Drug-Induced Hypothermia in Stroke Models: Does it Always Protect?

Zhang, Meijuan; Wang, Haiying; Zhao, Jinbing; Chen, Cong; Leak, Rehana K.; Xu, Yun; Vosler, Peter S.; Gao, Yanqin; Zhang, Feng

doi:10.2174/1871527311312030010

Cited by 38 publications

(23 citation statements)

References 121 publications

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“…These include epidural placement of cooling catheter (Inoue, et al, 2012), passive heat dissipation (D’Ambrosio, et al, 2013), local cold fluid infusion (Chen, et al, 2013) and extracorporeal veno-venous blood cooling (Kuboi, et al, 2013, Testori, et al, 2013). Recently, pharmacologically induced hypothermia (PIH) or drug-induced hypothermia (DIH) has drawn increased attention due to its target specific, receptor/channel mediated effect and effective inductions of regulated hypothermia (Muzzi, et al, 2013, Tupone, et al, 2013, Zhang, et al, 2013). For example, compounds acting at adenosine A1 receptors, opioid receptors, transient receptor potential (TRP) channels, and dopamine receptors can induce hypothermic effects (Muzzi, et al, 2013, Tupone, et al, 2013, Zhang, et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats

Wei

Espinera

et al. 2015

Experimental Neurology

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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 six-hour 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 15 min or 2 hr 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.

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Section: Introductionmentioning

confidence: 99%

Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats

Wei

Espinera

et al. 2015

Experimental Neurology

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“…There are 5 dopamine receptors, D1, D2, D3, D4, and D5, grouped into 2 major families: the D1-like (D1 and D5) and D2-like (D2, D3, and D4) receptor families. 37 It has been well reported in the 1980s that D2-like receptor family had a connection with hypothermia in rats. 105,106 D2 receptor agonists have been shown to play a role in neuroprotection in rats 107 and Mongolian gerbils.…”

Section: Dopamine Receptor Activatorsmentioning

confidence: 99%

“…[D-Ala2, D-Leu5] enkephalin (DADLE), a 44 kDa synthetic δ-opioid agonist peptide, has been shown to cause hypothermia and neuroprotection in mice. 37 Despite the successful demonstration of DADLE's neuroprotective effect, administration of DADLE (10 mg/kg) produced 50% reduction in arterial blood pressure in dogs 88 and arrhythmia in pigs. 89 These toxic effects would severely limit the translation of this agent in the treatment of stroke.…”

Section: Opioid Receptorsmentioning

confidence: 99%

“…102 The mechanism of action through which T1AM and T0AM elicited the hypothermic response was mediated by the G-protein-coupled receptor, TAAR1. 37 While there appears to be a strong pharmacological association of hypothermia induction by thyronamines through TAAR1 activation, 103 a recent study demonstrated that the thermoregulatory response of 3-T1AM was maintained in TAAR1 knockout mice to a similar extent as wild-type mice, 104 thereby casting doubt upon the actual receptors responsible for the hypothermic mechanism of action. Despite lingering questions about precise mechanisms involved and the effect of endogenous thyronamine levels on the thermoregulatory response, 102 the therapeutic effects of T1AM, T0AM, and other thyroxine derivatives warrant further exploration particularly because they appear to produce far less side effects than most other hypothermia-inducing drugs.…”

Section: Gaseous Hypothermiamentioning

confidence: 99%

“…35 There has been a recent surge of interest in the investigation of drug-induced hypothermia as a treatment option for ischemic stroke. 36,37 Several things must be kept in mind when assessing the final outcomes of a pharmacological agent under study. Firstly, a distinction must be made between hypothermic effects and hypothermia-like.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacological hypothermia: a potential for future stroke therapy?

Liu

Khan

et al. 2016

Neurological Research

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Mild physical hypothermia after stroke has been associated with positive outcomes. Despite the well-studied beneficial effects of hypothermia in the treatment of stroke, lack of precise temperature control, intolerance for the patient, and immunosuppression are some of the reasons which limit its clinical translation. Pharmacologically induced hypothermia has been explored as a possible treatment option following stroke in animal models. Currently, there are eight classes of pharmacological agents/agonists with hypothermic effects affecting a multitude of systems including cannabinoid, opioid, transient receptor potential vanilloid 1 (TRPV1), neurotensin, thyroxine derivatives, dopamine, gas, and adenosine derivatives. Interestingly, drugs in the TRPV1, neurotensin, and thyroxine families have been shown to have effects in thermoregulatory control in decreasing the compensatory hypothermic response during cooling. This review will briefly present drugs in the eight classes by summarizing their proposed mechanisms of action as well as side effects. Reported thermoregulatory effects of the drugs will also be presented. This review offers the opinion that these agents may be useful in combination therapies with physical hypothermia to achieve faster and more stable temperature control in hypothermia.

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Antipsychotic inductors of brain hypothermia and torpor-like states: perspectives of application

et al. 2016

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Hypothermia and hypometabolism (hypometabothermia) normally observed during natural hibernation and torpor, allow animals to protect their body and brain against the damaging effects of adverse environment. A similar state of hypothermia can be achieved under artificial conditions through physical cooling or pharmacological effects directed at suppression of metabolism and the processes of thermoregulation. In these conditions called torpor-like states, the mammalian ability to recover from stroke, heart attack, and traumatic injuries greatly increases. Therefore, the development of therapeutic methods for different pathologies is a matter of great concern. With the discovery of the antipsychotic drug chlorpromazine in the 1950s of the last century, the first attempts to create a pharmacologically induced state of hibernation for therapeutic purposes were made. That was the beginning of numerous studies in animals and the broad use of therapeutic hypothermia in medicine. Over the last years, many new agents have been discovered which were capable of lowering the body temperature and inhibiting the metabolism. The psychotropic agents occupy a significant place among them, which, in our opinion, is not sufficiently recognized in the contemporary literature. In this review, we summarized the latest achievements related to the ability of modern antipsychotics to target specific receptors in the brain, responsible for the initiation of hypometabothermia.

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Drug-Induced Hypothermia in Stroke Models: Does it Always Protect?

Cited by 38 publications

References 121 publications

Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats

Pharmacologically induced hypothermia attenuates traumatic brain injury in neonatal rats

Pharmacological hypothermia: a potential for future stroke therapy?

Antipsychotic inductors of brain hypothermia and torpor-like states: perspectives of application

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