The Renin Angiotensin System as a Therapeutic Target in Traumatic Brain Injury

Traumatic brain injury (TBI) is a major public health problem, with limited pharmacological options available beyond symptomatic relief. The renin angiotensin system (RAS) is primarily known as a systemic endocrine regulatory system, with major roles controlling blood pressure and fluid homeostasis. Drugs that target the RAS are used to treat hypertension, heart failure and kidney disorders. They have now been used chronically by millions of people and have a favorable safety profile. In addition to the systemic RAS, it is now appreciated that many different organ systems, including the brain, have their own local RAS. The major ligand of the classic RAS, Angiotensin II (Ang II) acts predominantly through the Ang II Type 1 receptor (AT1R), leading to vasoconstriction, inflammation, and heightened oxidative stress. These processes can exacerbate brain injuries. Ang II receptor blockers (ARBs) are AT1R antagonists. They have been shown in several preclinical studies to enhance recovery from TBI in rodents through improvements in molecular, cellular and behavioral correlates of injury. ARBs are now under consideration for clinical trials in TBI. Several different RAS peptides that signal through receptors distinct from the AT1R, are also potential therapeutic targets for TBI. The counter regulatory RAS pathway has actions that oppose those stimulated by AT1R signaling. This alternative pathway has many beneficial effects on cells in the central nervous system, bringing about vasodilation, and having anti-inflammatory and anti-oxidative stress actions. Stimulation of this pathway also has potential therapeutic value for the treatment of TBI. This comprehensive review will provide an overview of the various components of the RAS, with a focus on their direct relevance to TBI pathology. It will explore different therapeutic agents that modulate this system and assess their potential efficacy in treating TBI patients.