title: Exacerbation of apoptosis of cortical neurons following traumatic brain injury in par-4 transgenic mice.
abstract: Traumatic brain injury (TBI) is a significant clinical problem, yet few effective strategies for treating it have emerged. People that sustain and survive a TBI are left with significant cognitive, behavioral, and communicative disabilities. Apoptotic neuronal death occurs following TBI. Prostate apoptosis response-4 (Par-4) is a death domain-containing protein initially characterized as a critical regulator of apoptosis in prostate cancer cells. We have recently generated and characterized Par-4 transgenic mice in which the expression of the par-4 transgene was limited to cells of neuronal lineage. We now provide evidence that, in cortical neurons from these mice, Par-4 drastically increases apoptotic neuronal death in both in vitro and in vivo models of TBI. In vitro experiments were performed in 7-day-old primary cultures of cortical neurons using a previously published, scratch-induced mechanical trauma model. Neurons that overexpress Par-4 showed not only a significant decrease in overall neuron survival after TBI compared to wild-type cells, but also exhibited a sharper decrease in mitochondrial transmembrane potential, a higher degree of free radical accumulation, and earlier activation of caspase-3 than wild-type cells did. In vivo experiments were performed utilizing a weight drop TBI model. A significantly increased volume of cortical injury and exacerbated activation of caspase-3 were observed in Par-4 transgenic mice when compared to those in wild-type mice. These data suggests that aberrant Par-4 expression exacerbates neuronal cell death following TBI by altering mitochondrial function, enhancing oxidative damage, and execution of apoptosis via caspase activation.
authors.affiliation: Department of Physiology, The University of Oklahoma Health Sciences Center Oklahoma City, OK, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Payette
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.forename: Najeeb
authors.initials: N
authors.lastname: Shirwany
authors.forename: Qing
authors.initials: Q
authors.lastname: Guo
references.citation: Annu Rev Pharmacol Toxicol. 2007;47:117-41
references.pmid: 16879082
references.citation: J Neurotrauma. 2006 Aug;23(8):1241-53
references.pmid: 16928182
references.citation: J Biol Chem. 2004 Feb 6;279(6):4596-603
references.pmid: 14627703
references.citation: J Microsc. 1988 May;150(Pt 2):117-36
references.pmid: 3411604
references.citation: J Neurochem. 2000 Jul;75(1):117-24
references.pmid: 10854254
references.citation: Int J Dev Neurosci. 2004 Nov;22(7):485-96
references.pmid: 15465278
references.citation: Apoptosis. 1998 Mar;3(2):61-6
references.pmid: 14646502
references.citation: J Neurotrauma. 2000 Oct;17(10):927-38
references.pmid: 11063058
references.citation: J Neurotrauma. 2002 Apr;19(4):427-38
references.pmid: 11990349
references.citation: Clin Exp Pharmacol Physiol. 2001 Nov;28(11):919-21
references.pmid: 11703396
references.citation: Exp Cell Res. 2003 Feb 1;283(1):51-66
references.pmid: 12565819
references.citation: J Cereb Blood Flow Metab. 2001 Oct;21(10):1189-98
references.pmid: 11598496
references.citation: J Biol Chem. 2004 Jul 2;279(27):28266-75
references.pmid: 15090548
references.citation: J Neurochem. 2005 Jan;92(1):59-71
references.pmid: 15606896
references.citation: J Biol Chem. 2003 May 30;278(22):19995-20005
references.pmid: 12644474
references.citation: J Endocrinol. 2007 Jul;194(1):77-85
references.pmid: 17592023
references.citation: J Biol Chem. 2001 Mar 9;276(10):7320-6
references.pmid: 11058599
references.citation: Biochem J. 1999 Jul 15;341 ( Pt 2):233-49
references.pmid: 10393078
references.citation: J Neurosci Res. 2005 Jan 1-15;79(1-2):231-9
references.pmid: 15573402
references.citation: Cell Death Differ. 1999 Nov;6(11):1067-74
references.pmid: 10578175
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4125-30
references.pmid: 10097174
references.citation: Brain Res. 2001 Oct 5;915(1):1-10
references.pmid: 11578614
references.citation: Neuron. 1989 Jun;2(6):1541-5
references.pmid: 2576374
references.citation: Exp Neurol. 2001 Jul;170(1):140-8
references.pmid: 11421591
references.citation: Neurosci Behav Physiol. 2002 Sep-Oct;32(5):541-7
references.pmid: 12403008
references.citation: J Neurosci. 2006 Nov 8;26(45):11540-53
references.pmid: 17093075
references.citation: Nat Med. 1998 Aug;4(8):957-62
references.pmid: 9701251
references.citation: J Mol Neurosci. 1999 Aug-Oct;13(1-2):17-30
references.pmid: 10691289
references.citation: Anat Rec. 1998 Jun;253(3):79-90
references.pmid: 9700393
references.citation: Int J Legal Med. 2007 Sep;121(5):365-75
references.pmid: 17106737
references.citation: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4397-401
references.pmid: 7753817
references.citation: Exp Neurol. 1994 Dec;130(2):173-7
references.pmid: 7867748
references.citation: J Am Soc Nephrol. 2006 Dec;17(12):3336-46
references.pmid: 17065240
references.citation: J Neurochem. 1999 Mar;72(3):1019-29
references.pmid: 10037473
references.citation: Neurocrit Care. 2005;3(2):177-82
references.pmid: 16174891
references.citation: CNS Drugs. 2001;15(7):553-81
references.pmid: 11510625
references.citation: Neurobiol Dis. 2004 Jun;16(1):150-7
references.pmid: 15207272
references.citation: J Neurosci Res. 2007 Mar;85(4):805-15
references.pmid: 17243171
references.citation: J Neurosci. 1999 Aug 1;19(15):6248-56
references.pmid: 10414954
references.citation: Brain Pathol. 2004 Apr;14(2):215-22
references.pmid: 15193035
references.citation: Heart Lung Circ. 2006 Apr;15(2):124-9
references.pmid: 16490400
references.citation: Cell Death Differ. 1998 Dec;5(12):1004-16
references.pmid: 9894607
references.citation: J Comp Neurol. 1999 Aug 30;411(3):390-8
references.pmid: 10413774
references.citation: Am J Physiol Renal Physiol. 2007 Jan;292(1):F107-15
references.pmid: 16896190
references.citation: Annu Rev Neurosci. 2000;23:73-87
references.pmid: 10845059
references.citation: Oncogene. 1999 Jan 21;18(3):623-31
references.pmid: 9989812
references.citation: Mol Cell Biol. 1997 Jul;17(7):3823-32
references.pmid: 9199316
references.citation: Genes Dev. 1999 Aug 1;13(15):1899-911
references.pmid: 10444588
references.citation: Mol Cell Biol. 2003 Aug;23(16):5516-25
references.pmid: 12897127