PRE-CLINICAL DEVELOPMENT OF ANGIOTENSIN RECEPTOR BLOCKERS FOR TREATMENT OF TBI

Traumatic brain injury (TBI) continues to be an enormous public health problem with limited effective pharmacology therapies. Damage from the initial lesion is worsened by secondary inflammation and edema. Angiotensin II (Ang II), the major effector molecule of the renin-angiotensinogen system (RAS), is produced locally in the brain, and acts via specific AT1 and AT2 receptors that often have opposing actions. In the central nervous system, Ang II is a powerful proinflammatory mediator, and regulator of cerebral blood flow, blood pressure and fluid balance. Most of these actions of AngII are mediated through the AT1R. Drugs that antagonize the AT1 receptor (AT1R), the angiotensin receptor blockers (ARBs) are potent anti-inflammatory agents in the CNS, that also have vasodilatory and neuroprotective actions. As many different pathways are activated after TBI, using a drug that can target different pathways simultaneously could prove to be highly beneficial.Little is known about the response of the renin-angiotensinogen system (RAS) to TBI. We have preliminary data to show that pretreatment with the angiotensin receptor blocker, candesartan mitigated the severity of TBI in a mouse model. This suggests that RAS is activated by TBI and may contribute to some of the harmful sequelae of injury. Candesartan pre-treatment led to reduced inflammation, less neuronal cell death, a smaller lesion volume, increased cerebral blood flow and most importantly improved motor function tests and improved cognitive function in the Morris Water Maze 28 days after injury. Thus, our initial experiments have shown that candesartan has potential therapeutic value for treating TBI.We now propose to test candesartan efficacy when given pre and post treatment in two different models of TBI and in two different species, the rat and the mouse. First, we will perform a dose response for candesartan treatment in mouse controlled cortical impact, with pre and post injury administration to determine the optimal dose of candesartan that can be administered post treatment. Secondly, using this dose, we will determine the time window that can elapse between injury and drug administration to maintain efficacy in treating TBI in this mouse controlled cortical impact model. We will determine efficacy using both morphological and functional outcome measures extending our analyses to up to 2 months after injury. Thirdly, we will determine whether candesartan treatment also has efficacy in a rat model of closed heard injury that of the weight drop model. We will determine similar functional and morphological outcome measures in this clinically more relevant model of brain injury, and also determine the time window of beneficial administration of candesartan. We will also use MRI to follow the progression of the cortical lesion at several time points and compare these findings with those in fixed brain tissue after sacrifice.In summary, this pipeline proposal is a preclinical study to generate sufficient data on the efficacy of the ARB, candesartan, to determine whether it is worth proceeding to clinical trials. Establishing an optimal dose, and time of administration is critical to determining whether to proceed clinically. Our initial pilot study proved sufficiently promising that we wish to broaden the study to include a second species (rat) and a second TBI model (closed head injury) in addition to controlled cortical impact in the mouse. These experiments will provide the necessary data for an informed decision on whether to proceed with a clinical trial of candesartan in acute treatment of TBI.