Parkinson's disease (PD) is an age-related
neurodegenerative disease in which the role of
reactive oxygen species (ROS) is strongly implicated. The presence of oxidative stress has been detected in human and experimental PD using both direct and indirect indices. Scavenging ROS is, therefore, an important therapeutic avenue for the treatment of PD. Manganic
porphyrins are catalytic
antioxidants that scavenge a wide range of ROS. In this study, we tested the
therapeutic effects of a compound [5,15-bis(methoxycarbonyl)-10,20-bis-trifluoromethyl-porphyrinato
manganese (III)
chloride (
AEOL11207)] belonging to a new generation of lipophilic manganic
porphyrins for neuroprotection and oral bioavailability in the mouse
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP) model of
parkinsonism. Groups of adult C57BL/6 mice were administered
MPTP with varying subcutaneous or oral dosing regimens of
AEOL11207. Neurotoxicity was assessed by measurement of striatal
dopamine levels and quantification of
tyrosine hydroxylase-positive neurons in the substantial nigra pars compacta one week after the first dose of
MPTP.
Glutathione depletion, lipid peroxidation, and
3-nitrotyrosine (3-NT) formation were measured as indicators of oxidative stress in the ventral midbrain in vivo.
AEOL11207 administered either by subcutaneous or oral routes protected against
MPTP-induced
dopamine depletion in the striatum as well as dopaminergic neuronal loss,
glutathione depletion, lipid peroxidation, and 3-NT formation in the ventral midbrain. Neuroprotection correlated with brain
metalloporphyrin concentrations. This is the first demonstration of neuroprotection by an orally active catalytic
antioxidant in the
MPTP mouse model and suggests its potential clinical utility for the treatment of chronic
neurodegenerative diseases such as PD.