title: Oral uridine pro-drug PN401 decreases neurodegeneration, behavioral impairment, weight loss and mortality in the 3-nitropropionic acid mitochondrial toxin model of Huntington's disease.
abstract: Huntington's disease (HD) is associated with decreased activity of mitochondrial succinate dehydrogenase (complex II). De novo biosynthesis of uridine nucleotides is directly coupled to the respiratory chain. Cells with impaired mitochondrial function become uridine auxotrophs and can be maintained with high micromolar concentration of uridine and pyruvate. The therapeutic role of pyrimidines and possible changes in uridine content has not been assessed in neurological diseases involving mitochondrial dysfunction in vivo. Oral administration of PN401 delivers much higher levels of uridine to the circulation than oral administration of uridine itself. Administration of complex II inhibitor 3-nitropropionic acid (3NP) induced neuronal damage in the striatum, substantia nigra and/or thalamus in 80% of the mice and led to 38% mortality. Treatment with PN401 almost completely prevented the neuronal damage due to 3NP and completely prevented mortality. In two subsequent experiments, 3NP-induced weight loss, mortality and behavioral impairment in rotarod performance and spontaneous motor activity were attenuated by treatment with oral PN401. 3NP did not reduce forebrain total uridine nucleotides (TUN), though higher doses of PN401 associated with optimal neuroprotection did elevate TUN to supranormal levels. Thus, oral PN401 treatment has neuroprotective effects in a HD model of mitochondrial dysfunction and the mechanism is more complex than correction of a pyrimidine deficit.
authors.affiliation: Neuroscience Research, Wellstat Therapeutics Corporation, 930 Clopper Road, Gaithersburg, MD 20878, USA. jsaydoff@wellstattherapeutics.com
authors.forename: Joel A
authors.initials: JA
authors.lastname: Saydoff
authors.forename: Lian Sheng
authors.initials: LS
authors.lastname: Liu
authors.forename: Rolando A G
authors.initials: RA
authors.lastname: Garcia
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Hu
authors.forename: Donna
authors.initials: D
authors.lastname: Li
authors.forename: Reid W
authors.initials: RW
authors.lastname: von Borstel
mesh_terms: D000085:Acetates; D000284:Administration, Oral; D000818:Animals; D006816:Huntington Disease / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology; D009574:Nitro Compounds; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use*; D011422:Propionates / Q000633:toxicity*; D014529:Uridine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D015431:Weight Loss / Q000187:drug effects / Q000502:physiology
chemical_list: D000085:Acetates; D009574:Nitro Compounds; D011355:Prodrugs; D011422:Propionates; C000609666:uridine triacetate; C015392:3-nitropropionic acid; D014529:Uridine