Abstract
We have recently shown that p38MAP kinase (p38MAPK) stimulates ROS generation via the activation of NADPH oxidase during neonatal hypoxia-ischemia (HI) brain injury. However, how p38MAPK is activated during HI remains unresolved and was the focus of this study. Ca2+/calmodulin-dependent protein kinase II (CaMKII) plays a key role in brain synapse development, neural transduction and synaptic plasticity. Here we show that CaMKII activity is stimulated in rat hippocampal slice culture exposed to oxygen glucose deprivation (OGD) to mimic the condition of HI. Further, the elevation of CaMKII activity, correlated with enhanced p38MAPK activity, increased superoxide generation from NADPH oxidase as well as necrotic and apoptotic cell death. All of these events were prevented when CaMKII activity was inhibited with KN93. In a neonatal rat model of HI, KN93 also reduced brain injury. Our results suggest that CaMKII activation contributes to the oxidative stress associated with neural cell death after HI.
Highlights
Neonatal hypoxia ischemia (HI) brain injury occurs in,2–5/ 1000 births
In this study we investigated if calmodulin-dependent protein kinase II (CaMKII) is the upstream regulator of p38MAP kinase (p38MAPK) and if so whether CaMKII inhibition can attenuate the neural cell death associated with neonatal HI
Hippocampal slices from postnatal Day 7 (P7) rats were pretreated with the CaMKII inhibitor, KN93 (10- or 20-mM, 2 h), or its inactive analogy, KN92 (10 mM, 2 h), exposed to oxygen glucose deprivation (OGD)
Summary
Neonatal hypoxia ischemia (HI) brain injury occurs in ,2–5/ 1000 births. Approximately 30–40% of infants with brain injury will die and 20–40% of survivors develop significant neurological disorders and lifelong disability, including cerebral palsy, seizures, visual impairment, mental retardation, learning impairment and epilepsy [1,2,3]. The main mechanisms underlying neurological damage in HI are oxygen and glucose deprivation, which leads to energy failure, following a cascade of biochemical events such as Ca2+ influx, increased permeability of cell membranes and oxidative stress. It is well established that energy failure, increases in intracellular Ca2+ and overproduction of reactive oxygen species (ROS) play major roles in cell death for both immature and mature brains after HI [4,5,6]. We have recently shown that p38MAP kinase (p38MAPK) stimulates ROS generation via the activation of NADPH oxidase during neonatal HI injury [16]. It is unresolved how p38MAPK is activated during neonatal HI [16,17]
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