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The Journal of Neuroscience logoLink to The Journal of Neuroscience
. 1995 May 1;15(5):4093–4101. doi: 10.1523/JNEUROSCI.15-05-04093.1995

A specific inhibitor of calcium/calmodulin-dependent protein kinase-II provides neuroprotection against NMDA- and hypoxia/hypoglycemia-induced cell death

I Hajimohammadreza 1, AW Probert 1, LL Coughenour 1, SA Borosky 1, FW Marcoux 1, PA Boxer 1, KK Wang 1
PMCID: PMC6578204  PMID: 7538570

Abstract

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.


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