Neuroprotective Effects of Sig-1R-Znf179-Sp1 Pathway on Brain Injury

Rationale: Concussive traumatic brain injury (TBI) is a major cause of death and disability in adults. After primary injury causing immediately brain structural damage, secondary injury including ischemia, inflammation, cerebral edema, etc. may occur from days to weeks leading to more neuron death. Therefore, preventing more extensive neuronal damage in TBI is a very important issue. Preliminary results: Reactive oxygen species (ROS) as a well-known mediator activates cell death signaling pathways in TBI. Hence hydrogen peroxide was used in the cellular studies to produce ROS. Our preliminary data indicated that both models of in vivo weight drop (WD) injury and in vitro hydrogen peroxide-induced cytotoxicity elevated multiple cell death signaling pathways. By treatment with Sigma 1 receptor (Sig-1R) agonist, DHEAS, the activation of death pathways was attenuated significantly. In addition, we also found that Znf-179 was increased in TBI animals and hydrogen peroxide-treated cells and played neuroprotective effects. For the mechanism studies, hydrogen peroxide restrained Znf-179 nuclear shuttling through increasing cytoplasmic interaction of Sig-1R-Znf-179. However, agonists treatment activated Sig-1R to release Znf-179 into the nucleus. Znf-179 subsequently associated with Sp1 to auto-regulate promoter activity by itself as well as up-regulated other neuroprotective genes expression. Hypothesis: We assume that Sig-1R agonists as the potential neuroprotective agents for TBI via activating Sig-1R-Znf-179-Sp1 neuroprotective pathway against cell apoptosis. Specific Aim: Based on the hypothesis, there are three specific aims to be addressed. First, we will study the neuroprotective mechanisms of Sig-R, Znf-179 and Sp1 in a cellular model of hydrogen peroxide-induced oxidative damage. Second, we will further evaluate protective functions of Znf-179 and Sp1 by using Znf-179 transgenic and Sp1 knockout mice separately in the TBI models of WD and controlled cortical impact (CCI). Third, we will examine whether Sig-1R agonists protect neuron through inducing Sig-1R-Znf-179-Sp1 pathway as a therapeutic approach in TBI animal models. Novelty and application: In this study, Znf-179 is indicated playing a new function in neuroprotection. Additionally, by performing in vitro cellular experiments and in vivo animal testing, Sig-1R agonists such as DHEAS and Pre084 protect neurons and prevent more extensive damage following primary injury of TBI via activating the Sig-1R-Znf-179-Sp1 pathway.