Oncotarget

Research Papers: Autophagy and Cell Death:

5-HT1a activation in PO/AH area induces therapeutic hypothermia in a rat model of intracerebral hemorrhage

Tan Liang, Qianwei Chen, Qiang Li, Rongwei Li, Jun Tang, Rong Hu, Jun Zhong, Hongfei Ge, Xin Liu and Feng Hua _

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Oncotarget. 2017; 8:73613-73626. https://doi.org/10.18632/oncotarget.20280

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Abstract

Tan Liang1, Qianwei Chen1, Qiang Li1, Rongwei Li1, Jun Tang1, Rong Hu1, Jun Zhong1, Hongfei Ge1, Xin Liu1 and Hua Feng1

1 Department of Neurosurgery, Southwest Hospital, Third Military Medical University, Chongqing, China

Correspondence to:

Feng Hua, email:

Keywords: intracerebral hemorrhage, therapeutic hypothermia, 8-OH-DPAT, 5-HT1a, PO/AH area

Received: April 26, 2017 Accepted: July 12, 2017 Published: August 16, 2017

Abstract

Therapeutic hypothermia is widely applied as a neuroprotective measure on intracerebral hemorrhage (ICH). However, several clinical trials regarding physical hypothermia encountered successive failures because of its side-effects in recent years. Increasing evidences indicate that chemical hypothermia that targets hypothalamic 5-HT1a has potential to down-regulate temperature set point without major side-effects. Thus, this study examined the efficacy and safety of 5-HT1a stimulation in PO/AH area for treating ICH rats. First, the relationship between head temperature and clinical outcomes was investigated in ICH patients and rat models, respectively. Second, the expression and distribution of 5-HT1a receptor in PO/AH area was explored by using whole-cell patch and confocal microscopy. In the meantime, the whole-cell patch was subsequently applied to investigate the involvement of 5-HT1a receptors in temperature regulation. Third, we compared the efficacy between traditional PH and 5-HT1a activation-induced hypothermia for ICH rats. Our data showed that more severe perihematomal edema (PHE) and neurological deficits was associated with increased head temperature following ICH. 5-HT1a receptor was located on warm-sensitive neurons in PO/AH area and 8-OH-DPAT (5-HT1a receptor agonist) significantly enhanced the firing rate of warm-sensitive neurons. 8-OH-DPAT treatment provided a steadier reduction in brain temperature without a withdrawal rebound, which also exhibited a superior neuroprotective effect on ICH-induced neurological dysfunction, white matter injury and BBB damage compared with physical hypothermia. These findings suggest that chemical hypothermia targeting 5-HT1a receptor in PO/AH area could act as a novel therapeutic manner against ICH, which may provide a breakthrough for therapeutic hypothermia.


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