Michael R. Hoane, Ph.D. - US grants

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a major cause of long-term disability in the United States. Although more individuals survive traumatic brain injury than in the past, the survivors endure residual physical, cognitive, emotional and/or behavioral impairments from the cascade of biochemical responses resulting from TBI. The etiology of secondary brain injury is multi-factorial, with a host of likely interrelated processes: mitochondrial energy failure, excessive generation of reactive oxygen species, activation of destructive enzymes such as poly (ADP-ribose) polymerase (PARP), membrane disruption, neuronal death, thrombosis due to intravascular coagulation in small vessels, increased synaptic concentrations of excitatory amino acids, and activation of innate inflammatory responses. As secondary brain injury is multi-factorial, pharmacological strategies of neuroprotection must include drugs that target multiple mechanisms of the secondary injury. Translation of positive pre-clinical experimental studies into large randomized, controlled trials has been uniformly negative. The reason for the failure of the trials is probably due to many factors also. Specifically relevant to this proposal, the pre-clinical studies often failed to optimize the dose and dosage regimen, doses were often administered at non-clinically relevant times, i.e. pre-injury or immediately after injury with an overall absence of pharmacokinetic data to guide rational dosing. The primary objective of the proposal is to determine the optimal multi-drug therapy to promote neurological recovery in an animal model of traumatic brain injury using behavioral, histological and gene expression markers of neuroprotection to select the drugs and maximize the dosage regiment 1) by identifying combination therapy that targets the maximum number of molecular, cellular and biochemical secondary effects of TBI based on the pharmacologic properties of the drugs and 2) by determining the optimal dosage regimen in animals which would correlate to the proposed treatment of TBI in humans based on pharmacokinetic properties. Optimization includes the time of first dose, the dosage interval and the duration of treatment. PUBLIC HEALTH RELEVANCE: Trauma to the head is a major cause of long-term disability in the United States. People who survive a head injury often have chronic health problems, including physical, emotional and behavioral problems. The cause of the long-term health problems may be due to many different biochemical effects that start occurring immediately after the head injury as the brain attempts to heal itself. There have been many failed studies of single drugs in patients with head injuries suggesting that combinations of drugs may be more effective. This study will help to identify combinations of drugs that could be used to prevent the long-term effects.

DESCRIPTION (provided by applicant): Two million Americans suffer a moderate to severe traumatic brain injury (TBI) each year. In addition, current military action is resulting in a large spike in the number of additional TBI cases. These injuries produce enduring disabilities that include cognitive, sensory, motor and emotional impairments. The associated health care costs from these injuries can be staggering. Confounding this major public health issue is the fact that currently there are no pharmacological treatment options for patients who have suffered a TBI. One potential cause of these failures is the lack of preclinical assessment of dosing factors (e.g., treatment windows, dose responses, and mechanism studies);in addition, preclinical studies are rarely performed in animals over 4-5 months of age. We have recently demonstrated that administration of nicotinamide, vitamin B3 (B3), following cortical contusion injury (CCI) and fluid percussion injury (FPI) resulted in a significant improvement in the recovery of sensorimotor and cognitive function, as well as in a reduction of many of the secondary pathophysiological changes that occur following injury (e.g., neurodegeneration, edema formation and reactive gliosis). However, when B3 was investigated in middle-aged (14 month old) rats following CCI, we found that the preclinical effectiveness observed in the young rats did not occur in the middle-aged rats. This is a unique and troubling finding because few studies, if any, have addressed the potential preclinical efficacy of novel therapies in the middle-age or aged rodent populations. This age range would account for a large number of TBI patients in the clinical setting. If the treatment looses efficacy in the aged population, then the clinical trial might be more likely to fail. Thus, the primary objectives of this proposal are aimed at the continued examination of B3 in aged rats following TBI. The specific aims of this study are to: 1) Determine the age window at which B3 treatment looses efficacy following TBI in rats;2) Determine the effect of B3 treatment on NAD/NADH metabolism following TBI at different age points.;3) Evaluate the preclinical efficacy of sustained infusion of B3 in middle-aged rats (14-month old);4) Compare B3 treatment following bilateral frontal CCI to treatment with progesterone (Prog) (currently in Phase II trials and has been shown to be effective in aged rats) and to the combination of both in middle-aged rats. By examining many of these clinically relevant factors (e.g., dosing regimens, long-term behavioral outcomes, and potential mechanisms) in aged subjects, we hope to build a strong case for the potential translation of B3 into clinical trials. It is also hoped that these investigations will shed light on our initial findings demonstrating reduced efficacy with B3 therapy in middle- aged rodents. PUBLIC HEALTH RELEVANCE: Two million Americans suffer a moderate to severe traumatic brain injury (TBI) each year which can produce enduring disabilities that include cognitive, sensory, motor and emotional impairments. The associated health care costs from these injuries are staggering for the families and the general public. It is hoped that the research included in this proposal will help offset this major public health crisis by helping to identify a potential therapy for TBI.