Johansen Flemming Fryd, Hasseldam Henrik, Nybro Smith Matthias, Rasmussen Rune Skovgaard
Copenhagen Experimental Stroke Unit, Molecular Pathology at Biotech Research and Innovation Centre (BRIC), Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Copenhagen Experimental Stroke Unit, Molecular Pathology at Biotech Research and Innovation Centre (BRIC), Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
J Stroke Cerebrovasc Dis. 2014 Nov-Dec;23(10):2879-2887. doi: 10.1016/j.jstrokecerebrovasdis.2014.07.019. Epub 2014 Oct 11.
Drug-induced hypothermia reduces brain damage in animal stroke models and is an undiscovered potential in human stroke treatment. We studied hypothermia induced by the serotonergic agonists S14671 (1-[2-(2-thenoylamino)ethyl]-4[1-(7- methoxynaphtyl)]piperazine) and ipsapirone in a rat stroke model and in man by literature meta-analysis.
Rats had 60 minutes of middle cerebral artery occlusion (MCAO) and then 7 days of survival. Body temperatures were monitored for 22 hours. Thirty minutes after MCAO, 1 group (n = 9) received bolus of S14671 (.75 mg/kg) and continuous infusion of .06 mg/kg hour(-1) S14671 for 20 hours. Other MCAO rats (n = 7) had bolus of ipsapirone (.75 mg/kg) and continuous infusion of .25 mg/kg hour(-1) ipsapirone for 3 hours. Controls (n = 9; n = 5) received similar amounts of vehicle as bolus and continuous infusion for 20 hours/3 hours. Additional controls of the S14761 effect in MCAO were performed as previously mentioned (n = 10) but with rats kept normothermic by a heating lamp for 22 hours. Finally, a meta-analysis of ipsapirone-induced hypothermia in man was included.
Infarct volumes were reduced by 50% in hypothermic rats versus controls (P < .05). S14671 rats kept normothermic did not show infarct reduction (P > .05). The body temperature after stroke was reduced 1.0-3.0°C compared with controls for 20 hours with S14671 treatment and for 6 hours with ipsapirone treatment. In humans, ipsapirone reduced temperature in average with .55 °C ranging between .1-1.4 °C.
5-hydroxytryptamine receptor 1A (5HT(1A)) agonists significantly reduce infarct volumes in MCAO rats primarily because of the hypothermic drug effect. 5HT(1A) agonists may be introduced to reduce body temperatures rapidly and prepare patients for further therapeutic hypothermia.
药物诱导的体温过低可减轻动物中风模型中的脑损伤，是人类中风治疗中尚未被发现的潜在方法。我们通过文献荟萃分析，研究了5-羟色胺能激动剂S14671（1-[2-(2-噻吩甲酰氨基)乙基]-4[1-(7-甲氧基萘基)]哌嗪）和伊沙匹隆在大鼠中风模型及人体中诱导的体温过低情况。
大鼠进行60分钟的大脑中动脉闭塞（MCAO），然后存活7天。监测体温22小时。MCAO后30分钟，1组（n = 9）给予S14671推注（0.75 mg/kg），并以0.06 mg/kg·小时⁻¹的速度持续输注S14671 20小时。其他MCAO大鼠（n = 7）给予伊沙匹隆推注（0.75 mg/kg），并以0.25 mg/kg·小时⁻¹的速度持续输注伊沙匹隆3小时。对照组（n = 9；n = 5）给予与推注和持续输注相似量的赋形剂，持续20小时/3小时。如前所述，对S14761在MCAO中的作用进行了额外对照（n = 10），但用加热灯使大鼠保持正常体温22小时。最后，纳入了伊沙匹隆在人体中诱导体温过低的荟萃分析。
与对照组相比，体温过低的大鼠梗死体积减少了50%（P < 0.05）。保持正常体温的S14671大鼠梗死体积未减少（P > 0.05）。与对照组相比，S14671治疗使中风后的体温在20小时内降低1.0 - 3.0°C，伊沙匹隆治疗使体温在6小时内降低。在人体中，伊沙匹隆使体温平均降低0.55°C，范围在0.1 - 1.4°C之间。
主要由于药物的降温作用，5-羟色胺受体1A（5HT(1A)）激动剂可显著减少MCAO大鼠的梗死体积。5HT(1A)激动剂可用于快速降低体温，为患者进行进一步的治疗性低温做准备。
