Angiotensin Receptor Type 2 Activation Induces Neuroprotection and Neurogenesis After Traumatic Brain Injury

Gali Umschweif, Sigal Liraz-Zaltsman, Dalia Shabashov, Alexander Alexandrovich, Victoria Trembovler, Michal Horowitz, Esther Shohami*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

Angiotensin II receptor type 2 (AT2) agonists have been shown to limit brain ischemic insult and to improve its outcome. The activation of AT2 was also linked to induced neuronal proliferation and differentiation in vitro. In this study, we examined the therapeutic potential of AT2 activation following traumatic brain injury (TBI) in mice, a brain pathology that displays ischemia-like secondary damages. The AT2 agonist CGP42112A was continuously infused immediately after closed head injury (CHI) for 3 days. We have followed the functional recovery of the injured mice for 35 days post-CHI, and evaluated cognitive function, lesion volume, molecular signaling, and neurogenesis at different time points after the impact. We found dose-dependent improvement in functional recovery and cognitive performance after CGP42112A treatment that was accompanied by reduced lesion volume and induced neurogenesis in the neurogenic niches of the brain and also in the injury region. At the cellular/molecular level, CGP42112A induced early activation of neuroprotective kinases protein kinase B (Akt) and extracellular-regulated kinases 1/2 (ERK1/2), and the neurotrophins nerve growth factor and brain-derived neurotrophic factor; all were blocked by treatment with the AT2 antagonist PD123319. Our results suggest that AT2 activation after TBI promotes neuroprotection and neurogenesis, and may be a novel approach for the development of new drugs to treat victims of TBI.

Original languageAmerican English
Pages (from-to)665-678
Number of pages14
JournalNeurotherapeutics
Volume11
Issue number3
DOIs
StatePublished - Jul 2014

Bibliographical note

Funding Information:
This study was supported, in part, by grants (to ES) from the Brettler Foundation at the School of Pharmacy, and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF).

Keywords

  • CGP42112A
  • Traumatic brain injury
  • angiotensin receptor type 2
  • neurogenesis
  • neuroprotection
  • neurotrophins

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