New Drug Development for Mtbi

This project is designed to investigate the new treatments with our purified and characterized compounds from herbal medicine for mTBI. The traumatic brain injury (TBI) produces a broad range of short- and long-term physical, cognitive, behavioral and emotional impairments that depend on the severity of the injury. While it is relatively easy to diagnose severe TBI victims who suffer direct damage to the brain tissue or to the blood brain barrier who or develop post injury edema, the diagnosis of those suffering from moderate or mild TBI is less evident. Routine and extended laboratory and clinical evaluation of mTBI patients fails to show any clear morphological brain defects, but the patients frequently suffer lasting cognitive and emotional difficulties, including various degrees of amnesia, difficulty in concentration and executive functions, depression, apathy and anxiety. Although clinical signs and symptoms of mTBI usually resolve within the first year after injury, many patients continue to manifest prolonged or even permanent neurocognitive dysfunction, which has been termed "the post-concussive syndrome". We conducted an epidemiology study of mTBI in the Taipei city area from July 1, 2001 to June 30, 2002. Totally, 3,243 cases from 22 hospitals were procured. Among these cases, about 10% of them had severe disability and death, and 25% of them developed intracranial hematoma later on. In consistence with our data, the Centers for Disease Control of US have focused considerable attention to short and long-term consequences of blunt trauma and acceleration/deceleration mTBI. This programmatic effort recognizes the significant prevalence, morbidity and mortality rates and costs in civilian and military populations. More recently, Blast-Induced Traumatic Brain Injury (m-TBI) has become one of the most prevalent injuries occurring in US military operations in Southwest Asia. A recent study by the RAND Corporation, which has since been endorsed by the military, found that 19% of all individuals involved in combat in Southwest Asia have suffered some degree of traumatic brain injury. While there are many injured war fighters who have sustained moderate and severe TBI, the overwhelming vast majority of the individuals suffer mTBI. There are signs in the on-going clinical observations that underscore the urgency of this need. In addition to hearing loss and complaints of reduced cognitive function, mTBI effects appear to include an increased prevalence and severity of prominent signs of mTBI such as headaches, constant unsteadiness (poor balance) and true vertigo. Recently, it has been estimated that at least 15% of those who serve in Iraq suffer a clinically significant degree of mTBI. Since the symptoms are often unrecognized and untreated, they may be manifest at a later time in clinical entitities that include signs and symptoms of post-traumatic migraine and post-traumatic Meniere's disease. This research plan is a collaborative effort by experienced research teams from United States and Taiwan to use their unique expertise to improve detection, diagnosis, treatment and management of mTBI related symptoms of balance disorders, anxiety disorders and migraine. We will use the same exposure conditions to test the hypothesis that three novel ant卜apoptotic, anti-inflammatory and anti-oxidative therapeutic agents can ameliorate the development of alterations in noradrenergic, serotonergic, and melatonin transmission in animal models of mTBI. Three therapeutic approaches will be tested. The first approach will test the hypothesis that p53 inactivation will reduce neuronal cell death in rodents subjected to mTBI, and will translate to improved behavioral sequelae. In this project, we are to investigate (1) prototype therapies with purified herbal medicine for ameliorating damage from mTBI due to single or repeated exposures; (2) the hypothesis that p53 inactivation (with lipophilic imino-tetrahydrobenzothiazoles and -oxazoles) will reduce neuronal cell death and improve behavioral outcomes in rodents subjected to mTBI; (3) the hypothesis that similar improved outcomes will be achieved by inhibition of TNF-a synthesis with our compounds with similar effect as the thio analogs of the agent, N-a-phthalimidoglutarimide; (4) the medicinal chemistry of pharmacophores derived from herbal medicine that possess mitochondrial uncoupling activity (2,4-dinitrophenol (2,4-DNP) and carbonyl cyanide 4-trifluoromethoxy phenylhydrazone; and (5) test the hypothesis that the four most promising agents improve outcome in animal models of mTBI.