• HMGB1-TLR4 Signaling Following Traumatic Brain Injury

      Laird, Melissa D; Department of Neurosurgery (2011-05)
      Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Although preventative measures may reduce the incidence of TBI, over 1.7 million Americans suffer a head injury annually1. Brain edema, the abnormal accumulation of fluid within the brain parenchyma, contributes to elevated intracranial pressure (ICP), brain herniation, and a poor prognosis following head injury2"4. Clinically, the degree of swelling on the first computed tomography (CT) scan directly correlates with patient outcome, demonstrating the need to limit brain edema following head injury5. Unfortunately, current medical therapies do not effectively control brain edema and neurosurgical approaches to alleviate increased ICP are invasive and of limited utility. A longrange goal of our laboratory is to elucidate the molecular and cellular mechanisms that promote cerebral edema, which may aid in the development of novel therapeutics for head trauma patients. A central premise of our hypothesis is that activation of Toll-like receptor 4 (TLR4) increases brain edema following TBI. Toll-like receptors (TLR) are membrane proteins within the interleukin-1 receptor superfamily that mediate innate immunity6"8; however, recent evidence suggests TLR are also expressed within the CNS of humans and rodents9"12. Activation of TLR4 exacerbated neuronal injury and neuroinflammation following cerebral ischemia13,14, although the involvement of TLR4 following TBI has only just begun to be examined and comparatively little is known15,16. Given the association between inflammation, neurological injury, and patient outcome17, TLR4 may represent an unexplored therapeutic target following TBI. We hypothesize that High Mobility Group Box Protein B1 (HMGB1), a putative endogenous ligand forTLR4, is released via an NR2B mechanism and promotes cellular edema following TBI.
    • mTOR inhibition reduces cellular proliferation and sensitizes pituitary adenoma cells to ionizing radiation

      Sukumari-Ramesh, Sangeetha; Singh, Nagendra; Dhandapani, Krishnan M.; Vender, John R.; Department of Neurosurgery; Department of Biochemistry and Molecular Biology (2011-02-23)
      Background:: Pituitary adenomas are the most frequent brain tumor in adults. Although histologically benign, pituitary tumors cause significant morbidity and mortality. Neurosurgery and medical therapeutics may lessen the morbidity and mortality associated with pituitary tumors; however, these treatments are associated with significant adverse side effects. Thus, an improved understanding of pituitary adenomas at the molecular and cellular level is needed to design novel therapeutic compounds.
    • Neuronal and Astroglial Injury and Recovery from Stroke-Induced Depolarizations

      Risher, William Christopher; Department of Neurosurgery (2010-12)
    • The Role of TNF-Alpha Signaling in the Pathophysiology of Intracerebral Hemorrage

      King, Melanie Dawn Ivester; Department of Neurosurgery (2013-05)
      Intracerebral hemorrhage (ICH), the most common form of hemorrhagic stroke, exhibits the highest acute mortality and the worst long-term prognosis of all stroke subtypes. Unfortunately, treatment options for ICH are lacking due in part to a lack of feasible therapeutic targets. Inflammatory activation is associated with neurological deficits in pre-clinical ICH models and with patient deterioration after clinical ICH. In the present study, we tested the hypothesis that R-7050, a novel cell-permeable triazoloquinoxaline inhibitor of the tumor necrosis factor receptor (TNFR) complex, attenuates neurovascular injury after ICH in mice. Up to 2h post-injury administration of R-7050 significantly reduced blood-brain barrier opening and attenuated edema development at 24h post-ICH. Neurological outcomes were also improved over the first days after injury. In contrast, R-7050 did not reduce hematoma volume, suggesting the beneficial effects of TNFR inhibition were downstream of clot formation/resolution. These data suggest a potential clinical utility for TNFR antagonists as an adjunct therapy to reduce neurological injury and improve patient outcomes after ICH.
    • Therapeutic Targeting of P2X7 After Traumatic Brain Injury

      Kimbler, Donald E.; Department of Neurosurgery (2012-02)
      Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Cerebral edema, the abnormal accumulation of fluid within the brain parenchyma, contributes to elevated intracranial pressure (ICP) and is a common life-threatening neurological complication following TBI. Unfortunately, neurosurgical approaches to alleviate increased ICP remain controversial and medical therapies are lacking due in part, to the absence of viable drug targets. In the present study, genetic inhibition (P2X7-/- mice) of the purinergic P2X7 receptor attenuated the expression of the pro-inflammatory cytokine, interleukin-iP (IL-ip) and reduced cerebral edema following controlled cortical impact, as compared to wild-type mice. Similarly, the clinically useful P2X7 inhibitor, brilliant blue G (BBG), inhibited the expression of IL-ip, limited edemic development and prevented the development of post-traumatic depression and anxiety. The beneficial effects of BBG were observed following either prophylactic administration via the drinking water for one week prior to injury or via an intravenous bolus administration up to four hours after TBI, suggesting a clinically-implementable therapeutic window. Notably, P2X7 localized within astrocytic end feet and administration of BBG decreased the expression of glial fibrillary acidic protein (GFAP), a reactive astrocyte marker, and reduced the expression of aquaporin-4 (AQP4), an astrocytic water channel that promotes cellular edema. Together, these data implicate P2X7 as a novel therapeutic target to prevent secondary neurological injury after TBI, a finding that warrants further investigation.