Oxidative stress accompanies both normal and pathological processes. Organisms have developed protective mechanisms to deal with release of reactive oxygen species resulting from oxidative stress. However, the initial injury can unleash a cascade of radicals and the products of these detoxification steps can yield other radicals or unstable molecules that require additional detoxification. Normally, sufficient levels f protective enzymes cope with these products. Under pathological circumstances these intermediate steps are overwhelmed; radicals and their deleterious products accumulate. Antioxidants with limited capacity that modify only one radical in this cascade may, in the face of inadequate downstream protective mechanisms, lead to injury propagation. Most antioxidants with broader activity have limited capacity to deal with this cascade while others require regeneration, often by the same molecules consumed in the injured environment. Because most antioxidants share one or more limitations, it is not surprising that clinical trials of conventionl antioxidant therapies administered after injury have generally failed. We developed a new class of antioxidant based on highly modified carbon nanoparticles we term PEGylated hydrophilic carbon clusters (PEG-HCCs). We show that these particles have high radical quenching capacity, are active against two major oxy-radicals without effect on nitric oxide and are consistent with high capacity superoxide (SO) dismutase mimetics. Unlike 2 prototype antioxidants, PEG-SOD and PBN, PEG-HCCs were effective after administration of a mitochondrial toxin in culture and rapidly restored neurovascular unit function in vivo ischemia/reperfusion model. Our overall hypothesis is that these features of PEG-HCCs can be optimized in structures more readily translatable to the clinic through an integrated project in which the biochemistry of radical quenching drives chemical modifications that are confirmed in-vivo ischemic/reperfusion. We will address this hypothesis via the following specific aims to determine whether:
Aim 1. Highly conjugated planar graphene domain(s) with (or without) polarized spin distribution of the intrinsic radical of carbon nanostructures is responsible for th rapid dismutation of SO.
Aim 2. Carbon nanoparticles and polyaromatics developed in Aim 1 efficiently turn over ROS by direct neutralization (e.g., OH?) or catalytic turnover (e.g., SO).
Aim3. Materials developed in Aim 1 and tested in Aim 2 will improve oxidative balance, reverse cerebrovascular dysfunction and reduce brain lesion size when tested in a rat model of traumatic brain injury. Completion of these aims will lead to better antioxidants with the potentia to treat oxidative stress in patients.
While oxygen is essential for life, it is also a highly reactive molecule that needs a complex biological system to prevent it from causing damage after nervous system injury. However, approaches to treat this injury have not worked in patients. Our laboratories have identified that new carbon based nanomaterials have a remarkably favorable profile that could overcome limitations of current therapies and in this project we will determine what are the key features that lead to this protection and test whether simpler materials can be developed that are more likely to be translatable to the patient.
