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The Journal of Neuroscience, April 18, 2007, 27(16):4326-4333; doi:10.1523/JNEUROSCI.0019-07.2007

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Neurobiology of Disease
An Orally Active Catalytic Metalloporphyrin Protects against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Neurotoxicity In Vivo

Li-Ping Liang,¹ Jie Huang,² Ruth Fulton,¹ Brian J. Day,^1,2 and Manisha Patel¹

¹Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center and ²Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado 80262

Correspondence should be addressed to Dr. Manisha Patel, Department of Pharmaceutical Sciences, 4200 East Ninth Avenue, Box C238, Denver, CO 80262. Email: manisha.patel{at}uchsc.edu

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.

Key words: Parkinson's disease; oxidative stress; antioxidants; neuroprotection; dopamine; lipid peroxidation

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Received Jan. 3, 2007; revised March 15, 2007; accepted March 16, 2007.

Correspondence should be addressed to Dr. Manisha Patel, Department of Pharmaceutical Sciences, 4200 East Ninth Avenue, Box C238, Denver, CO 80262. Email: manisha.patel{at}uchsc.edu

This article has been cited by other articles:

				P. R. Castello, D. A. Drechsel, B. J. Day, and M. Patel Inhibition of Mitochondrial Hydrogen Peroxide Production by Lipophilic Metalloporphyrins J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 970 - 976. [Abstract] [Full Text] [PDF]

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