title: Ca²⁺/calmodulin-dependent protein kinase II contributes to hypoxic ischemic cell death in neonatal hippocampal slice cultures.
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.
authors: Vascular Biology Center, Georgia Regents University, Augusta, Georgia, United States of America.
authors: Qing
authors: Q
authors: Lu
authors: Valerie A
authors: VA
authors: Harris
authors: Xutong
authors: X
authors: Sun
authors: Yali
authors: Y
authors: Hou
authors: Stephen M
authors: SM
authors: Black
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001596:Benzylamines / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D009249:NADP / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism; D046509:Tissue Culture Techniques; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005947:Glucose; D009249:NADP; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D013481:Superoxides; D048051:p38 Mitogen-Activated Protein Kinases; C072105:KN 93; D000096926:Benzenesulfonamides
references: Pediatr Res. 2001 Jun;49(6):735-41
references: 11385130
references: Mol Cell Biol. 1996 Mar;16(3):1247-55
references: 8622669
references: Pediatr Res. 2003 Jul;54(1):77-82
references: 12646716
references: Circ Res. 2009 Aug 14;105(4):316-25
references: 19608982
references: Brain Res. 1998 Apr 20;790(1-2):129-40
references: 9593859
references: J Neurochem. 1992 May;58(5):1743-53
references: 1313852
references: Cochrane Database Syst Rev. 2008 Apr 16;(2):CD006817
references: 18425971
references: Biochim Biophys Acta. 2002 Nov 4;1600(1-2):128-37
references: 12445468
references: Dev Neurosci. 2001;23(3):198-202
references: 11598320
references: Am J Physiol Heart Circ Physiol. 2008 Oct;295(4):H1809-14
references: 18676689
references: Science. 2000 Oct 27;290(5492):750-4
references: 11052931
references: J Biol Chem. 2010 Jul 2;285(27):20675-82
references: 20424167
references: Free Radic Biol Med. 2012 Sep 1;53(5):1139-51
references: 22728269
references: J Cereb Blood Flow Metab. 2008 Oct;28(10):1686-96
references: 18545259
references: Neurochem Res. 2002 Jun;27(6):477-84
references: 12199152
references: J Neurosci. 2009 Aug 5;29(31):9778-93
references: 19657031
references: Dev Neurosci. 2011;33(3-4):312-9
references: 21659718
references: Am J Physiol Cell Physiol. 2012 Feb 1;302(3):C505-17
references: 22049209
references: J Mol Cell Cardiol. 2010 Jun;48(6):1298-306
references: 20060004
references: Stroke. 1986 Nov-Dec;17(6):1304-8
references: 2433817
references: Pediatr Res. 2011 Nov;70(5):535-40
references: 21796017
references: Mol Cell Neurosci. 2011 Apr;46(4):720-30
references: 21316454
references: Exp Brain Res. 2007 Sep;182(1):1-10
references: 17665180
references: Stroke. 1993 Jan;24(1):117-21
references: 8418534
references: Neurosci Lett. 1994 Feb 28;168(1-2):221-4
references: 8028780
references: Eur J Pharmacol. 1999 Apr 9;370(2):117-23
references: 10323259
references: Dev Neurosci. 2011;33(3-4):288-98
references: 21757865
references: J Cereb Blood Flow Metab. 2002 Sep;22(9):1098-106
references: 12218415
references: Acta Neuropathol. 2003 May;105(5):425-37
references: 12677442
references: Nature. 1993 Jan 7;361(6407):31-9
references: 8421494
references: Int J Neurosci. 2012 Sep;122(9):532-40
references: 22524690
references: Acta Neurochir Suppl. 1999;73:7-13
references: 10494335
references: Brain Res. 1992 Oct 9;593(1):97-104
references: 1333874
references: Mol Neurobiol. 2001 Feb;23(1):1-19
references: 11642541
references: Annu Rev Biochem. 2002;71:473-510
references: 12045104
references: J Neurosci. 2000 Jun 15;20(12):4506-14
references: 10844020
references: Pediatr Res. 2006 May;59(5):680-3
references: 16627881
references: Dev Pharmacol Ther. 1992;18(3-4):139-44
references: 1306803
references: Stroke. 1997 Dec;28(12):2539-44
references: 9412646
references: J Cereb Blood Flow Metab. 1996 Jan;16(1):1-6
references: 8530541
references: Am J Physiol Heart Circ Physiol. 2009 Aug;297(2):H735-42
references: 19525372
references: J Neurosci. 1995 May;15(5 Pt 2):4093-101
references: 7538570
references: Brain Res. 2007 Jul 16;1158:39-49
references: 17559813
references: Acta Neurochir Suppl. 2003;86:113-6
references: 14753417
references: Am J Physiol Renal Physiol. 2000 Aug;279(2):F243-51
references: 10919842
references: Neurotoxicology. 2008 Jan;29(1):152-9
references: 18061678
references: PLoS One. 2012;7(9):e40881
references: 22984394
references: Ment Retard Dev Disabil Res Rev. 2002;8(4):241-8
references: 12454900
references: Prog Neurobiol. 1989;32(4):235-76
references: 2655008
references: J Neurosci. 2010 Feb 10;30(6):2077-87
references: 20147536
references: Dev Neurosci. 2008;30(6):410-8
references: 19127062
references: EMBO Rep. 2004 Feb;5(2):161-6
references: 14749717
references: Eur J Neurosci. 2011 Oct;34(7):1093-101
references: 21939459
references: Ann Neurol. 1981 Feb;9(2):131-41
references: 7235629
references: J Neurochem. 2004 Oct;91(2):429-37
references: 15447676
references: Science. 1992 Jul 10;257(5067):206-11
references: 1321493
references: Brain Res Dev Brain Res. 2000 Oct 28;123(2):119-27
references: 11042340
references: Brain Dev. 2001 Aug;23(5):349-54
references: 11504607
references: Cardiovasc Res. 2007 Mar 1;73(4):689-98
references: 17217936
references: Stroke. 2004 Mar;35(3):753-7
references: 14963271
references: Mol Cell Biol. 2003 Jan;23(1):131-9
references: 12482967
references: Science. 1995 Feb 3;267(5198):682-5
references: 7839144
references: Neuroscientist. 2002 Jun;8(3):212-20
references: 12061501
references: Neuron. 2005 Nov 23;48(4):635-46
references: 16301179
references: Neuron. 2002 Oct 24;36(3):483-91
references: 12408850
references: J Neurochem. 2010 Jan;112(1):271-81
references: 19860859
references: Pediatr Res. 1995 Sep;38(3):306-11
references: 7494651
references: J Biol Chem. 2012 Mar 9;287(11):8495-506
references: 22253441
references: Neuroscience. 2006 Jul 7;140(3):857-63
references: 16581191
references: J Biol Chem. 1998 Jan 16;273(3):1741-8
references: 9430721
references: Neurol Res. 2001 Sep;23(6):662-8
references: 11547940
references: Neurobiol Dis. 1995 Jun;2(3):145-55
references: 9173998
references: FEBS Lett. 1996 Oct 28;396(1):67-70
references: 8906868
references: Acta Neurol Scand. 2002 Dec;106(6):333-40
references: 12460137
references: J Biol Chem. 1997 Nov 28;272(48):30122-8
references: 9374491
references: N Engl J Med. 2004 Nov 4;351(19):1985-95
references: 15525724
references: Arch Biochem Biophys. 1987 Feb 1;252(2):418-25
references: 3028265
references: Dev Neurosci. 2005 Mar-Aug;27(2-4):169-75
references: 16046851
references: J Neurosci. 2003 Nov 19;23(33):10645-9
references: 14627649