Roles of Autophagy and Heme Oxygenases(-1, -2) in Brain Injuries: in Vivo and in Vitro Studies

Traumatic brain injury (TBI) is often caused by traffic accidents (particularly with motorcycles in Taiwan), crashing from high attitude, sport or leisure activities and about half the survivors have neurological sequelae. TBI often causes edema and elevated intracranial pressure (ICP) which leads to ischemia and then reperfusion (ischemia/reperfusion, I/R) when ICP falls. TBI and I/R both trigger similar pathogenetic events including sensory, motor and cognitive behavioural impairments and necrotic and apoptotic cell death.. Autophagy, a highly regulated cellular degradation process responsible for the turnover of long-lived proteins and organelles. Although it is clear that autophagy is increased in brains after acute TBI, the role for autophagy (beneficial or detrimental in TBI ) is not clear. Heme oxygenase (HO) degrades heme into carbon monoxide (CO), ferric iron and biliverdin (BV). Among the three isoforms of HO, the HO-1(inducible) and HO-2 (constutive) have been described for their cerebroprotective function. However, their relative roles in brain injuries remains unclear. We have previously established two animal models of brain injuries, i.e. the rat model of cerebral ischemia / reperfusion (I/R) and traumatic brain injury (TBI). Our recent in vivo data have indicated that expression of autophagy-related proteins, including microtubule associated protein light chain 3 (LC3II) and beclin-1 in a time-dependent manner in cortical tissue from TBI and I/R rats. Using primary cultures of neuron/glia, we also found expression of heme oxygenase-1 (HO-1) is time-depently induced in acute neuronal injury caused by oxidative insults (such as H2O2). This 3-year project is aimed to elucidate the roles of autophagy in acute brain injuries. In the first year (2010-2011), we would also like to systematically investigate the role of the autophagy in animal models (TBI and I/R) and cell cultures (exposed to scrach wound injury or oxidative insults).In the second year (2011-2012), we will explore temporal and spatial expression pattern of HO-1 and HO-2 in injured cortical tissue of rat with TBI or I/R .We will examine the functional role of HOs ( in terms of alleviate or aggravate injury)by HO-inducers or activity inhibitors (and/or shRNA of HO-1 and HO-2). In the third year (2012-2013), We recently found that baicalein ,G-CSF , and Vitamin C have beneficial effects on brain injuries. We will ellucidate whether their beneficial effects are, at least partially, mediated through regulation on either autophagy or HOs (or both systems) . The results from this project will help us to understand the functional roles of autophagy and HOs in acute brain injury. Based on the recent report on the identification of eight compounds that can induce autophagy and promote long-lived protein degradation, we believe that future application of drugs that can manipulate autophagy may help TBI patients . Interestingly, seven of eight compounds are FDA-approved drugs for treatment of human diseases. Results from this studies may advance our knowledge of autophagy in TBI and shed some light on the drug development.