Central action of rapamycin on early ischemic injury and related cardiac depression following experimental subarachnoid hemorrhage

Shuzo Yamamoto, Tatsushi Mutoh, Kazumasu Sasaki, Tomoko Mutoh, Yasuyuki Taki

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Early brain injury and related cardiac consequences play a key role in the devastating outcomes after subarachnoid hemorrhage (SAH). We reported that rapamycin exerts neuroprotection against cortical hypoxia early after SAH, but its mechanism is poorly understood. This in vivo study aimed to determine the potential role of the transcription factor STAT3 in the rapamycin-mediated neuroprotection in a mouse model of SAH. Forty C57BL/6 N mice were treated with an intracerebroventricular injection of rapamycin or vehicle (control) given after SAH induction by a filament perforation method, with or without STAT3 (Stattic) or ERK (PD98059) inhibitor pretreatment. Cerebral blood flow signals (%vascularity), brain tissue oxygen saturation (SbtO2), and cardiac output (CO) were analyzed using an ultrasound/photoacoustic imaging system. Clinically relevant neurocardiac depression was notable in severe SAH mice. Rapamycin improved %vascularity, SbtO2, and CO on day 1 after SAH onset. The beneficial effects of rapamycin on cerebral blood flow and oxygenation persisted until day 3, resulting in a significant reduction in post-SAH new cerebral infarctions and survival, as well as improved neurological functions, compared to the control group. All of the effects were attenuated by pretreatment with Stattic or PD98059. These data suggest that ERK and JAK/STAT3 pathways play an important role in the neurocardiac protection by rapamycin after SAH. We propose that rapamycin is a novel pharmacological strategy to target STAT3 activation, with a possible crosstalk through the ERK pathway, for the treatment of post-SAH early brain injury.

Original languageEnglish
Pages (from-to)85-91
Number of pages7
JournalBrain Research Bulletin
Publication statusPublished - 2019 Jan


  • Early brain injury
  • Mammalian target of rapamycin (mTOR)
  • Neuroprotection
  • Subarachnoid hemorrhage
  • Translational mouse model


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