TY - JOUR
T1 - Subcutaneous Administration of Angiotensin-(1-7) Improves Recovery after Traumatic Brain Injury in Mice
AU - Janatpour, Zachary C.
AU - Korotcov, Alexandru
AU - Bosomtwi, Asamoah
AU - Dardzinski, Bernard J.
AU - Symes, Aviva J.
N1 - Funding Information:
This work was supported by a grant from the Department of Defense Centre for Neuroscience and Regenerative Medicine (AJS). We thank Dr. Rick Franklin (Constant Pharmaceuticals) for the gift of the Ang-(1-7) and Dr. Rick Franklin and Professor Thomas Walter for many informative discussions. We are grateful to Dr. Cara Olson for biostatistical consultations and members of the Symes laboratory and Zachary Janatpour’s thesis committee for their helpful comments and suggestions.
Publisher Copyright:
© Copyright 2019, Mary Ann Liebert, Inc., publishers 2019.
PY - 2019/11/15
Y1 - 2019/11/15
N2 - 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.
AB - 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.
KW - Mas receptor
KW - angiotensin-(1-7)
KW - controlled cortical impact
KW - renin-angiotensin system
KW - traumatic brain injury
UR - http://www.scopus.com/inward/record.url?scp=85069446743&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85069446743&partnerID=8YFLogxK
U2 - 10.1089/neu.2019.6376
DO - 10.1089/neu.2019.6376
M3 - Article
C2 - 31037999
AN - SCOPUS:85069446743
SN - 0897-7151
VL - 36
SP - 3115
EP - 3131
JO - Journal of Neurotrauma
JF - Journal of Neurotrauma
IS - 22
ER -