Abstract

Reactive oxygen species have an emerging role in the pathological consequences of status epilepticus (SE). We have previously demonstrated the efficacy of a water-for-injection formulation of the meso-porphyrin catalytic antioxidant, AEOL10150 against oxidative stress, neuroinflammation, and neuronal death initiated by kainic acid, pilocarpine, diisopropylflurophosphate (DFP) and soman. This previous dose and dosing strategy of AEOL10150 required smaller multiple daily injections, precluding our ability to test its efficacy against delayed consequences of nerve agent exposure such as neurodegeneration and cognitive dysfunction. Therefore, we developed formulations of AEOL10150 designed to deliver a larger dose once daily with improved brain pharmacodynamics. We examined four new formulations of AEOL10150 that resulted in 8 times higher subcutaneous dose with lower acute toxicity, slower absorption, longer half-life, and higher maximal plasma concentrations compared to our previous strategy. AEOL10150 brain levels exhibited improved pharmacodynamics over 24h with all four formulations. We tested a subcutaneous dose of 40 mg/kg AEOL10150 in two formulations (2% CMC and 4% PEG-4000) in the DFP rat model and both formulations exhibited significant protection against DFP-induced oxidative stress. Additionally, and in one formulation (4% PEG-4000), AEOL10150 significantly protected against DFP-induced neuronal death, microglial activation, delayed memory impairment and mortality. These results suggest that reformulation of AEOL10150 can attenuate acute and delayed outcomes of organophosphate neurotoxicity.

Significance Statement Reformulation of AEOL10150 allowed higher tolerated doses of the compound with improved pharmacodynamics. Specifically, one new formulation allowed fewer daily doses and improvement in acute and delayed outcomes of organophosphate toxicity