Abstract 8: Modulation of Cytochrome c Oxidase Activity with Specific Infrared Light Wave Lengths: Noninvasive Therapy for Reperfusion Injury
Reperfusion injury plays a major role in multiple pathologies by inducing generation of reactive oxygen species (ROS) at high mitochondrial membrane potentials (ΔΨm). Traditional attempts to scavenge ROS have failed, due to inherent difficulties in sub-cellular delivery within the early minutes of reflow. Accordingly, we developed a non-pharmacologic therapy that targets cytochrome c oxidase (CcO) using infrared light (IRL), and discovered 4 specific IRL wavelengths that reversibly reduce the activity of CcO. We propose that these wavelengths will stabilize ΔΨm during reperfusion and, thus, provide a non-invasive strategy to attenuate cerebral ischemia-reperfusion injury.
Methods and Results: In Protocol 1, we tested this hypothesis in cell culture. All 4 IRL wavelengths that reduce CcO activity: i) decreased mitochondrial respiratory rate (n=5; p<0.05); ii) reduced ΔΨm in a switch-like manner (n=3; p<0.05); iii) attenuated mitochondrial superoxide production detected in situ (n=5; p<0.05); and, most importantly iv) attenuated neuronal death following oxygen glucose deprivation (n = 7, p<0.05). In contrast, wavelengths that activate CcO provided no benefit. In Protocol 2, we evaluated the neuroprotective effect of the 4 candidate wavelengths in the in vivo rat model of global brain ischemia. All possible wavelength combinations were evaluated using a randomized and blinded study design (15 treatments; n = 8-12/group; total n=153,). At 14 days post-reperfusion, untreated controls demonstrated an 88% loss of neurons in the CA1 hippocampus. Strikingly, all 15 IRL combinations were protective, with neuronal loss ranging from only 11% (best treatment) to 58%: all p-values <0.05 vs control. The neurologic protection in IRL treated rats was accompanied by preservation of neurologic function, as demonstrated by a 40% improvement in spatial learning deficits (n = 10/group, p<0.05). Finally, in ongoing translational experiments (Protocol 3) we developed a prototype capable of delivering the 4 candidate IRL wavelengths to deep structures of the pig brain with no detectable increase in scalp or brain temperature (ΔT<0.1°C).
Conclusion: Non-invasive reduction of CcO activity with specific IRL wavelengths is profoundly neuroprotective.
Author Disclosures: T.H. Sanderson: None. J.M. Wider: None. C.A. Reynolds: None. B.D. Lepore: None. K. Przyklenk: None. M. Huttemann: None.
- © 2014 by American Heart Association, Inc.