Pre-clinical and Clinical Development of Low Dose Methamphetamine for the Treatment of Traumatic Brain Injury

Abstract : This proposal addresses additional preclinical characterization of low dose methamphetamine as a neuroprotective agent for TBI. We have previously demonstrated that treatment with methamphetamine within 12 hours after TBI significantly improved cognition and functional behavior in 2-3 month old male Wistar rats. These studies were intended to examine the therapeutic effects of methamphetamine in female and aged male rats. We also repeated a MRI time course study with the intent of determining if there was a dose response effect associated with methamphetamine induced white matter track remodeling. We have determined that female rats represent a poor model for TBI. Unlike humans, female rats have a 3-day estrous cycle. This means they are endogenously exposed to the neuroprotective effects of estrogen and progesterone before, during and after injury. This allows them to recover to near normal levels within a few weeks of after injury. In this context, it is not possible to observe any kind of drug effect on cognitive or behavioral outcomes. We have determined that methamphetamine does not exhibit a therapeutic effect in aged rats. A number of changes exist in aged rats that could account for this observation. First, they have reduced dopamine receptors. We have shown that methamphetamine-mediated neuroprotection is dependent, in part, on the activation of dopamine receptors. This reduction of dopamine receptors also contributes to a condition of chronic inflammation. We have shown that methamphetamine reduces neuroinflammatory signaling. Thus, the reduction of dopamine receptor mediated signaling could explain the loss of protective effect in aged rats. The MRI time course series confirmed our previous results but we did not observe a dose response effect. However, we did determine that methamphetamine treatment significantly increased neurovascular staining in the perilesional region. This data suggests that methamphetamine treatment also enhances angiogenesis after