THE ALTERNATE RENIN ANGIOTENSIN SYSTEM AS A THERAPEUTIC TARGET FOR TBI

Despite many clinical trials, there is still no FDA approved therapeutic to treat acute or chronic effects of traumatic brain injury (TBI). Brain injury results in an immediate loss of tissue, but also initiates secondary biochemical cascades that are detrimental. These cascades increase excitotoxicity, oxidative stress and inflammation in the brain that leads to greater tissue loss, and provides a therapeutic window for treatment. However, it can take months and sometimes years for the normal homeostasis of the brain to recover, so there is the hope that drugs can be administered after the acute injury phase and still provide benefit. We have been investigating drugs that inhibit the renin angiotensin system, specifically angiotensin receptor blockers (ARBs), to bring therapeutic benefit after TBI in a mouse model. We have shown that the ARB candesartan, increases cerebral blood flow, reduces glial activation, increases neuronal survival, decreases lesion size, and improves learning and memory up to a month after injury. Also, mice that do not express the angiotensin II receptor 1 (AT1R) perform better after injury. Combined these data show that angiotensin II signaling through its AT1R is detrimental to the response to injury. Recently, a new counter-regulatory arm of the renin angiotensin system has been discovered. ACE2 breakdown of Ang II leads to formation of Ang (1-7) that signals through the MasR. This alternate axis of the renin angiotensin system acts to counter Ang II signaling at many levels, and has anti-inflammatory, vasodilatory and neuroprotective effects of its own. Importantly, in rat stroke models Ang (1-7) can improve recovery when administration is started 50 days after injury, providing evidence that this peptide may be beneficial in the more chronic stages of injury. Therefore we hypothesize that the alternate renin angiotensin system axis, and specifically Ang (1-7) signaling through the Mas receptor will be beneficial to recovery from TBI in both male and female mice. This pilot proposal seeks to test this hypothesis in the controlled cortical impact injury model of TBI in mice. Specifically we will ask 1) whether administration of Ang (1-7) at different time points after CCI injury in male and female mice enhances recovery and 2) whether MasR signaling is beneficial to recovery from CCI injury. We will administer Ang (1-7) subcutaneously starting at 6 hours post injury, or starting at 30 days post injury to determine whether Ang (1-7) has the potential to ameliorate either the acute and/ or chronic effects of TBI. Further, we will determine whether mice deficient for the Mas receptor have a different recovery than wild type mice from CCI injury, in the expectation that the presence of Mas receptor will protect from some of the effects of injury. If successful these experiments should open a new avenue to examine different aspects of the angiotensin axis that may be able to show efficacy at chronic in addition to acute treatment stages.