Dr. Kimberly Mendoza
University of Texas Medical Branch
Objectives: Hypotension worsens traumatic brain injury (TBI). Reactive oxygen species (ROS) contribute to loss of autoregulation and poor reperfusion. However, antioxidant therapy has not demonstrated clinical benefit. Most available antioxidants have limited capacity, narrow therapeutic range or require regeneration. We developed a novel carbon nanoparticle (PEG-HCCs) that is a catalytic antioxidant with broad and high capacity ROS-quenching1. PEG-HCCs restored cerebral perfusion and improved functional outcome in mild TBI transformed to severe by hypotension/resuscitation. We hypothesized that the structural features we believe responsible for this remarkable efficacy1 could be mimicked in simpler materials more likely to achieve regulatory approval. Methods: Graphitic quantum dots (7 nm; PEG-GQDs) were prepared from bituminous coal under fuming nitric acid and sulfuric acid and compared to PEG-HCC. 35 Long Evans rats underwent mild cortical compression injury (3m/s, 2.5mm deformation). MAP of 40 mmHg was achieved by blood withdrawal and reinfused 80 minutes later simultaneous with intravenous PBS or 4mg/kg pegylated-GQDs. Regional cerebral perfusion was measured using Perimed laser speckle. Results: In-vitro results indicated equivalent PEG-GQD potency to PEG- HCCs protecting against oxidative injury and demonstrated catalytic superoxide-quenching activity. In the mild TBI model, PEG-GQD (2 mg/kg) showed partial recovery with a single dose and full recovery (4 mg/kg) with a double dose. PEG-GQD was equally effective as PEG-HCCs and completely restored cerebral perfusion even when administered 80 minutes following injury without acute toxicity. Conclusions: In-vitro results in cultured neurons (SH5y) and brain endothelial cells (b.End3) indicated equivalent PEG-GQDs were effective in restoring perfusion and providing protection even when administered after the mitochondrial toxin, Antimycin A. Lesion size and neurological outcome measurements will be presented. Given that perfusion reduction is a major factor in worsening outcome after TBI, these agents deserve consideration as potential clinical therapeutics.
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