Traumatic brain injury (TBI) is the leading cause of death in the young age group and the most commonly identified cause of epilepsy in adult populations older than 35 years. It triggers a cascade of events characterized by the activation of molecular and cellular responses, mostly harmful, leading to secondary injury. Parallel to these deleterious processes, neuroprotective events also take place including secretion of growth factors, and activation of anti-apoptotic signalling pathways. Despite the acute need of an effective pharmacological means to treat TBI victims, pharmaco-therapy remains scarce and new drug targets are clinically necessary. Previously it was shown that treatment with synthetic cannabinoid 2-AG, attenuated edema formation, infarct volume, blood-brain barrier permeability, neuronal cell loss at the CA3 hippocampal region and neuro-inflammation following closed head injury (CHI). Moreover, improved recovery of neurobehavioral function was noted for up to 3 months after treatment of CHI mice with 2-AG. Based on these studies it is clear that the cannabinoid system plays a critical role in neuroprotection following TBI. However, little is known about the role of the cannabis plant in TBI. Our preliminary results indicate that mice treated with one of the major compounds that were found in the cannabis plant, cannabidiol (CBD), after CHI, show a remarkable recovery profile in motor function compared to control untreated mice. Therefore, we propose to investigate the molecular basis of the neuroprotective role of CBD following CHI in mice. We will examine the optimal time course and dose of treatment with CBD after CHI. We will characterize changes in gene-expression in specific injured tissues in order to evaluate the molecular basis of CBD treatment. We will examine the possibility that part of the neuroprotection of CBD is due to epigenetic mechanism. To this end, we will analyze changes in gene methylations, histone modifications on chromatin structure and composition in mice treated with CBD in specific brain areas during the course of recovery. If successful, the results of the present study will provide the first evidence that the cannabis plant is useful for treating TBI and will set the basis for future deep examination of its neuroprotective potential.