Characterization and therapeutic evaluation of a traumatic brain injury model in compliance with common data elements

Traumatic brain injury (TBI) is a major public health problem. It represents the leading cause of morbidity and mortality in children and young adults, resulting in long- term sequelae for a considerable number of survivors. Development of effective therapeutics for patients with TBI is an unmet need. A critical step to address this need is to establish reproducible and comparable animal models that will allow preclinical meta- analyses, and has led to an increasing interest in generating common data elements in TBI research. This project addresses TBI and research-related issues in three ways. First, an existing closed-skull weight drop TBI model was optimized by the incorporation of three novel sensors, which allowed the detection of important factors that could induce variability. This finding led to the redesign of the model and the addition of an impactor. Additionally, the sensors allowed measurement and comparison of forces applied on the head of the animal to monitor mechanical reproducibility. The outcomes of these injuries were further evaluated with a comprehensive of battery of behavioral and pathological analyses. Second, an artificial model of a mouse, “the professional mouse” was developed to aid the precise measurement for reproducibility of closed-head injury models or compare between models. Finally, this newly optimized TBI model was used to initiate the assessment of a potentially therapeutic drug to treat neurotrauma. Olaparib (Lynparza®) is a Poly(ADP-polymerase) 1 (PARP1) inhibitor approved by the FDA for the treatment of breast and ovarian cancer. Several studies reported the activation of PARP1 after injury in the central nervous system. This activation has been correlated with increased inflammation, mitochondrial dysfunction and necrosis. Furthermore, the inhibition of PARP1 is neuroprotective in different models of brain injury. This study shows that olaparib administered after TBI reduces astrogliosis and cognitive deficits. Although further studies are needed, we are enthusiastic that PARP inhibition may prove efficacious in the acute phase, as well as prevent the later-stage neurological deterioration secondary to single or repetitive TBI.