following an acute excitotoxic insult.