作者: Yang, Jin ; Xiao, Yan ; Li, Hao ; Bradley, Jennifer L ; Wang, Wei ; Hua, Tianfeng ; Peberdy, Mary Ann ; Miao, Changqing ; Tang, Wanchun ; Wu, Xiaobo ; Dix, Thomas A ; Beck, Tyler ; Huang, Weiping ; Ornato, Joseph

ABSTRACTNeurotensin is an endogenous tridecapeptide that binds to neurotensin receptors in the brain, which induce hypothermia. The aim of this study was to investigate whether the receptor agonist ABS 201 could induce therapeutic hypothermia and improve postresuscitation outcomes in a ventricular fibrillation cardiac arrest (VFCA) rat model. VF was electrically induced in 12 rats. Defibrillation was achieved after 6 min of cardiopulmonary resuscitation. After successful resuscitation, animals were randomized to receive ABS 201 (8 mg/kg/h) or placebo. Postresuscitation myocardial function and neurological deficit scores (NDS) were assessed, and postresuscitation survival duration was observed for up to 72 h. After administration of ABS 201, blood temperature decreased significantly from 37°C to 34°C, and was maintained for 2.5 h. There was a significant improvement of postresuscitation myocardial dysfunction, NDS, and survival duration in animals treated with ABS 201. These results demonstrated that ABS 201 induces therapeutic hypothermia in a VFCA rat model, ameliorates postresuscitation myocardial–neurological dysfunction, and prolongs survival duration. ABS 201 may therefore be an alternative method to induce therapeutic hypothermia with current cooling methods and improve postresuscitation outcomes.

2016-07-01·Stroke1区 · 医学

Improved Therapeutic Benefits by Combining Physical Cooling With Pharmacological Hypothermia After Severe Stroke in Rats

1区 · 医学

Article

作者: Lee, Jin Hwan ; Wei, Ling ; Yu, Shan Ping ; Wei, Zheng Zachory ; Won, Soonmi ; Dix, Thomas A. ; Gu, Xiaohuan

Background and Purpose—Therapeutic hypothermia is a promising strategy for treatment of acute stroke. Clinical translation of therapeutic hypothermia, however, has been hindered because of the lack of efficiency and adverse effects. We sought to enhance the clinical potential of therapeutic hypothermia by combining physical cooling (PC) with pharmacologically induced hypothermia after ischemic stroke.Methods—Wistar rats were subjected to 90-minute middle cerebral artery occlusion by insertion of an intraluminal filament. Mild-to-moderate hypothermia was induced 120 minutes after the onset of stroke by PC alone, a neurotensin receptor 1 (NTR1) agonist HPI-201 (formally ABS-201) alone or the combination of both. The outcomes of stroke were evaluated at 3 and 21 days after stroke.Results—PC or HPI-201 each showed hypothermic effect and neuroprotection in stroke rats. The combination of PC and HPI-201 exhibited synergistic effects in cooling process, reduced infarct formation, cell death, and blood-brain barrier damages and improved functional recovery after stroke. Importantly, coapplied HPI-201 completely inhibited PC-associated shivering and tachycardia.Conclusions—The centrally acting hypothermic drug HPI-201 greatly enhanced the efficiency and efficacy of conventional PC; this combined cooling therapy may facilitate clinical translation of hypothermic treatment for stroke.

2015-05-01·Experimental Neurology2区 · 医学

Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats

2区 · 医学

Article

作者: Dix, Thomas A ; Lee, Jin Hwan ; Gu, Xiaohuan ; Ji, Xiaoya ; Wei, Ling ; Wei, Zheng Zachory ; Espinera, Alyssa ; Yu, Shan Ping

Neonatal brain trauma is linked to higher risks of mortality and neurological disability. The use of mild to moderate hypothermia has shown promising potential against brain injuries induced by stroke and traumatic brain injury (TBI) in various experimental models and in clinical trials. Conventional methods of physical cooling, however, are difficult to use in acute treatments and in induction of regulated hypothermia. In addition, general anesthesia is usually required to mitigate the negative effects of shivering during physical cooling. Our recent investigations demonstrate the potential therapeutic benefits of pharmacologically induced hypothermia (PIH) using the neurotensin receptor (NTR) agonist HPI201 (formerly known as ABS201) in stroke and TBI models of adult rodents. The present investigation explored the brain protective effects of HPI201 in a P14 rat pediatric model of TBI induced by controlled cortical impact. When administered via intraperitoneal (i.p.) injection, HPI201 induced dose-dependent reduction of body and brain temperature. A 6-h hypothermic treatment, providing an overall 2-3°C reduction of brain and body temperature, showed significant effect of attenuating the contusion volume versus TBI controls. Attenuation occurs whether hypothermia is initiated 15min or 2h after TBI. No shivering response was seen in HPI201-treated animals. HPI201 treatment also reduced TUNEL-positive and TUNEL/NeuN-colabeled cells in the contusion area and peri-injury regions. TBI-induced blood-brain barrier damage was attenuated by HPI201 treatment, evaluated using the Evans Blue assay. HPI201 significantly decreased MMP-9 levels and caspase-3 activation, both of which are pro-apototic, while it increased anti-apoptotic Bcl-2 gene expression in the peri-contusion region. In addition, HPI201 prevented the up-regulation of pro-inflammatory tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6. In sensorimotor activity assessments, rats in the HPI201 treated group exhibited improved functional recovery after TBI versus controls. These data support that PIH therapy using our NTR agonist is effective in reducing neuronal and BBB damage, attenuating inflammatory response and detrimental cellular signaling, and promoting functional recovery after TBI in the developing brain, supporting its potential for further evaluation towards clinical development.

100 项与 ABS-201(Argolyn Bioscience) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
精神障碍	药物发现	美国	Argolyn Bioscience, Inc.	-
精神分裂症	药物发现	美国	Halimed Pharmaceuticals Inc.	-
脑卒中	药物发现	美国	Halimed Pharmaceuticals Inc.	-