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

Zachary C. Janatpour, Alexandru Korotcov, Asamoah Bosomtwi, Bernard J. Dardzinski, Aviva J. Symes

Research output: Contribution to journalArticle

3 Scopus citations

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 cerebrovascular-protective 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.

Original languageEnglish (US)
Pages (from-to)3115-3131
Number of pages17
JournalJournal of Neurotrauma
Volume36
Issue number22
DOIs
StatePublished - Nov 15 2019
Externally publishedYes

Keywords

  • angiotensin-(1-7)
  • controlled cortical impact
  • Mas receptor
  • renin-angiotensin system
  • traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology

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