Pre-clinical therapeutic development of a series of metalloporphyrins for Parkinson's disease
Journal Article
·
· Toxicology and Applied Pharmacology
- Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States)
- Department of Medicine, National Jewish Health, Denver, CO (United States)
Reactive oxygen species are a well-defined therapeutic target for Parkinson's disease (PD) and pharmacological agents that catalytically scavenge reactive species are promising neuroprotective strategies for treatment. Metalloporphyrins are synthetic catalytic antioxidants that mimic the body's own antioxidant enzymes i.e. superoxide dismutases and catalase. The goal of this study was to determine if newly designed metalloporphyrins have enhanced pharmacodynamics including oral bioavailability, longer plasma elimination half-lives, penetrate the blood brain barrier, and show promise for PD treatment. Three metalloporphyrins (AEOL 11216, AEOL 11203 and AEOL 11114) were identified in this study as potential candidates for further pre-clinical development. Each of these compounds demonstrated blood brain barrier permeability by the i.p. route and two of three compounds (AEOL 11203 and AEOL 11114) were orally bioavailable. All of these compounds protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, including dopamine depletion in the striatum, dopaminergic neuronal loss in the substantial nigra, and increased oxidative/nitrative stress indices (glutathione disulfide and 3-nitrotyrosine) in the ventral midbrain of the mice without inhibiting MPTP metabolism. Daily therapeutic dosing of these metalloporphyrins were well tolerated without accumulation of brain manganese levels or behavioral alterations assessed by open field and rotarod tests. The study identified two orally active metalloporphyrins and one injectable metalloporphyrin as clinical candidates for further development in PD. - Highlights: • A series of metalloporphyrins were optimized in a mouse model of parkinsonism. • Two novel orally active, brain permeable antioxidant metalloporphyrins were identified. • The identified metalloporphyrins were well tolerated.
- OSTI ID:
- 22690997
- Journal Information:
- Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Vol. 326; ISSN TXAPA9; ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
Similar Records
Parkinson's disease: Studies on the pathology of the disease and the mechanism of action of the neurotoxin MPTP
Distribution of 1-methyl-4-phneyl-1,2,3,6-tetrahydropyridine in experimental animals studied by positron emission tomography and whole body autoradiography
Resveratrol prolongs lifespan and improves 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced oxidative damage and behavioural deficits in Drosophila melanogaster
Thesis/Dissertation
·
Thu Dec 31 23:00:00 EST 1987
·
OSTI ID:5647254
Distribution of 1-methyl-4-phneyl-1,2,3,6-tetrahydropyridine in experimental animals studied by positron emission tomography and whole body autoradiography
Journal Article
·
Sun Jan 05 23:00:00 EST 1986
· Life Sci.; (United States)
·
OSTI ID:6425572
Resveratrol prolongs lifespan and improves 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced oxidative damage and behavioural deficits in Drosophila melanogaster
Journal Article
·
Sat Sep 15 00:00:00 EDT 2018
· Biochemical and Biophysical Research Communications
·
OSTI ID:23105636