PRE-CLINICAL DEVELOPMENT OF MEASUREMENTS OF CANDESARTAN EFFECTIVENESS IN TREATING TBI

Traumatic brain injury (TBI) is a major public health problem with no approved pharmacologic therapies. In the search for therapeutics to treat TBI, drugs that target several different pathophysiological mechanisms have a greater potential for benefit. Angiotensin receptor blockers (ARBs) are anti- inflammatory, neuroprotective and promote the normalization of decreased cerebral blood flow after injury, therefore attacking several different pathways that are perturbed after injury. We have been studying the angiotensin receptor blocker (ARB), candesartan as a treatment for TBI for several years. Candesartan is a widely used, well-tolerated FDA approved ARB used in the treatment of hypertension, diabetic nephropathy and for the prevention of stroke. Our results to date suggest that candesartan is a promising therapeutic to treat TBI. We have shown that candesartan administered up to 6 hours after injury, ameliorates the detrimental morphological and functional deficits after controlled cortical impact injury (CCI) in the mouse. Candesartan treatment reduces the lesion volume, improves cerebral blood flow after injury and reduces the amount of reactive astrocytes, microglia and infiltrating neutrophils in the peri-lesional area. Candesartan treatment also improves motor recovery at early time points and reduces cognitive impairment in the Morris Water Maze. Our data provide strong pre-clinical evidence that candesartan is effective in reducing the detrimental outcomes of CCI in the mouse. The failure of over 30 drugs in clinical trials for TBI suggests the need for different processes to evaluate suitability of potential therapies in the laboratory. One suggested change is the development of non–invasive measures of drug efficacy in pre-clinical models so that these same measures can be transferred to early- phase clinical trials, in order to demonstrate that the therapy is engaging the molecular target and resulting in a biologic effect. Having shown significant efficacy of candesartan in a mouse model of TBI, the objective of this proposal is to provide broader and better targeted pre-clinical data on the efficacy of candesartan for treating TBI to determine whether candesartan is a good candidate for phase III clinical trials. We aim to develop methods to assess candesartan efficacy through development of blood biomarkers, and imaging studies, which can be used as non-invasive measurements of efficacy in early phase clinical trials. Additionally, to date we have only shown candesartan efficacy in one animal model – the male mouse. In order to provide a stronger case for taking candesartan into clinical trials we will determine efficacy in a second animal and in both sexes of mice. These experiments will therefore determine whether or not candesartan has efficacy in a broader context, and if so, will provide stronger rationale for candesartan clinical trials for TBI.In this proposal we will 1) Determine which blood proteins are altered by candesartan treatment after TBI in mice to develop one or more biomarkers of candesartan efficacy; 2) Evaluate whether candesartan has efficacy in ameliorating deficits after lateral fluid percussion injury in the rat in order to show if candesartan has efficacy in a second species and a different injury model and 3) Assess whether candesartan treatment is effective in improving morphological and functional recovery after CCI in female as well as male mice. These data will provide much needed information as to the breadth of candesartan actions and therefore if positive, much stronger evidence to advance candesartan to phase III clinical trials. Development of non- invasive methods of detection of candesartan’s actions will also provide additional tools to design outcome measures for clinical trials.