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.
Highlights
Spontaneous intracerebral hemorrhage (ICH), as a subtype of stroke, accounts for approximately two million (10-15%) of 15 million stroke patients worldwide each year, and leads to a higher rates of death and disability than ischemic stroke [1]
Increased brain temperature was related to worse outcomes in ICH patients There was no significant difference between the hematoma volumes of normal and increased BT patients on admission; a significant higher hematoma absorption rate was identified in normal BT patients than increased BT patients at 7 d after onset (Figure 1A and 1E)
The current findings demonstrated that early increase in brain temperature was correlated with worse neurological outcomes in ICH patients
Summary
Spontaneous intracerebral hemorrhage (ICH), as a subtype of stroke, accounts for approximately two million (10-15%) of 15 million stroke patients worldwide each year, and leads to a higher rates of death and disability than ischemic stroke [1]. Therapeutic hypothermia could be achieved via surface, intravascular or pharmacological routes, among which physical cooling was the most extensively used one in clinical practices [8]. Most of previous multi-center randomized clinical trials failed to verify the neuroprotective effect of physical hypothermia (PH) for ICH [9,10,11]. These successive failures are likely due to the side-effects of exogenous cooling methods www.impactjournals.com/oncotarget [12]. The novel neurotensin receptor 1 agonists such as HPI 201 and HP I363 were reported to reduce 3-5 °C in body temperature of rats and showed promising results in different models of CNS injury [15,16,17]. It is needed to explore more pharmacological-induced hypothermia avenue to overcome the “bottle neck” in therapeutic hypothermia for ICH
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