Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neonatal hypoxic-ischemic encephalopathy is known to cause long-term neurodevelopmental impairment. Experimental studies and clinical trials demonstrated that treatment with hypothermia after hypoxic-ischemic insults reduced brain injury. As a result of these data, hypothermia has emerged as the standard of care for treatment of neonatal hypoxic-ischemic encephalopathy. However up to 40% of newborns with hypoxic-ischemic encephalopathy who are treated with hypothermia have significant neurocognitive deficits on follow-up. Obviously, there remains a need to further optimize cooling strategies and to identify adjuvant therapies that could potentially augment the neuroprotective effects and accentuate neuroprotection by hypothermia. As the occurrence of hypoxia in the newborn brain can not be predicted beforehand, the only opportunity we have to improve outcomes after hypoxic-ischemic encephalopathy is to pursue neuroprotective strategies that can be used as an adjunct to therapeutic hypothermia in the post-hypoxia-ischemia period, with special emphasis on mechanism mediating the early stages of hypoxic injury. Previously, we have demonstrated in the newborn piglet that within one hour of exposure to hypoxia, there is increased activation of the enzyme Ca++/calmodulin kinase (CaM Kinase) IV localized in the nucleus, a key regulator of transcription of apoptotic genes. We have also demonstrated that the hypoxia-induced enzyme CaM kinase IV activation is mediated by activation of two protein tyrosine kinases, Src kinase and EGFR kinase and by increased Ca++ influx into the nucleus. Inhibition of Src kinase by the selective inhibitor PP2 and of EGFR kinase by the selective inhibitor PD168393 at the onset of hypoxia prevented CaM kinase IV activation and decreased subsequent hypoxia-induced neuronal death. The aim of this study was to test the hypothesis that the combined treatment with hypothermia and PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine), a highly selective inhibitor of Src kinase, immediately after the hypoxic insult may augment the beneficial effect of hypothermia on hypoxia/ischemia- induced neuronal necrosis. To this aim we assessed the levels of CaM Kinase IV activity as well as the levels of Na+-K+-ATPase in the Cerebral Cortex of Newborn Piglets exposed experimental hypoxia that were treated with hypothermia with or without concomitant PP2 administration. 2-3 day old piglets were anesthetized and ventilated. In conclusion, our preliminary data show that concurrent administration of Src kinase inhibitor in combination with induction of whole body hypothermia results in augmented neuroprotection as indicated by further attenuation of hypoxic-ischemic induced CaM kinase IV activation and improvement in neuronal membrane integrity compared to hypothermia alone.
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PMID:Effect of concurrent administration of apoptotic inhibitors and hypothermia on post hypoxic cerebral injury in the newborn. 2439 64

As documented in our previous study, notoginsenoside R1 (NGR1) can inhibit neuron apoptosis and the expression of endoplasmic reticulum (ER) stress-associated pro-apoptotic proteins in hypoxic-ischemic encephalopathy. Recent evidence indicates that the Phospholipase C (PLC)/inositol 1,4,5-trisphosphate receptor (IP3R) is important for the regulation of Ca2+ release in the ER. Ca2+ imbalance can stimulate ER stress, CAMKII, and cell apoptosis. The purpose of this study was to further investigate the neuroprotective effect of NGR1 and elucidate how NGR1 regulates ER stress and cell apoptosis in the oxygen-glucose deprivation/reoxygenation (OGD/R) model. Cells were exposed to NGR1 or the PLC activator m-3M3FBS. Then, IP3R- and IP3-induced Ca2+ release (IICR) and activation of the ER stress and CaMKII signal pathway were measured. The results showed that NGR1 inhibited IICR and strengthened the binding of GRP78 with PERK and IRE1. NGR1 also alleviated the activation of the CaMKII pathway. Pretreatment with m-3M3FBS attenuated the neuroprotective effect of NGR1; IICR was activated, activation of the ER stress and CaMKII pathway was increased, and more cells were injured. These results indicate that NGR1 may suppress activation of the PLC/IP3R pathway, subsequently inhibiting ER Ca2+ release, ER stress, and CaMKII and resulting in suppressed cell apoptosis.
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PMID:Notoginsenoside R1 Alleviates Oxygen-Glucose Deprivation/Reoxygenation Injury by Suppressing Endoplasmic Reticulum Calcium Release via PLC. 2917 53