Traumatic brain injury (TBI) is a devastating neurological injury afflicting over 1 million people annually, including a large number of young adults and military personnel. Cerebral edema is associated with increased intracranial pressure (ICP) and a poor clinical outcome following TBI, although the cellular mechanisms underlying this process remain unknown. This gap in the understanding of cerebral edema formation contributes to the lack of clinically- effective therapeutics for TBI patients. Recent work by our laboratory demonstrates that acute neuronal necrosis stimulates the passive release of high mobility group box protein 1 (HMGB1), which in turn induces glial swelling and cerebral edema.
Specific Aim 1 will establish whether activation of individual NMDA receptor subunits increase neuronal injury and cerebral edema following experimental TBI. The incorporation of NR2A and NR2B knockout mice will determine whether individual NR2 subunits contribute to HMGB1 release, brain swelling, and neurological outcome using following head trauma.
Specific Aim 2 will determine whether toll-like receptor-4 (TLR4) mediates the pro- inflammatory and cerebral edema promoting effects of HMGB1. The ability of HMGB1 to stimulate the astrocytic water channel, AQP4, will also be addressed in TLR4 mutant mice.
Specific Aim 3 will determine whether HMGB1 may represent a novel biomarker to predict the development of cerebral edema folowing head trauma in humans. Measurement of HMGB1 levels within the cerebrospinal fluid (CSF) and serum of neurotrauma patients will be correlated with acute neuronal injury and neurological outcome. Together, the proposed studies will investigate the novel possibility that HMGB1-TLR4 signaling contributes to the development of cerebral edema and increased ICP following TBI. The results of these studies may support the future development of novel therapeutics directed against this pathway to limit neurological injury following head trauma.

Public Health Relevance

Traumatic brain injury (TBI) is a serious medical condition that hospitalizes and disables many Americans, placing a large economic burden on society. Current medical therapies do not effectively control brain swelling, in part, due to a lack of mechanistic understanding regarding the development of cerebral edema following TBI. An improved understanding of these mechanisms at the cellular levels may aid in the discovery of novel therapeutics, which could substantially reduce patient mortality and improve patient outcome. The present application will assess the potential role of neuronal necrosis, secondary to glutamate excitotoxicity, as a causative factor in the development of cellular edema following TBI.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
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Hicks, Ramona R
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Georgia Regents University
Schools of Medicine
United States
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Eroglu, Binnur; Kimbler, Donald E; Pang, Junfeng et al. (2014) Therapeutic inducers of the HSP70/HSP110 protect mice against traumatic brain injury. J Neurochem 130:626-41
Laird, Melissa D; Shields, Jessica S; Sukumari-Ramesh, Sangeetha et al. (2014) High mobility group box protein-1 promotes cerebral edema after traumatic brain injury via activation of toll-like receptor 4. Glia 62:26-38
King, Melanie D; Alleyne Jr, Cargill H; Dhandapani, Krishnan M (2013) TNF-alpha receptor antagonist, R-7050, improves neurological outcomes following intracerebral hemorrhage in mice. Neurosci Lett 542:92-6
Kimbler, Donald E; Murphy, Marguerite; Dhandapani, Krishnan M (2011) Concussion and the adolescent athlete. J Neurosci Nurs 43:286-90
King, Melanie D; McCracken, D Jay; Wade, F Marlene et al. (2011) Attenuation of hematoma size and neurological injury with curcumin following intracerebral hemorrhage in mice. J Neurosurg 115:116-23
Sukumari-Ramesh, Sangeetha; Bentley, J Nicole; Laird, Melissa D et al. (2011) Dietary phytochemicals induce p53- and caspase-independent cell death in human neuroblastoma cells. Int J Dev Neurosci 29:701-10
King, Melanie D; Laird, Melissa D; Ramesh, Sangeetha Sukumari et al. (2010) Elucidating novel mechanisms of brain injury following subarachnoid hemorrhage: an emerging role for neuroproteomics. Neurosurg Focus 28:E10
Wakade, Chandramohan; Sukumari-Ramesh, Sangeetha; Laird, Melissa D et al. (2010) Delayed reduction in hippocampal postsynaptic density protein-95 expression temporally correlates with cognitive dysfunction following controlled cortical impact in mice. J Neurosurg 113:1195-201
Laird, Melissa D; Sukumari-Ramesh, Sangeetha; Swift, Andrew E B et al. (2010) Curcumin attenuates cerebral edema following traumatic brain injury in mice: a possible role for aquaporin-4? J Neurochem 113:637-48
Sukumari-Ramesh, Sangeetha; Laird, Melissa D; Singh, Nagendra et al. (2010) Astrocyte-derived glutathione attenuates hemin-induced apoptosis in cerebral microvascular cells. Glia 58:1858-70