Faculty Book
W. DALTON DIETRICH, Ph.D.
Scientific Director
Professor, Neurological Surgery, Neurology, and Cell Biology & Anatomy
Neuroprotection and Improved Recovery of Function following CNS Trauma
Research
Interests
My research interest is the pathobiology and treatment of CNS injury in both the acute and chronic setting. Animal models of cerebral ischemia, and brain and spinal cord trauma are utilized to investigate the mechanisms of tissue injury. The ultimate goal is to target specific injury processes for pharmacological intervention, including the addition of growth factors, to promote circuit plasticity, regeneration and recovery of function.
Recent studies have demonstrated the neuroprotective effects of moderate hypothermia following traumatic brain injury. Brain cooling has been shown to protect the brain histopathologically and to improve functional outcome. These experimental studies have led to the initiation of clinical trials for hypothermia in humans in traumatic brain and spinal cord injury. Studies are currently in progress to demonstrate the potential benefits of hypothermia following spinal cord injury. In contrast to hypothermia, brain hyperthermia following ischemia and trauma significantly aggravates outcome. Thus, fever appears to be a potentially severe secondary injury mechanism that must be avoided in head or spinal cord injured (SCI) patients.
Various potentially neuroprotective agents are currently being tested in models of CNS trauma. Nitric oxide (NO) produced at high levels following CNS injury can act as a free radical intermediate and produce cytotoxicity. Ongoing studies are investigating novel way to target abnormal NO production by inhibiting inducible nitric oxide synthase (iNOS) early after SCI. In this regard, both pharmacological and gene therapeutic inhibition of iNOS appear to be neuroprotective and enhance behavioral recovery after CNS injury.
The neurotrophic factor, basic fibroblast growth factor (bFGF), has recently been shown to be neuroprotective in models of cerebral ischemia and traumatic brain injury. These experimental data have led to the initiation of a multicenter clinical trial of bFGF in acute stroke patients. In addition to neuroprotection, various strategies are being shown to promote recovery of function when given days after the primary insult. Recent animal studies have demonstrated that bFGF given 24 hours after focal ischemia accelerates recovery of function. Importantly, bFGF-induced improved functional recovery appears to be associated with brain circuit reorganization. Thus, the possibility exists that in chronic injury states, such as spinal cord injury, neurotrophic factors may be given to induce circuit rewiring and, thus, improve outcome. Studies are currently underway to determine the specific mechanisms by which bFGF and other neurotrophic factors improve outcome in models of spinal cord injury.
Video Introduction
Atkins CM, Oliva, Jr. AA, Alonso OF, Pearse DD, Bramlett HM, Dietrich WD (2007) Modulation of the cAMP signaling pathway after traumatic brain injury. Exp Neurol. 2007 Aug 29; [Epub ahead of print]. [Abstract]
Atkins, CM, Oliva, Jr, AA, Alonso OF, Chen S, Bramlett HM, Hu BR, Dietrich WD (2007) Hypothermia treatment potentiates ERK1/2 activation after traumatic brain injury. Eur J Neurosci 26:810-819. [Abstract]
Davis AR, Lotocki G, Marcillo AE, Dietrich WD, Keane RW (2007) FasL, Fas, and Death-Inducing Signaling Complex (DISC) Proteins Are Recruited to Membrane Rafts after Spinal Cord Injury. J Neurotrauma 24(5): 823-834. [Abstract]
Urrea C, Castellanos DA, Sagen J, Tsoulfas P, Bramlett HM, Dietrich WD (2007) Widespread cellular proliferation and focal neurogenesis after traumatic brain injury in the rat. Restor Neurol Neurosci 25(1):65-76. [Abstract]
Chen S, Atkins CM, Liu CL, Alonso OF, Dietrich WD, Hu B (2007) Alterations in mammalian target of rapamycin signaling pathways after traumatic brain injury. J Cereb Blood Flow Metab 27(5):939-49.
