Introduction: While oxidative stress mediates many of the pathologies in stroke, antioxidant therapies have been unsuccessful. Current antioxidants are limited either by a narrow range of radicals quenched or by low capacity. Some can yield toxic intermediates. We developed a new class of antioxidant, highly modified carbon nanoparticles called PEGylated hydrophilic carbon clusters (PEG-HCCs). These 40 nM particles quench superoxide by a high capacity novel catalytic mechanism (PNAS 2015: 2343-8), are effective against -OH and recouple nitric oxide synthase. Here we report the effect of PEG-HCCs administered during reperfusion after transient MCA suture occlusion in the rat under varying glucose levels. Hyperglycemia occurs in 1/3 of stroke patients and worsens outcome in part by accelerating release of radicals during reperfusion.
Methods: Variation in glucose was induced by streptozocin IP 2 days prior to MCAO. At 90 mins, 23 rats were injected IV with PBS or PEG-HCCs (4 mg/kg) and the suture removed. A second dose was given 2 hours later (dosing based on half-life and in-vitro efficacy). At 3 days, infarct size corrected for edema and neurological function (Bederson Score, BS) was obtained. An outcome curve was developed using a range of baseline glucose in controls and the effect of PEG-HCCs compared at rat’s baseline glucose values.
Results: We found a strong sigmoidal relationship between infarct size and glucose level in control rats (Fig. R2=.93; p=.0001; blue curve: control arm ± 95% confidence intervals). All PEG-HCC treated rats showed infarct size below the confidence interval (red stars; p<.003 vs control). Preliminary results for 120 min occlusion showed improved BS compared to control (3.5±2.4 vs 5.4±1.8; p=.047).
Conclusions: This novel, broadly active, high capacity antioxidant was able to improve outcome in a severe test of pre-clinical stroke at clinically relevant times. Studies are ongoing to assess the treatment window and longer term outcomes.