title: 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.
abstract: Recently, we demonstrated that dimeric apocynin prevented loss of motor function in the leucine-rich repeat kinase 2 (LRRK2(R1441G)) transgenic (tg) mouse (treated with 200mg/kg, three times per week) [B.P. Dranka et al., Neurosci. Lett. 549 (2013) 57-62]. Here we extend those studies by treating LRRK2(R1441G) mice with an orally-available, mitochondrially-targeted apocynin derivative. We hypothesized that the increased mitochondrial permeability of Mito-apocynin, due to the triphenylphosphonium moiety, would allow improvement of Parkinson's disease (PD) symptoms at lower doses than those required for diapocynin. Tests of motor coordination (pole test, Rotor-Rod) revealed a significant deficit in coordinated motor function in LRRK2(R1441G) mice by 15 months of age. Decreased performance on the pole test and Rotor-Rod in the LRRK2(R1441G) mice was prevented with Mito-apocynin treatment (3mg/kg, three times per week). Decreased olfactory function is an early indication of PD in human patients. LRRK2(R1441G) tg mice displayed deficits in sense of smell in both the hidden treat test, and a radial arm maze test. Interestingly, treatment with Mito-apocynin prevented this hyposmia, and animals retained normal ability to identify either a scented treat or a food pellet as well as wild type littermates. Together, these data demonstrate that the mitochondria-targeted apocynin analog is effective in preventing early PD-like symptoms in the LRRK2(R1441G) mouse model.
authors.affiliation: Department of Biophysics, and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, United States.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Dranka
authors.affiliation: Department of Biophysics, and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, United States.
authors.forename: Alison
authors.initials: A
authors.lastname: Gifford
authors.affiliation: Department of Biophysics, and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, United States.
authors.forename: Donna
authors.initials: D
authors.lastname: McAllister
authors.affiliation: Department of Biophysics, and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, United States.
authors.forename: Jacek
authors.initials: J
authors.lastname: Zielonka
authors.affiliation: Department of Biophysics, and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, United States.
authors.forename: Joy
authors.initials: J
authors.lastname: Joseph
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States.
authors.forename: Crystal L
authors.initials: CL
authors.lastname: O'Hara
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Stucky
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, United States.
authors.forename: Anumantha G
authors.initials: AG
authors.lastname: Kanthasamy
authors.affiliation: Department of Biophysics, and Free Radical Research Center, Medical College of Wisconsin, Milwaukee, WI, United States. Electronic address: balarama@mcw.edu.
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
mesh_terms: D000098:Acetophenones / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D009048:Motor Skills / Q000187:drug effects; D000857:Olfaction Disorders / Q000517:prevention & control* / Q000523:psychology; D009943:Organophosphorus Compounds / Q000737:chemistry; D010300:Parkinson Disease / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology / Q000523:psychology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D000098:Acetophenones; D009943:Organophosphorus Compounds; C061896:triphenylphosphine; C056165:acetovanillone; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Apocynin; Hyposmia; Neurodegeneration; Parkinson's disease