The mechanism(s) of delayed secondary injury following traumatic brain injury (TBI) may involve the alteration of specific intracellular signaling pathways involving the mitogen activated protein (MAP) kinases JNK and Erk 1/2, as well as long-term genomic changes. These pathogenic molecular events provide targets for treatment with growth factors intended to prevent or limit neurologic disability. The investigators, among others, have generated preliminary data suggesting that acute (24 hr postinjury) administration of exogenous NGF or basic fibroblast growth factor (bFGF) may be neuroprotective in experimental models of brain injury.
Specific Aim 1 will assess whether administration of either NGF or bFGF in the acute post-traumatic period (beginning 24 hr postinjury) will attenuate long-term neurologic disability and neurodegenerative (apoptotic/necrotic) cell loss following experimental lateral fluid percussion (FP) brain injury in rats. The investigators will selectively infuse these growth factors directly into the injured brain over a 2-week postinjury period, and behaviorally evaluate the animals over a chronic 3-month postinjury period for neurologic motor and sensorimotor dysfunction, cognitive deficits, and regional cell death.
Specific Aim 2 will evaluate the temporal and regional alterations in specific MAP kinase (JNK/Erk 1/2) signaling pathways following experimental FP brain injury, and relate the neuroprotective effects of therapy with NGF or bFGF to a reversal of the pathologic changes in JNK/Erk induced by trauma. They will use Western blotting and immunohistochemistry to support their pilot data that TBI results in activation of the pro-death kinase JNK signaling pathway and a concomitant decrease in signaling through the pro-survival Erk 1/2 pathway. The effects of NGF or bFGF therapy and cessation of 2-week therapy (i.e., growth factor withdrawal) on these trauma-induced signal transduction cascades will then be regionally and temporally evaluated.
In Specific Aim 3, they will quantify the effects of NGF or bFGF therapy on trauma-induced alterations in expression profiles of genes involved in cell death/survival and long-term plasticity/remodeling of the injured CNS. The investigators will use laser capture microdissection and reverse-Northern hybridization techniques with custom-designed slot-blots to quantify expression levels of a selected panel of genes, including cell death/survival genes, cytoskeletal genes, growth-related proteins, and cytokines. Genomic changes will be confirmed at a translational level with immunohistochemistry for selected proteins.
In Specific Aim 4, the investigators will selectively infuse NGF or bFGF into the injured brain over a 2-week treatment period beginning 2 weeks or 1 month postinjury and evaluate the ability of these delayed treatment paradigms to improve long-term neurological motor and cognitive function (up to 3 months postinjury) and attenuate progressive post-traumatic cell death.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS040978-01
Application #
6256519
Study Section
Special Emphasis Panel (ZRG1-BDCN-1 (01))
Program Officer
Michel, Mary E
Project Start
2000-12-01
Project End
2005-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
1
Fiscal Year
2001
Total Cost
$342,000
Indirect Cost
Name
University of Pennsylvania
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Malik, Saafan Z; Maronski, Margaret A; Dichter, Marc A et al. (2012) The use of specific AAV serotypes to stably transduce primary CNS neuron cultures. Methods Mol Biol 846:305-19
Malik, Saafan Z; Motamedi, Shahab; Royo, Nicolas C et al. (2011) Identification of potentially neuroprotective genes upregulated by neurotrophin treatment of CA3 neurons in the injured brain. J Neurotrauma 28:415-30
Hånell, Anders; Clausen, Fredrik; Björk, Maria et al. (2010) Genetic deletion and pharmacological inhibition of Nogo-66 receptor impairs cognitive outcome after traumatic brain injury in mice. J Neurotrauma 27:1297-309
Ortinski, Pavel I; Dong, Jinghui; Mungenast, Alison et al. (2010) Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat Neurosci 13:584-91
Marklund, N; Morales, D; Clausen, F et al. (2009) Functional outcome is impaired following traumatic brain injury in aging Nogo-A/B-deficient mice. Neuroscience 163:540-51
Conte, Valeria; Raghupathi, Ramesh; Watson, Deborah J et al. (2008) TrkB gene transfer does not alter hippocampal neuronal loss and cognitive deficits following traumatic brain injury in mice. Restor Neurol Neurosci 26:45-56
Royo, Nicolas C; Vandenberghe, Luk H; Ma, Jing-Yuan et al. (2008) Specific AAV serotypes stably transduce primary hippocampal and cortical cultures with high efficiency and low toxicity. Brain Res 1190:15-22
Marklund, Niklas; Bareyre, Florence M; Royo, Nicolas C et al. (2007) Cognitive outcome following brain injury and treatment with an inhibitor of Nogo-A in association with an attenuated downregulation of hippocampal growth-associated protein-43 expression. J Neurosurg 107:844-53
Royo, N C; LeBold, D; Magge, S N et al. (2007) Neurotrophin-mediated neuroprotection of hippocampal neurons following traumatic brain injury is not associated with acute recovery of hippocampal function. Neuroscience 148:359-70
Chen, H Isaac; Bakshi, Asha; Royo, Nicolas C et al. (2007) Neural stem cells as biological minipumps: a faster route to cell therapy for the CNS? Curr Stem Cell Res Ther 2:13-22

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