Renin Angiotensin System as a Potential Treatment Target for Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Abstract

Traumatic brain injury (TBI) is a major health concern and leading cause of death and disability in young adults in the UK and worldwide, however, there is a paucity of disease modifying therapies for the treatment of TBI. This review investigates the potential of the reninangiotensin system (RAS) as a treatment pathway for traumatic brain injury (TBI) in adults.Relevant electronic databases were searched on 18 December 2019, updated 16 May 2021. All English language articles with adult human or animal populations investigating RAS drugs as an intervention for TBI or reporting genetic evidence relevant to the RAS and TBI were screened.Eighteen preclinical RCTs (n=2269) and 2 clinical cohort studies (n=771) were included. Metaanalyses of 6 preclinical randomised-controlled trials (n=99) indicated candesartan improved neurological function short-term (<7 days: standardised mean difference (SMD) 0.61, 95% confidence interval (CI) 0.19 -1.03, I2=0%) and long-term (≥7 days: SMD 1.06, 95% CI 0.38; 1.73, I2=0%) post-TBI. Findings were similar for most secondary outcomes. There was a suggestion of benefit from other RAS-targeting drugs, although evidence was limited due to few small studies. There was insufficient evidence to enable strong assessment of these drugs on mortality post-TBI. We conclude that angiotensin-receptor blockers, especially candesartan, show positive outcomes post-TBI in preclinical studies with moderate quality of evidence (GRADE). More research into the effect of regulatory-RAS targeting drugs is needed. Clinical trials of candesartan following TBI are recommended, due to strong and consistent evidence of neuroprotection shown by these preclinical studies.

Mini-Review: Role of Drugs Affecting Renin-Angiotensin System (RAS) in Traumatic Brain Injury (TBI): What We Know and What We Should Know

“…Although this has historically been known as the RAS pathway, recent studies have shown that the pathway is more complicated and detailed than previously thought. 4 16 40) …”

“…In addition to natural ligands, receptors can be activated or inhibited through pharmacological or genetic manipulation. 4 40) AT1R activation leads to neuroinflammation, the induction of oxidative stress, BBB disruption, and cell death. In contrast to AT1R, AT2R induces DNA repair and cell differentiation.…”

“…In future human studies, this is an important factor to consider as hypotension reduces cerebral blood flow and contributes to brain damage following TBI. 4 47 51) …”

“…Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are drug groups used primarily to treat hypertension and have recently become the focus of TBI research. 4) The renin-angiotensin system (RAS), which is generally associated with the cardiovascular regulatory system, also significantly affects the brain, making it a potential target for developing new TBI treatments. 16 40 52 53) Following TBI, local RAS activation in the brain tissue may result in cellular damage and insult, contributing to neuroinflammation and progressive brain atrophy.…”

“…These effects are mediated by regulatory RAS (rRAS; Ang-[1-7]) signaling through the Mas receptor (MasR) and AT2R. 4 36) …”