Nitric Oxide Metabolism in Acute Traumatic Brain Injury

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Cerebral contusion (CC), the most common form of traumatic brain injury (TBI), is often associated with blood- brain barrier (BBB) disruption, vasogenic cerebral edema (VCE), increased intracranial pressure (ICP), and intracranial hemorrhage (ICH) resulting in severe disability or death. Thrombin has been implicated in BBB disruption and VCE following the injury, but its inhibition without considering the ICH is potentially risky as thrombin inhibition can cause more bleeding. Recently, our laboratory reported novel findings of CC-induced imbalance of endothelial nitric oxide (NO) redox metabolites (peroxynitrite/ONOOˉ > S-nitrosoglutathione/GSNO) as a potential target to attenuate early events of thrombin-induced BBB disruption. In cultured brain endothelial cells, thrombin-induced ONOOˉ synthesis led to RhoA-mediated endothelial barrier disruption. On the other hand, GSNO treatment inhibited thrombin-induced endothelial barrier disruption via inhibiting RhoA-mediated mechanisms. Based on these findings, the goal of this proposal is to evaluate drugs targeting imbalanced NO redox metabolites (ONOOˉ > GSNO) for inhibition of non-hemostatic thrombin activity and associated vascular pathology in TBI. ONOOˉ inhibits platelet activity for hemostatic blood coagulation. For this reason, scavenging ONOOˉ by its scavenger FeTPPS might be also beneficial for control of bleeding as well as protection of BBB disruption. Alternatively, systemic exogenous GSNO treatment might also be beneficial for BBB protection. However, it is potentially risky, if the injury involves active ICH, because of its anti-platelet activity in the blood. GSNO is synthesized intracellularly and is not readily diffusible across the cell membrane. In the cells, GSNO is degraded by cytosolic enzyme GSNO reductase (GSNOR) and thus its inhibition primarily increases intracellular GSNO levels while minimizing the elevation of GSNO in blood. Based on the above rationale, we hypothesize that N6022 (inhibitor of GSNOR) will provide better outcomes than systemic GSNO treatment by increasing the intracellular GSNO levels, thus inhibiting the endothelial cell signaling for BBB disruption, while minimizing the elevation of blood GSNO levels, thus sparing the blood coagulation activity. We further hypothesize that scavenging ONOOˉ by FeTTPs also provide additional efficacy by inhibiting the pathological role of ONOOˉ in BBB disruption as well as blood coagulation. To test these hypotheses, the proposed specific aims are; Aim 1: To evaluate the efficacy of NO-metabolomic drugs (GSNO, N6022, and FeTPPS) on primary vs. secondary injuries following the CC. Aim 2: To investigate the role of NO-metabolomic drugs on hemostatic blood coagulation process and BBB disruption induced by non-hemostatic endothelial cell signaling pathway. The proposed studies are built upon our recent findings identifying NO metabolome as a novel target of VCE. If successful, these studies will result in new insights into the mechanism-based treatment paradigms for early events of TBI leading to inhibition of VCE and ICP in pre-hospital and emergency department settings.