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Int J Clin Exp Pathol 1(1):44-56;2008
Original Article
Exacerbation of Apoptosis of Cortical Neurons Following Traumatic Brain Injury in Par-4
Transgenic Mice
Daniel J. Payette, Jun Xie, Najeeb Shirwany and Qing Guo
Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
Received 15 July 17 2007; accepted 18 July 2007; available online 1 January 2008
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 by neuron specific enolase. 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
suggest 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. (IJCEP707008).
Key Words: Traumatic brain injury, cerebral cortex, apoptosis, prostate apoptosis response-4, cell culture
Full Text PDF
Address all correspondence to: Qing Guo, PhD, Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma
City, OK 73104, Phone: 405-271-2226 ext. 56268. FAX: 405-271-3181. E-mail: qing-guo@ouhsc.edu
Original Article
Exacerbation of Apoptosis of Cortical Neurons Following Traumatic Brain Injury in Par-4
Transgenic Mice
Daniel J. Payette, Jun Xie, Najeeb Shirwany and Qing Guo
Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
Received 15 July 17 2007; accepted 18 July 2007; available online 1 January 2008
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 by neuron specific enolase. 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
suggest 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. (IJCEP707008).
Key Words: Traumatic brain injury, cerebral cortex, apoptosis, prostate apoptosis response-4, cell culture
Full Text PDF
Address all correspondence to: Qing Guo, PhD, Department of Physiology, The University of Oklahoma Health Sciences Center, Oklahoma
City, OK 73104, Phone: 405-271-2226 ext. 56268. FAX: 405-271-3181. E-mail: qing-guo@ouhsc.edu
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