Pharmacological hypothermia: a potential for future stroke therapy?

Abstract

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.

Insightful Backbone Modifications Preventing Proteolytic Degradation of Neurotensin Analogs Improve NTS1-Induced Protective Hypothermia

“…Hypothermia therapy has been found to exert neuroprotective effects in many neurological diseases, such as stroke, traumatic brain injury, intracranial pressure elevation, and neonatal encephalopathy (Huber et al, 2019;Sun et al, 2019). In light of this, there is now growing evidence demonstrating that NT(8-13) analogs induce regulated reduction of body and brain temperatures through activation of the NTS1 receptor subtype (Liu et al, 2016). Indeed, administration of the NTS1 agonists, NT69L, PD149163, HPI-201, or HPI-363, produced mild hypothermia and improved the neurological outcomes compared with that of results from external cooling (Katz et al, 2001;Choi et al, 2012;Wei et al, 2013;Lee et al, 2014Lee et al, , 2016Gu et al, 2015;Xue et al, 2017;Zhao et al, 2020;Zhong et al, 2020).…”

“…There is now growing evidence demonstrating that NT and its derivatives induce persistent hypothermia through activation of the NTS1 receptor subtype (Liu et al, 2016). The abilities of each NT(8-13) analog to reduce body temperature were then assessed every 10 min for up to 1 h following central administration.…”

Transient selective brain cooling confers neurovascular and functional protection from acute to chronic stages of ischemia/reperfusion brain injury

“…38 Compared to physical cooling methods, pharmacological cooling may protect against brain injury through additional mechanisms other than hypothermia per se. 38 Like two sides of the same coin, this multi-faceted action of pharmacological hypothermia may offer more robust protection as well as unexpected toxicity and side effects. [39][40][41] Thus, there has been a recent trend in investigating the combination of physical and pharmacological cooling with the hope of reducing the dosage of drug while achieving comparable or even more protective effects.…”

Therapeutic Hypothermia and Neuroprotection in Acute Neurological Disease

“…There has been a recent surge of interest in the investigation of drug-induced hypothermia as a treatment option for acute brain injuries [29]. This approach has been proposed for the aim of maximizing the beneficial effect of hypothermia in clinical settings with less adverse reactions.…”