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 (2mg/kg bolus injection followed by 2
injections of 1mg/kg, i.p.) were initiated at 1 or 24h after ICH.
HPI-201 induced mild hypothermia within 30 min and body and brain temperatures were maintained at 32.7 ± 0.4°C for at least 6h without causing observable shivering. With the 1-h
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 24h 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 matrix metallopeptidase-9 (MMP-9), reduced
caspase-3 activation, and increased Bcl-2 expression in the ICH brain. Moreover, ICH mice received 1-h delayed
HPI-201 treatment performed significantly better in the neurological behavior test 48 h 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.