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

Published: 11-24-2018 In Publication

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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.


Link to the publication : https://www.sciencedirect.com/science/article/pii/S0361923018307767