Subcutaneous Administration of Angiotensin-(1-7) Improves Recovery after Traumatic Brain Injury in Mice

Abstract

Angiotensin II (Ang II)-mediated activation of its type I receptor (AT1R) in the central nervous system promotes glial proliferation, local inflammation, and a decrease of cerebral blood flow. Angiotensin-(1-7) (Ang-(1-7))-an Ang II derivative peptide-signals through the Mas receptor (MasR) in opposition to Ang II/AT1R, promoting anti-inflammatory, vasodilatory, and neuroprotective effects. As our laboratory has previously demonstrated beneficial effects of AT1R inhibition following controlled cortical impact (CCI) in mice, we asked whether activation of Ang-(1-7)/MasR signaling would also be beneficial in this model. Adult male C57BL/6 mice were injured by CCI. Ang-(1-7) or vehicle was administered subcutaneously (S.Q.) at 1 mg/kg/day at 1 or 6 h post-injury, until animals were sacrificed at 3 or 29 days post-injury (dpi). Ang-(1-7) attenuated motor deficits at 3 dpi and improved performance in the Morris Water Maze at 28 dpi. Brain histology or magnetic resonance imaging (MRI) indicated that Ang-(1-7)-treated mice had smaller lesion volumes at 3, 10, 24, and 29 dpi. Pre-treatment with A779, a MasR antagonist, prevented Ang-(1-7) from reducing lesion volume at 3 dpi, suggesting that the benefits of Ang-(1-7) were MasR-dependent. Immunohistochemistry revealed that Ang-(1-7) reduced microgliosis at 3 and 29 dpi, and astrogliosis at 29 dpi. Ang-(1-7) decreased neuronal and capillary loss at 29 dpi. In summary, S.Q. administration of Ang-(1-7) after injury had anti-inflammatory, neuroprotective, and cerebrovascularprotective actions leading to improved functional and pathological recovery in a mouse model of traumatic brain injury (TBI). These data show for the first time that Ang-(1-7) has potential therapeutic use for TBI.

The counter regulatory axis of the renin angiotensin system in the brain and ischaemic stroke: Insight from preclinical stroke studies and therapeutic potential

“…Aside from cardiovascular regulation however, Ang-(1–7) and Mas receptor signalling have demonstrated specific effects on brain cells such as: reduced nuclear and mitochondrial superoxide production [ 147 ]; improved neuronal survival and reduced oxidative stress in the brain mediated via PKA [ 148 ], or improved survival and reduced levels of ROS in rotenone induced injury of cultured neurons mediated by increased antioxidant activity and reduced NOX activity [ 149 ]; reduced microglial activation and astrogliosis allowing for improved neuronal density following traumatic brain injury [ 150 ]; reduced inflammation in astrocytes mediated by the MAPK inhibition signalling pathway [ 151 ]; reduced Shiga toxin 2 (Stx2) induced neuronal, astrocyte and oligodendrocyte damage [ 152 ]; or a switch to the anti-inflammatory M2 microglia phenotype with a reduction in pro-inflammatory cytokines (TNFα and IL1β) and increased levels of anti-inflammatory IL-10 [ 153 ]. Moreover, central Ang-(1–7) administration has demonstrated an increase in bradykinin levels and expression of bradykinin receptors [ 154 ] which may itself have neuroprotective effects [ 155 ]; or protection against cerebral endothelial cell dysfunction and oxidative stress via NOX inhibition and the PI3K/NO signalling pathway [ 156 ].…”

Peptidase neurolysin is an endogenous cerebroprotective mechanism in acute neurodegenerative disorders

“…Angiotensin I is an inactive peptide, serving as a precursor for bioactive angiotensins. Cleavage of angiotensin I by Nln results in angiotensin-(1–7), which was shown to have neuroprotective and anti-inflammatory effects in in vivo stroke and TBI models [33,34]. Complementary to this, Nln inactivates angiotensin II, which is the most studied peptide in the renin-angiotensin system with mounting evidence supporting its pathological role in stroke and TBI [35,36].…”

“…Angiotensin I is an inactive peptide, serving as a precursor for bioactive angiotensins. Cleavage of angiotensin I by Nln results in angiotensin-(1-7), which was shown to have neuroprotective and anti-inflammatory effects in in vivo stroke and TBI models [33,34].…”

Transcriptomic Analysis of Mouse Brain After Traumatic Brain Injury Reveals That the Angiotensin Receptor Blocker Candesartan Acts Through Novel Pathways

“…As candesartan has been shown to induce activity and expression of ACE2, the enzyme that converts Ang II to the Mas receptor ligand, Ang-(1-7), it has been postulated that some of candesartan's beneficial effects may be mediated by enhancing activation of the ACE2/Ang-(1-7)/MasR axis (Pernomian et al, 2015). Indeed, we have previously shown that Ang-(1-7) treatment after TBI can also enhance recovery (Janatpour et al, 2019). Further delineation of which receptor mediates candesartan's regulation of gene expression will await experiments involving specific receptor knockout mice.…”