Involvement of Renin-Angiotensin system (RAS) components in mild traumatic brain injury

• Published in: Brain research 2025-01, Vol.1846, p.149266, Article 149266
• Main Authors: Machado, Caroline Amaral, Oliveira, Bruna da Silva, de Barros, João Luís Vieira Monteiro, Fernandes, Heliana de Barros, de Brito Toscano, Eliana Cristina, Miranda Kangussu, Lucas, Guimarães, Pedro Pires Goulart, Simões e Silva, Ana Cristina, Teixeira, Antonio Lucio, de Miranda, Aline Silva
• Format: Article
• Language: English
• Subjects: Angiotensin I - metabolism; Angiotensin II; Angiotensin II - metabolism; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Brain Concussion - metabolism; Brain Concussion - physiopathology; Brain Injuries, Traumatic - metabolism; Brain Injuries, Traumatic - physiopathology; Disease Models, Animal; Hippocampus - drug effects; Hippocampus - metabolism; Male; Mas receptor; Mice; Mice, Inbred C57BL; Mild traumatic brain injury; Peptide Fragments - metabolism; Peptidyl-Dipeptidase A - metabolism; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Receptor, Angiotensin, Type 1 - metabolism; Receptor, Angiotensin, Type 2 - metabolism; Renin angiotensin system; Renin-Angiotensin System - drug effects; Renin-Angiotensin System - physiology; Weight-drop model
• ISSN: 0006-8993; 1872-6240; 1872-6240
• DOI: 10.1016/j.brainres.2024.149266

[Display omitted] •RAS seems to play an important role in mild TBI outcomes.•Changes in RAS components occur in both ipsilateral and contralateral lesion hemispheres.•RAS axes undergo alterations in key brain areas following a mTBI in a time and hemisphere dependent manner.•Pharmacological blockage of RAS classical axis promotes neuroprotective effects in experimental mTBI.•RAS might be a potential therapeutic target in mTBI. The Renin Angiotensin System (RAS) plays a pathophysiological role in traumatic brain injury (TBI) but the evidence of its involvement in mild TBI (mTBI) is still limited. We aimed at investigating the levels of components from both the classical and counter-regulatory axis of the RAS in a mTBI animal model. Mice with mTBI displayed enhanced ACE/Ang II/AT1R axis ipsilateral- and contralaterally to the trauma in the hippocampus and prefrontal cortex during acute (24 and 72 h) and later (30 days) timepoints. Increase in Ang-(1–7) levels alongside reduction in Mas receptor expression in hippocampus and prefrontal cortex was also observed after injury. Conversely, mTBI-mice presented higher expression of AT2 receptor in the contralateral hippocampus and the ipsilateral prefrontal cortex. Importantly, treatment with telmisartan, an AT1R blocker, and perindopril, an ACE inhibitor, were able to prevent mTBI-associated locomotor activity impairment and anxiety-like behavior, corroborating the involvement of RAS in the pathophysiology of mTBI. We provided original evidence that components of classical and alternative RAS axes undergo alterations in key brain areas following a mTBI in a time and hemisphere dependent manner. Our findings also open new avenues for investigating the therapeutic potential of RAS components in mTBI.