The long-term goal of this multiple PI proposal is to develop neuroprotective strategies that involve synthesis and testing of mitochondria-targeted antioxidants in a preclinical mouse model of Parkinson's Disease (PD) that can be subsequently translated to patients with PD. In this proposal, we have combined the expertise and experience of individuals in synthetic organic chemistry, free radical biology, neuropharmacology, and neurotoxicology from two institutions, the Medical College of Wisconsin and Iowa State University. This proposal is based on the discovery that mitochondria- targeted antioxidants (MTAs) inhibit oxidative stress and neuronal damage in 1-methyl-4- phenylpyridinium (MPP+) treated neuronal cell culture models of PD as well as in 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) animal models of PD. We hypothesize that MTAs provide an effective neuroprotective strategy for treatment of PD. As a corollary, we propose that MTAs attenuate mitochondria-derived reactive oxygen and nitrogen species (ROS/RNS), thereby protecting against inactivation of key redox sensors in response to mitochondrial neurotoxin exposure. Specifically, we will: (i) Design and synthesize MTAs and assess their cytoprotection in neuronal cell culture models of PD, (ii) Determine the molecular mechanisms of cytoprotection of MTAs in neuronal cell culture models of PD, (iii) Assess the neuroprotective effects of MTAs in a well-established preclinical MPTP mouse model of PD, (iv) Determine the activation/inactivation of key redox targets in mitochondria in response to MTA treatment in the preclinical MPTP mouse model, and (iv) Investigate the long-term tolerability of MTAs during chronic treatment in the mouse model. We will use several analytical techniques (low-temperature EPR, HPLC-fluorescence and electrochemical detection, HPLC/MS, proteomics) to detect and quantitate ROS/RNS, molecular biological approaches (apoptosis measurements, transcription factor translocation) to define the molecular mechanisms, and neurobehavioral and histopathological analyses to evaluate the neuroprotective effects. Abnormal generation of mitochondrial ROS/RNS in response to environmental toxins has been implicated in the pathogenesis of PD. Numerous antioxidants and iron chelators have been used with partial success in experimental animal models of PD. Emerging literature suggests that antioxidants specifically targeted to mitochondria might serve as promising neuroprotectants for treatment of PD. In this proposal, we will assess the neuroprotective efficacy of several novel MTAs in a cell culture and preclinical mouse model of PD. Systematic characterization of neuroprotective properties and long-term tolerability of novel MTAs in both cell culture and animal models will yield comprehensive preclinical data for the clinical development of efficacious mitochondria-targeted antioxidant therapies for PD.

Public Health Relevance

Parkinson's Disease (PD) is a debilitating neurodegenerative disease. Effective treatment to intervene the progression of neurodegenerative processes in PD remains unavailable. Using a cell culture and a mouse model of PD, we propose to develop a "mitochondria-targeted" antioxidant - based neuroprotective strategy for treating PD. Proposed studies which bring together chemical and neuropharmacological expertise from two institutions (Medical College of Wisconsin and Iowa State University), will help us develop efficacious mitochondria-targeted antioxidants for treatment of PD as well as understand the possible neuroprotective mechanisms of these novel class of agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039958-13
Application #
8423024
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sutherland, Margaret L
Project Start
2000-04-10
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
13
Fiscal Year
2013
Total Cost
$510,053
Indirect Cost
$86,518
Name
Medical College of Wisconsin
Department
Biophysics
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Ghosh, Anamitra; Langley, Monica R; Harischandra, Dilshan S et al. (2016) Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson's Disease. J Neuroimmune Pharmacol 11:259-78
Charli, Adhithiya; Jin, Huajun; Anantharam, Vellareddy et al. (2016) Alterations in mitochondrial dynamics induced by tebufenpyrad and pyridaben in a dopaminergic neuronal cell culture model. Neurotoxicology 53:302-13
Gendelman, Howard E; Anantharam, Vellareddy; Bronich, Tatiana et al. (2015) Nanoneuromedicines for degenerative, inflammatory, and infectious nervous system diseases. Nanomedicine 11:751-67
Michalski, Radoslaw; Michalowski, Bartosz; Sikora, Adam et al. (2014) On the use of fluorescence lifetime imaging and dihydroethidium to detect superoxide in intact animals and ex vivo tissues: a reassessment. Free Radic Biol Med 67:278-84
Dranka, Brian P; Gifford, Alison; McAllister, Donna et al. (2014) A novel mitochondrially-targeted apocynin derivative prevents hyposmia and loss of motor function in the leucine-rich repeat kinase 2 (LRRK2(R1441G)) transgenic mouse model of Parkinson's disease. Neurosci Lett 583:159-64
Jin, Huajun; Kanthasamy, Arthi; Ghosh, Anamitra et al. (2014) Mitochondria-targeted antioxidants for treatment of Parkinson's disease: preclinical and clinical outcomes. Biochim Biophys Acta 1842:1282-94
Dranka, Brian P; Gifford, Alison; Ghosh, Anamitra et al. (2013) Diapocynin prevents early Parkinson's disease symptoms in the leucine-rich repeat kinase 2 (LRRK2R¹⁴⁴¹G) transgenic mouse. Neurosci Lett 549:57-62
Michalski, Radoslaw; Zielonka, Jacek; Hardy, Micael et al. (2013) Hydropropidine: a novel, cell-impermeant fluorogenic probe for detecting extracellular superoxide. Free Radic Biol Med 54:135-47
Ghosh, Anamitra; Kanthasamy, Arthi; Joseph, Joy et al. (2012) Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson's disease. J Neuroinflammation 9:241
Dranka, Brian P; Zielonka, Jacek; Kanthasamy, Anumantha G et al. (2012) Alterations in bioenergetic function induced by Parkinson's disease mimetic compounds: lack of correlation with superoxide generation. J Neurochem 122:941-51

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