Acute and delayed protective effects of pharmacologically induced hypothermia in an intracerebral hemorrhage stroke model of mice

Abstract

Hemorrhagic stroke, including intracerebral hemorrhage (ICH), is a devastating subtype of stroke; yet, effective clinical treatment is very limited. Accumulating evidence has shown that mild to moderate hypothermia is a promising intervention for ischemic stroke and ICH. Current physical cooling methods, however, are less efficient and often impractical for acute ICH patients. The present investigation tested pharmacologically induced hypothermia (PIH) using the second generation neurotensin receptor (NTR) agonist HPI-201 (formerly known as ABS-201) in an adult mouse model with ICH. Acute or delayed administrations of HPI-201 (2 mg/kg bolus injection followed by 2 injections of 1 mg/kg, i.p.) were initiated at 1 or 24 hrs after ICH. HPI-201 induced mild hypothermia within 30 min and maintained body and brain temperatures at 32.7±0.4°C for at least 6 hrs without causing observable shivering. With the 1 hr delayed treatment, HPI-201-induced PIH significantly reduced ICH-induced cell death and brain edema compared to saline-treated ICH animals. When HPI-201-induced hypothermia was initiated 24 hrs after the onset of ICH, it still significantly attenuated brain edema, cell death and blood brain barrier breakdown. HPI-201 significantly decreased the expression of MMP-9, reduced caspase-3 activation, and increased Bcl-2 expression in the ICH brain. Moreover, ICH mice received 1-hr delayed HPI-201 treatment performed significantly better in the neurological behavior test 48 hrs after ICH. All together, these data suggest that systemic injection of HPI-201 is an effective hypothermic strategy that protects the brain from ICH injury with a wide therapeutic window. The protective effect of this PIH therapy is partially mediated through the alleviation of apoptosis and neurovascular damage. We suggest that pharmacological hypothermia using the newly developed neurotensin analogs is a promising therapeutic treatment for ICH.

Pharmacologically induced hypothermia via TRPV1 channel agonism provides neuroprotection following ischemic stroke when initiated 90 min after reperfusion

“…Safer and more effective methods for producing TH are needed that are compatible with conscious subjects to make TH a viable treatment option for a broader patient population. Indeed, there has been renewed interest in a variety of pharmacological methods of promoting hypothermia without the need for sedation (19,45).…”

Regulation of therapeutic hypothermia on inflammatory cytokines, microglia polarization, migration and functional recovery after ischemic stroke in mice

“…They show high affinity for human NTR1 and induce regulated hypothermia in a dose-dependent manner (Hadden et al, 2005; Orwig et al, 2009). Our group has demonstrated that acute and delayed administrations of HPI-201 and HPI-363 show marked protective effects against brain injury after ischemic and hemorrhagic strokes as well as traumatic brain injury (TBI) in adult and neonatal rodent models (Choi et al, 2012; Lee et al, 2014; Lee et al, 2016b; Wei et al, 2013). NRT1 agonists additionally show antinociceptive and antipsychotic actions (Guillemette et al, 2012; Mechanic et al, 2009).…”

Localized Hypothermia Aggravates Bleeding in the Collagenase Model of Intracerebral Hemorrhage

“…We did not assess initial severity, which would be interesting given that the effects of TH would likely diminish with smaller doses of collagenase (e.g., less or no hematoma expansion after smaller bleeds). Finally, our results likely apply to other cooling methods, such as intentional druginduced TH (Wei et al, 2013) or unintended cooling (e.g., drug side effect).…”