The Role of Cell Kinematics and the N-Methyl D-Aspartate Receptor in Apoptosis and Necrosis in the in Vitro Hippocampus Following Mechanical Injury

There are an estimated 1.4 million cases of traumatic brain injury (TBI) per year in the United States, yet no suitable pharmacological treatment has been developed that provides treatment without undesirable side effects. Through the use of computational models, thresholds have been developed for the forces necessary to induce injury in the brain, but these models have not yet examined the contribution of the cellular components of the tissue to these thresholds. Additionally, there has not been a thorough examination of the relationship between cellular mechanics and the resulting pattern of cell death which is observed following TBI. A more thorough understanding of the correlation of the mechanics of injury to the extent and distribution of apoptotic and necrotic cell death may aid in the understanding of the progression of brain injury and aid in the development of treatments. In this dissertation, organotypic cultures are used to examine both the mechanical response of the tissue to a quasistatic biaxial deformation and the levels of stretch necessary to induce the activation of markers of apoptosis and necrosis. Both the cellular components of the tissue as well as the extracellular matrix are shown to play important roles in the nonlinear behavior of the tissue. Further, with a dynamic stretch injury, there is a transition from apoptotic to necrotic cel! death at higher stretch levels. Within the hippocampus, there is a shift in regional susceptibility from the dentate gyrus to the CAS region with the increase in the level of stretch. Finally, selective inhibition of extrasynaptic N-methyl D-aspartate (NMDA) -NR2B receptors attenuated both caspase-3 activity and calpain-mediated spectrin breakdown product. Alternatively, inhibition of synaptic receptors (NMDA-NR2A containing) resulted in the appearance of activated caspase-3 and enhanced calpain-mediated SBDP following severe stretch. Together, these studies provide further evidence of the correlation between the severity of injury and the cellular response. Further studies into the contribution of cascades associated with the synaptic and extrasynaptic NMDA receptors may lead to the development of pharmacotherapies capable of reducing or redirecting the cellular response to injury and improving the management of TBI.

