Combination therapy with normobaric oxygen (NBO) plus thrombolysis in experimental ischemic stroke

Norio Fujiwara, Yoshihiro Murata, Ken Arai, Yasuhiro Egi, Jie Lu, Ona Wu, Aneesh B Singhal, Eng H Lo, Norio Fujiwara, Yoshihiro Murata, Ken Arai, Yasuhiro Egi, Jie Lu, Ona Wu, Aneesh B Singhal, Eng H Lo

Abstract

Background: The widespread use of tissue plasminogen activator (tPA), the only FDA-approved acute stroke treatment, remains limited by its narrow therapeutic time window and related risks of brain hemorrhage. Normobaric oxygen therapy (NBO) may be a useful physiological strategy that slows down the process of cerebral infarction, thus potentially allowing for delayed or more effective thrombolysis. In this study we investigated the effects of NBO started simultaneously with intravenous tPA, in spontaneously hypertensive rats subjected to embolic middle cerebral artery (MCA) stroke. After homologous clot injection, animals were randomized into different treatment groups: saline injected at 1 hour; tPA at 1 hour; saline at 1 hour plus NBO; tPA at 1 hour plus NBO. NBO was maintained for 3 hours. Infarct volume, brain swelling and hemorrhagic transformation were quantified at 24 hours. Outcome assessments were blinded to therapy.

Results: Upon clot injection, cerebral perfusion in the MCA territory dropped below 20% of pre-ischemic baselines. Both tPA-treated groups showed effective thrombolysis (perfusion restored to nearly 100%) and smaller infarct volumes (379 +/- 57 mm3 saline controls; 309 +/- 58 mm3 NBO; 201 +/- 78 mm3 tPA; 138 +/- 30 mm3 tPA plus NBO), showing that tPA-induced reperfusion salvages ischemic tissue and that NBO does not significantly alter this neuroprotective effect. NBO had no significant effect on hemorrhagic conversion, brain swelling, or mortality.

Conclusion: NBO can be safely co-administered with tPA. The efficacy of tPA thrombolysis is not affected and there is no induction of brain hemorrhage or edema. These experimental results require clinical confirmation.

Figures

Figure 1
Figure 1
Cerebral perfusion during embolic focal ischemia and reperfusion after tPA thrombolysis. Cerebral perfusion as measured with laser Doppler flowmetry (mean ± SD) dropped rapidly below 20% after clot injection. Intravenous tPA therapy almost fully restored perfusion. Saline did not have detectable effects on cerebral perfusion values.
Figure 2
Figure 2
Cerebral infarction volumes. (a) Representative images of TTC staining are shown. (b) Effects of tPA and NBO on infarction volume at 24 hours. Intravenous tPA reduced infarct volumes but NBO did not alter this neuroprotective effect. Data expressed as mean ± SD; *$ P < 0.05.
Figure 3
Figure 3
Effects of tPA and NBO on brain hemorrhage and brain swelling. Bar-graphs show the quantity of brain hemorrhage without (a) and with (b) correction for infarction volume, and (c) brain swelling at 24 hours. Intravenous tPA and NBO did not induce hemorrhagic conversion, and did not increase brain swelling.

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