http://online.liebertpub.com/doi/abs/10.1089/ther.2013.0010
ABSTRACT
Therapeutic
hypothermia has shown neuroprotective promise, but whether it can be
used to improve outcome in stroke has yet to be determined in patients.
Recombinant tissue plasminogen activator (rt-PA) is only given to a
minority of patients with acute ischemic stroke, and is not without
risk, namely significant brain hemorrhage. We explored whether mild
hypothermia, in combination with rt-PA, influences the safety of rt-PA.
Mice were subjected to middle cerebral artery occlusion (MCAO) using a
filament model, followed by 24 hours reperfusion. Two paradigms were
studied. In the first paradigm, cooling and rt-PA treatment began at the
same time upon reperfusion, whereas in the second paradigm, cooling
began soon after ischemia onset, and rt-PA began after re-warming and
upon reperfusion. Experimental groups included: tPA treatment at
normothermia (37°C), rt-PA treatment at hypothermia (33°C), no rt-PA at
normothermia, and no rt-PA treatment at hypothermia. Infarct size,
neurological deficit scores, blood brain barrier (BBB) permeability,
brain hemorrhage, and expression of endogenous tissue plasminogen
activator (tPA) and its inhibitor, plasminogen activator inhibitor
(PAI-1) were assessed. For both paradigms, hypothermia reduced infarct
size and neurological deficits compared to normothermia, regardless of
whether rt-PA was given. rt-PA treatment increased brain hemorrhage and
BBB disruption compared to normothermia, and this was prevented by
cooling. However, mortality was higher when rt-PA and cooling were
administered at the same time, beginning 1–2 hours post MCAO. Endogenous
tPA expression was reduced in hypothermic mice, whereas PAI-1 levels
were unchanged by cooling. In the setting of rt-PA treatment,
hypothermia reduces brain hemorrhage, and BBB disruption, suggesting
that combination therapy with mild hypothermia and rt-PA appears safe.
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