Molecular Mechanisms of Propofol-Involved Protection against Ischemia Brain Injuries

Stroke and brain trauma usually leads to ischemia brain injury. In the processing of ischemia brain injury, brain neurons undergo die over days and months after ischemia, and that reperfusion following cerebral ischemia contributes substantially to ischemic injury. The major contributors to ischemia-reperfusion injury include production of reactive oxygen species, release of proinflammatory cytokines and chemokines, and activation of immune cells to promote inflammation and tissue damage. Nitric oxide (NO) is one of such oxidative effectors participating in regulation of ischemia-reperfusion-induced brain injury. Our previous studies have shown that NO can induce cell insults via an apoptotic mechanism. Alleviating the oxidative stress-induced insults may be beneficial for the treatment of stroke or brain trauma. Propofol, an intravenous anesthetic agent, can be used for induction and maintenance of anesthesia in surgical procedures or applied as a sedative drug for patients with stroke or brain trauma. Our previous studies have shown that propofol at clinically relevant concentrations can protect macrophages from NO-induced apoptotic injuries. Other studies done by our lab also demonstrated the anti-inflammatory effects of propofol. In the processing of ischemia and reperfusion, mitogen-activated protein kinases (MAPKs) have been reported to trigger a serial of signal-transducing events and consequently regulate iNOS gene expression and NO production. Our previous studies reported propofol can downregulate MAPK signals to inhibit expressions of iNOS and inflammatory cytokine genes. In our preliminary results, we showed that propofol at clinical relevant concentrations could protect cerebrovascular endothelial cells from ischemia-reperfusion-induced apoptotic insults (Preliminary Results, Fig. 1). Other preliminary results done by our lab also demonstrated that after trauma impact, the levels of iNOS in brain tissues are significantly augmented (Preliminary Results, Fig. 2). Thus, the anti-oxidative and anti-inflammatory characteristics of propofol may be helpful to the therapy of ischemia brain injury. This project is designed to evaluate the effects of propofol on protection of brain neurons from ischemia brain injury and its possible molecular mechanisms. We hypothesize “Propofol can protect neurons from ischemia brain injuries through downregulating MAPK-mediated iNOS gene expression (Figs. 1 and 2). In the 1st and 2nd years, we will establish two animal models of middle cerebral artery occlusion (MCAO) and traumatic brain impact (TBI) to mimic ischemia brain injury (Fig. 1). By using these two animal models, this project is expected to evaluate the protection of propofol against two different types of ischemia brain injuries. In the 3rd year, we will use an in vitro neural cell model of oxygen-glucose deprivation (OGD) to determine the molecular mechanisms of propofol-involved protection from ischemia- and reperfusion-induced insults to neurons, especially in Ras-Raf-MEK-MAPK-AP-1/NFκB-mediated iNOS gene expression. After executing this project, we expect to understand the pathophysiological mechanisms of stroke- and brain trauma-induced ischemia brain injury, and simultaneously to determine if propofol can protect brain neurons against such insults and their possible molecular mechanisms.