Truettner JS, Hu B, Alonso OF, Bramlett HM, Kokame K, Dietrich WD (2007) Subcellular stress response after traumatic brain injury. J Neurotrauma 4:599-612. [Abstract]
Lozano JD, Abulafia P, Danton GH, Watson BD, Dietrich WD (2007) Characterization of a thromboembolic photochemical model of repeated stroke in mice. J Neuroscience Methods 162:244-254. [Abstract]
Lane MA, Truettner JS, Brunschwig J-P, Gomez A, Bunge MB, Dietrich WD, Dziegielewska, Elk CJ, JL VandeBerg, Saunders NR (2007) Age-related differences in the local cellular and molecular responses to injury in developing spinal cord of the opossum, Monodelphia domestica/. Eur J Neurosci 25:1725-1742. [Abstract]
Atkins CM, Chen S, Alonso OF, Dietrich WD, Hu B (2006) Activation of calcium/calmodulin-dependent protein kinases after traumatic brain injury. J Cereb Blood Flow Metab 26:1507-1518. [Abstract]
Fleming JC, Norenberg MD, Ramsay DA, Dekaban GA, Marcillo AE, Saenz AD, Dietrich WD, Weaver LC (2006) The cellular inflammatory response after human spinal cord injury. Brain 129:3249-3269. [Abstract]
Lotocki G, Keane RW, Alonso OF, Curbello K, Dietrich WD (2006) Therapeutic hypothermia modulates TNFR1 signaling in the traumatized brain via early transient activation of the JNK pathway and suppression of XIAP cleavage. Eur J Neurosci 24:2283-2290. [Abstract]
Keane RW, Davis A, Dietrich WD (2006) Inflammatory and apoptotic signaling following spinal cord injury. J Neurotrauma 23(3/4):335-344. [Abstract]
Truettner JS, Alonso OF, Dietrich WD (2005) Influence of therapeutic hypothermia on matrix metalloproteinase activity after traumatic brain injury in rats. J Cereb Blood Flow Metab 25:1505-1516.
Blits B, Kitay BM, Farahvar A, Caperton CV, Dietrich WD, Bunge MB (2005) Lentiviral vector-mediated transduction of neural progenitor cells before implantation into injured spinal cord and brain to detect their migration, deliver neurotrophic factors and repair tissue. Restor Neurol Neurosci 23:313-324. [Abstract]
Pearse DD, Lo TP, Cho KS, Lynch MA, Garb MS, Marcillo AE, Sanchez AR, Bunge MB, Dietrich WD (2005) Histopathological and behavioral characterization of a novel cervical spinal cord displacement contusion injury in the rat. J Neurotrauma 22:680-702. [Abstract]
Truettner JS, Suzuki T, Dietrich WD (2005) The effect of therapeutic hypothermia on the expression of inflammatory response genes following moderate traumatic brain injury in the rat. Molec Brain Res 138:124-134. [Abstract]
Suzuki T, Bramlett HM, Dietrich WD (2004) The effects of post-traumatic hyperthermia in female and ovariectomized rats. J Neurotrauma 21(7):842-853. [Abstract]
Bramlett HM, Dietrich WD (2004) Pathophysiology of cerebral ischemia and brain trauma. Similarities and differences. J Cereb Blood Flow Metab, 24(2):133-150. [Abstract]
Hu B, Liu C, Bramlett H, Sick TJ, Chen S, Alonso OF, Dietrich WD (2004) Activation of TrkB – ERK ½ - CREB/Elk-1 Pathways in hippocampal mossy fiber organization after traumatic brain injury. J Cereb Blood Flow Metab 24 (8):933-943.
Lotocki G, Alonso OF, Dietrich WD, Keane RW (2004) TNF receptor 1 and its signaling intermediates are recruited to lipid rafts in the traumatized brain. J Neurosci 24(49):11010-11016.
Urrea C, Danton GH, Dietrich WD. (2004) The beneficial effect of mild hypothermia in a rat model of repeated thromboembolic insults. Acta Neuropathol, 107(5):413-420. [Abstract]
Vitarbo E, Chatzipanteli K, Kinoshita K, Truettner JS, Alonso, OF, Dietrich WD. (2004) Tumor necrosis factor alpha expression and protein levels following fluid percussion injury in rats: The effect of injury severity and brain temperature. Neurosurgery 55(2):416-424.
Updated October 21, 2007
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