J147 Treatment for Traumatic Brain Injury in Brain Damage and Long-Term Functional Recovery

ABSTRACT Traumatic brain injury (TBI) is a significant clinical problem with few therapeutic interventions successfully translated from the bench to the clinic. In this proposal, we hypothesize that the therapeutic treatment of J147 protects against secondary brain damage and promotes long-term functional recovery following TBI. J147, a curcumin-derived small molecule compound which can easily cross the BBB, has been shown to have multiple neuroprotective and neurotrophic properties against age-related neurodegenerative disorders. In addition, J147 is shown to be neuroprotective against experimental ischemic stroke and glutamate-induced neuronal death in cortical neuron culture. However, the effects of J147 in TBI has not yet been investigated. In a mouse controlled cortical impact model of TBI, our preliminary data show that J147 treatment prevents neuronal cell degeneration and attenuates prolonged ER stress in the perilesional area after TBI. Moreover, J147 treatment significantly promotes the recovery of neurological functions during the 2-week observation period after TBI, with a substantial improvement in neuronal plasticity. These exciting preliminary data suggest that J147 treatment may represent a promising therapeutic approach to prevent and/or reduce secondary brain damage, improving long-term outcomes following TBI. In this application, we propose to develop a new TBI therapy with J147 treatment and to investigate molecular mechanisms underlying J147 therapy-mediated beneficial effects. We now propose three aims to investigate this new TBI therapy. In aim 1, we will explore the optimal dose of J147 treatment for TBI in functional recovery and injury severity. Brain contusion volume, hippocampal neuronal loss and white matter damage will be examined 35 days after brain injury. A battery of neurobehavioral tests will be performed during the 35-day survival time. In aim 2, we will explore the therapeutic time-window of J147, and its effects on long-term recovery and impacts among different ages. For exploring the therapeutic time-window, the optimal dose of J147 will be initiated 1- 12h. The animals will be allowed to survive for 35 days. For testing long-term effects of J147 and its impacts among different ages, two different age groups will be subjected to TBI and treated with J147. Animals will be allowed to survive for 6 months. All measurements will be performed similarly to Aim 1. In aim 3, we will explore the potential mechanisms underlying the J147 treatment that attenuate brain damage and promote functional recovery, with a focus on ER stress, apoptosis, and neuronal plasticity. The spatial and temporal variation of ER stress and stress-related Sirt1 activation will be assessed. The neuronal cell degeneration and apoptosis in the perilesional area will be determined. The RNAi experiment will be performed to identify the actions of J147 in the relation of Sirt1 activation with ER stress and apoptosis after TBI. The role of J147 in post-injury neuronal plasticity will also be explored.