Neuroprotection after traumatic brain injury in heat-acclimated mice involves induced neurogenesis and activation of angiotensin receptor type 2 signaling

Gali Umschweif, Dalia Shabashov, Alexander G. Alexandrovich, Victoria Trembovler, Michal Horowitz, Esther Shohami*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Long-term exposure of mice to mild heat (34°C±1°C) confers neuroprotection against traumatic brain injury (TBI); however, the underling mechanisms are not fully understood. Heat acclimation (HA) increases hypothalamic angiotensin II receptor type 2 (AT 2) expression and hypothalamic neurogenesis. Accumulating data suggest that activation of the brain AT 2 receptor confers protection against several types of brain pathologies, including ischemia, a hallmark of the secondary injury occurring following TBI. As AT 2 activates the same pro-survival pathways involved in HA-mediated neuroprotection (e.g., Akt phosphorylation, hypoxia-inducible factor 1α (HIF-1α), and brain-derived neurotrophic factor (BDNF)), we examined the role of AT 2 in HA-mediated neuroprotection after TBI. Using an AT 2 -specific antagonist PD123319, we found that the improvements in motor and cognitive recovery as well as reduced lesion volume and neurogenesis seen in HA mice were all diminished by AT 2 inhibition, whereas no significant alternations were observed in control mice. We also found that nerve growth factor/tropomyosin- related kinase receptor A (TrkA), BDNF/TrkB, and HIF-1α pathways are upregulated by HA and inhibited on PD123319 administration, suggesting that these pathways play a role in AT 2 signaling in HA mice. In conclusion, AT 2 is involved in HA-mediated neuroprotection, and AT 2 activation may be protective and should be considered a novel drug target in the treatment of TBI patients.

Original languageAmerican English
Pages (from-to)1381-1390
Number of pages10
JournalJournal of Cerebral Blood Flow and Metabolism
Volume34
Issue number8
DOIs
StatePublished - Aug 2014

Keywords

  • PD123319
  • angiotensin receptor type 2
  • heat acclimation
  • neurogenesis
  • neuroprotection
  • traumatic brain injury

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