Adjuvant therapies using normobaric oxygen with hypothermia or ethanol for reducing hyperglycolysis in thromboembolic cerebral ischemia

Background and purpose: Normobaric oxygen (NBO), ethanol (EtOH), and therapeutic hypothermia (TH) delivered alone or in combination have neuroprotective properties after acute stroke. We used an autologous thromboembolic rat stroke model to assess the additive effects of these treatments for reducing the deleterious effects of hyperglycolysis post-stroke in which reperfusion is induced with recombinant tissue plasminogen activator (rt-PA).

Methods: Sprague-Dawley rats were subjected to middle cerebral artery (MCA) occlusion with an autologous embolus. One hour after occlusion, rt-PA was administered alone or with NBO (60%), EtOH (1.0 g/kg), TH (33 °C), either singly or in combination. Infarct volume and neurological deficit were assessed at 24h after rt-PA-induced reperfusion with or without other treatments. The extent of hyperglycolysis, as determined by cerebral glucose and lactate levels was evaluated at 3 and 24h after rt-PA administration. At the same time points, expressions of glucose transporter 1 (Glut1), glucose transporter 3 (Glut3), phosphofructokinase1 (PFK-1), and lactate dehydrogenase were (LDH) measured by Western blotting.

Results: Following rt-PA in rats with thromboembolic stroke, NBO combined with TH or EtOH most effectively decreased infarct volume and neurological deficit. As compared to rt-PA alone, EtOH or TH but not NBO monotherapies significantly reduced post-stroke hyperglycolysis. The increased utilization of glucose and production of lactate post-stroke was prevented most effectively when NBO was combined with either EtOH or TH after reperfusion with rt-PA, as shown by the significantly decreased Glut1, Glut3, PFK-1, and LDH levels.

Conclusions: In a rat thromboembolic stroke model, both EtOH and TH used individually offer neuroprotection after the administration of rt-PA. While NBO monotherapy does not appear to be effective, it significantly potentiates the efficacy of EtOH and TH. The similar neuroprotection and underlying mechanisms pertaining to the attenuation of hyperglycolysis provided by EtOH or TH in combination with NBO suggest a possibility of substituting EtOH for TH. Thus a combination of NBO and EtOH, which are widely available and easily used, could become a novel and effective neuroprotective strategy in the clinical setting.