Year	Entry
2002	Brands DWA, Bovendeerd PHM, Wismans JSHM. On the potential importance of non-linear viscoelastic material modelling for numerical prediction of brain tissue response: test and application. Stapp Car Crash J. 2002;46:103-121. SAE 2002-22-0006.
1982	Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP. Diffuse axonal injury and traumatic coma in the primate. Ann Neurol. 1982;12(6):564-574.
2004	Nicolle S, Lounis M, Willinger R. Shear properties of brain tissue over a frequency range relevant for automotive impact situations: new experimental results. Stapp Car Crash J. 2004;48:239-258. SAE 2004-22-0011.
1997	Smith DH, Chen X-H, Xu B-N, McIntosh TK, Gennarelli TA, Meaney DF. Characterization of diffuse axonal pathology and selective hippocampal damage following inertial brain trauma in the pig. J Neuropathol & Exp Neurol. July 1997;56(7):822-834.
2003	Takhounts EG, Crandall JR, Darvish K. On the importance of nonlinearity of brain tissue under large deformations. Stapp Car Crash J. 2003;47:79-92. SAE 2003-22-0005.
1998	Morrison B III, Saatman KE, Meaney DF, McIntosh TK. In vitro central nervous system models of mechanically induced trauma: a review. J Neurotrauma. November 1998;15(11):911-928.
1999	Morrison B III. Differential Genomic Expression After Mechanical Injury of Organotypic Brain Slice Cultures: An in Vitro Model of Traumatic Brain Injury [PhD thesis]. Philadelphia, PA: University of Pennsylvania; 1999.
1995	Smith DH, Soares HD, Pierce JS, Perlman KG, Saatman KE, Meaney DF, Dixon CE, McIntosh TK. A model of parasagittal controlled cortical impact in the mouse: cognitive and histopathologic effects. J Neurotrauma. April 1995;12(2):169-178.
2000	Ivarsson J, Viano DC, Lövsund P, Aldman B. Strain relief from the cerebral ventricles during head impact: experimental studies on natural protection of the brain. J Biomech. February 2000;33(2):181-189.
1995	Mendis KK, Stalnaker RL, Advani SH. A constitutive relationship for large deformation finite element modeling of brain tissue. J Biomech Eng. August 1995;117(3):279-285.
1995	Ueno K, Melvin JW, Li L, Lighthall JW. Development of tissue level brain injury criteria by finite element analysis. J Neurotrauma. August 1995;12(4):695-706.
2002	Miller K, Chinzei K. Mechanical properties of brain tissue in tension. J Biomech. April 2002;35(4):483-490.
1995	Meaney DF, Smith DH, Shreiber DI, Bain AC, Miller RT, Ross DT, Gennarelli TA. Biomechanical analysis of experimental diffuse axonal injury. J Neurotrauma. November 1995;12(4):689-694.
1995	Sosin DM, Sniezek JE, Waxweiler RJ. Trends in death associated with traumatic brain injury, 1979 through 1992: success and failure. JAMA. June 14, 1995;273(22):1778-1780.
1972	Shuck LZ, Advani SH. Rheological response of human brain tissue in shear. J Basic Eng. December 1972;94(4):905-911.
1994	Gennarelli TA. Animate models of human head injury. J Neurotrauma. August 1994;11(4):357-368.
1998	Arbogast KB, Margulies SS. Material characterization of the brainstem from oscillatory shear tests. J Biomech. September 1998;31(9):801-807.
2001	Bain AC, Raghupathi R, Meaney DF. Dynamic stretch correlates to both morphological abnormalities and electrophysiological impairment in a model of traumatic axonal injury. J Neurotrauma. May 2001;18(5):499-511.
1978	Pamidi MR, Advani SH. Nonlinear constitutive relations for human brain tissue. J Biomech Eng. February 1978;100(1):44-48.
1996	Zhang L, Rzigalinski BA, Ellis EF, Satin LS. Reduction of voltage-dependent Mg²⁺ blockade of NMDA current in mechanically injured neurons. Science. December 13, 1996;274(5294):1921-1923.
1991	Dixon CE, Clifton GL, Lighthall JW, Yaghmai AA, Hayes RL. A controlled cortical impact model of traumatic brain injury in the rat. J Neurosci Meth. October 1991;39(3):253-262.
2002	Prange MT, Margulies SS. Regional, directional, and age-dependent properties of the brain undergoing large deformation. J Biomech Eng. 2002;124(2):244-252.
2001	Zhang L, Yang KH, King AI. Biomechanics of neurotrauma. Neurol Res. March–April 2001;23(2-3):144-156.
1970	Galford JE, McElhaney JH. A viscoelastic study of scalp, brain, and dura. J Biomech. 1970;3(2):211-221.
1996	Schinagl RM, Ting MK, Price JH, Sah RL. Video microscopy to quantitate the inhomogeneous equilibrium strain within articular cartilage during confined compression. Ann Biomed Eng. July–August 1996;24(4):500-512.
1990	Margulies SS, Thibault LE, Gennarelli TA. Physical model simulations of brain injury in the primate. J Biomech. 1990;23(8):823-836.
1999	Smith DH, Wolf JA, Lusardi TA, Lee VM-Y, Meaney DF. High tolerance and delayed elastic response of cultured axons to dynamic stretch injury. J Neurosci. June 1, 1999;19(11):4263-4269.

Year

Entry

2002

Brands DWA, Bovendeerd PHM, Wismans JSHM. On the potential importance of non-linear viscoelastic material modelling for numerical prediction of brain tissue response: test and application. Stapp Car Crash J. 2002;46:103-121. SAE 2002-22-0006.

1982

Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP. Diffuse axonal injury and traumatic coma in the primate. Ann Neurol. 1982;12(6):564-574.

2004

Nicolle S, Lounis M, Willinger R. Shear properties of brain tissue over a frequency range relevant for automotive impact situations: new experimental results. Stapp Car Crash J. 2004;48:239-258. SAE 2004-22-0011.

1997

Smith DH, Chen X-H, Xu B-N, McIntosh TK, Gennarelli TA, Meaney DF. Characterization of diffuse axonal pathology and selective hippocampal damage following inertial brain trauma in the pig. J Neuropathol & Exp Neurol. July 1997;56(7):822-834.

2003

Takhounts EG, Crandall JR, Darvish K. On the importance of nonlinearity of brain tissue under large deformations. Stapp Car Crash J. 2003;47:79-92. SAE 2003-22-0005.