University of Colorado School of Pharmacy
Mail Stop C238
12850 E. Montview Blvd.
Aurora, CO 80045
Research 2 (P15)
Research 2 (P15)
- University of Colorado, Program in Neuroscience
- National Jewish Medical & Research Center, Department of Medicine
Training and Education:
- BS, Pharmacy, M.S. University
- PhD, Pharmacology and Toxicology, Purdue University
- Post-doc, Neuroscience, Duke University.
The overarching theme of the laboratory is to understand the role of reactive species and mitochondrial mechanisms in neuronal disorders. Research in the laboratory is focused on three major areas.
Oxidative stress and mitochondrial dysfunction in temporal lobe epilepsy
Epilepsy is a recent addition to the diverse array of acute and chronic neurological disorders in which the role of oxidative stress and mitochondrial dysfunction is rapidly emerging. Work from our laboratory has identified distinct subcellular sources and mechanisms of seizure-induced free radical production and impaired mitochondrial redox status. Ongoing efforts are aimed at determining the role of mitochondrial dysfunction and oxidative mechanisms in epileptogenesis.
- Liang LP, Y.S. Ho and Patel M. Mitochondrial superoxide production in kainate-induced hippocampal damage. Neuroscience 101(3):563-570, 2000.
- Liang LP, Patel, M. Seizure-induced changes in mitochondrial redox status Free Rad. Biol. Med. 40(4): 2006.
- Patel M, Liang L-P, Hou H, Williams BB, Kmiec M, Swartz, HM, Fessel J, Roberts LJ. Seizure-induced formation of isofurans: novel products of lipid peroxidation whose formation is positively modulated by oxygen tension J. Neurochem.104:264-270, 2008.
- Jarrett SJ, Liang LP, Hellier J, Staley, KJ, Patel M. Mitochondrial DNA damage and impaired base excision repair during epileptogenesis, Neurobiol. Dis. 30(1):130-8; 2008.
- Liang L-P, Jarrett SG, Patel M. Chelation of mitochondrial iron amerliorates seizure induced neuronal injury. J. Neurosci. 28(45):11550-11556. 2008.
- Milder JB, Liang LP, Patel M. Acute oxidative stress and systemic Nrf2 activation by the ketogenic diet. Neurobiol. Dis. 4(1) 238-244, 2010.
- Waldbaum S and Patel M. Mitochondrial (dys)function in epilepsy. Epilepsy Res. 88:23-45, 2010.
Mitochondrial mechanisms of oxidative damage in Parkinson’s Disease
One important mechanism of superoxide toxicity is based on its direct oxidation and resultant inactivation of iron-sulfur (Fe-S) proteins such as aconitases and ability to act as a precursor of more potent oxidants e.g. hydroxyl radical. Current efforts in the laboratory are focused on addressing the hypothesis that superoxide toxicity via oxidative inactivation of mitochondrial aconitase contributes to neuronal death in animal models of Parkinson’s disease. We have identified a novel pool of mitochondrial iron that correlates with mitochondrial aconitase inactivation in experimental Parkinson’s disease. Efforts are also underway to determine mitochondrial mechanisms by which environmental redox cycling agents generate reactive oxygen species.
- Liang LP and Patel M. Iron-sulfur enzyme mediated mitochondrial superoxide toxicity in experimental Parkinson’s disease. J. Neurochem. 90:1076-1084, 2004.
- Castello PR, Drechsel D, Patel M. Mitochondria are a major source of paraquat-induced reactive oxygen species production. J. Biol. Chem. Vol 282 (19): 14186-14193, 2007.
- Liang L-P, Huang J, Fulton R, Day BJ, Patel M. An orally active metalloporphyrin protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in vivo. J. Neurosci. 27(16):4326-4333, 2007.
- Drechsel DA, Patel, M. Mechanisms of environmental neurotoxicant-induced oxidative stress, Invited review, Free Rad. Biol. Med. 44(11):1873-86; 2008.
- Drechsel DA and Patel M. Paraquat-induced production of reactive oxygen species in brain mitochondria in Methods in Enzymology on "Mitochondrial Electron Transport Complexes and Reactive Oxygen Species" Editors: Bill Allison and Immo Scheffler Vol. 456: 381-93, 2009.
- Cantu D, Schaack J, Patel M. Oxidative inactivation of mitochondrial aconitase results in increased iron, hydrogen peroxide and neuronal death. PloS One Vol 4 (9): e7095; 2009.
- Drechsel DA, Patel M. Respiration-dependent hydrogen peroxide removal in brain mitochondria via the thioredoxin/peroxiredoxin system J. Biol. Chem. 10.1074/jbc.M110.101196, 2010.
Manganese porphyrin catalytic antioxidants as neuroprotective agents
A major goal of our research is to develop neuroprotective therapeutic entities designed to scavenge and detoxifying reactive oxygen species. One approach has been to utilize mice that overexpress endogenous superoxide dismutases (SOD1/2/3). A second approach is the use of manganese porphyrin compounds that can catalytically eliminate a variety of reactive oxygen species. We utilize a two-tier approach composed of vitro and in vivo models to assess neuroprotective actions of manganese porphyrins and correlate them with their pharmacokinetic parameters and ability to protect cellular targets against oxidation. We have recently identified an orally active metalloporphyrin that is efficacious in a mouse model of parkinsonism.
- Patel M and Day BJ. Metalloporphyrin class of therapeutic catalytic antioxidants. Trends Pharmacol Sci 20:359-364, 1999.
- Patel M. Metalloporphyrins improve the survival of Sod2 deficient neuronal cultures. Aging Cell 2(4):219-222, 2003.
- Castello P.R., Drechsel, DA, Day BJ, Patel M. Inhibition of mitochondrial hydrogen peroxide production by glyoxylate metalloporphyrins J. Pharm. Exp. Ther. 324:970-976, 2008.
- Golden T and Patel M. Metallopophryin antioxidants in neurodegeneration. Antioxidants and Redox Signaling 11(3):555-70; 2009.
- Professional Program: Instructional Methods II, Integrated Organ Systems IV (neuropharmacology)
- Graduate Program: TXCL 7322 (Principles of Toxicology), University of Colorado, Department of Medicine