Authors :
Presenting Author: Li-Ping Liang, MD – University of Colorado Anschutz Medical Campus
Jennifer Pearson-Smith, PhD – University of Colorado Anschutz Medical Campus; Brian Day, PhD – professor, National Jewish Health; Manisha Patel, PhD – professor, University of Colorado Anschutz Medical Campus
Rationale:
Oxidative stress plays an important 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,
diisopropylflurophoshate (DFP) and soman. This previous dosing strategy of AEOL10150 required multiple daily injections, precluding our ability to test its efficacy against delayed consequences of nerve agent exposure such as neurodegeneration and cognitive dysfunction.
Methods:
We developed formulations of AEOL10150 designed to deliver the compound once daily with improved brain pharmacodynamics. Administration of AEOL10150 to rats in four new formulations resulted in eight times higher subcutaneous dose with slower absorption, longer half-life, and higher maximal plasma concentrations compared to our previous strategy.
Results:
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 damage, microglial activation, delayed memory impairment and mortality. Conclusions:
These results suggest that reformulation of AEOL10150 can attenuate acute and delayed outcomes of organophosphate neurotoxicity.
Funding:
This research work was support by NIH U01NS083422 (M.P)