Abstract
Oxidative stress plays a crucial role in the pathogenesis of Parkinson's disease (PD) and one strategy for neuroprotective therapy for PD is to scavenge reactive species using a catalytic antioxidant. Previous studies in our laboratory revealed that pretreatment of lipophilic metalloporphyrins showed protective effects in a mouse PD model. In this study, we optimized the formulations of these metalloporphyrins to deliver them orally and tested their efficacy on disease outcomes in a second species after initiation of an insult (i.e. disease modification). In this study, a pharmaceutical formulation of two metalloporphyrin catalytic antioxidants, AEOL11207 and AEOL11114 was tested for oral drug delivery. Both compounds showed gastrointestinal absorption, achieved high plasma concentrations, and readily penetrated the blood brain barrier after intravenous or oral delivery. AEOL11207 and AEOL11114 bioavailabilities were calculated to be 24 % and 25 %, respectively at a dose of 10 mg/kg via the oral route. In addition, both compounds significantly attenuated 6-hydroxydopamine (6-OHDA) induced neurotoxic damage, including dopamine depletion, cytokine production and microglia activation in the striata, dopaminergic neuronal loss in the substantial nigra, oxidative/nitrative stress indices (glutathione disulfide and 3-nitrotyrosine) in the ventral midbrain and rotation behavioral abnormality in rats. These results indicate that AEOL11207 and AEOL11114 are orally active metalloporphyrins and protect against 6-OHDA neurotoxicity one to three days post-lesioning suggesting disease-modifying properties and translational potential for PD.
Significance Statement Two catalytic antioxidants showed gastrointestinal absorption, achieved high plasma concentrations, and readily penetrated the blood brain barrier. Both compounds significantly attenuated dopamine depletion, cytokine production, microglia activation, dopaminergic neuronal loss, oxidative/nitrative stress indices and behavioral abnormality in a Parkinson’s disease rat model. The results suggest that both metalloporphyrins possess disease-modifying properties which may be useful in treating Parkinson’s disease.
- behavioral neuroscience
- cytokines
- Dopamine
- microglia
- neurodegeneration
- Neuroinflammation
- neurotoxins
- Oxidative stress/antioxidants
- Parkinson's Disease
- pharmacokinetic
- Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics