title: Oral uridine pro-drug PN401 is neuroprotective in the R6/2 and N171-82Q mouse models of Huntington's disease.
abstract: Previously, uridine pro-drug 2',3',5'-tri-O-acetyluridine (PN401) was shown to be protective in the mitochondrial complex II inhibitor 3-nitropropionic acid model of Huntington's disease (HD). In this study, PN401 increased survival and improved motor function on the rotarod in both R6/2 and N171-82Q polyglutamine repeat mouse models of HD. PN401 significantly decreased neurodegeneration in both the piriform cortex and striatum although PN401 decreased huntingtin protein aggregates only in the striatum. Cortical and striatal brain-derived neurotrophic factor (BDNF) protein levels were reduced in the +/- compared to the -/- N171-82Q mice and PN401 treatment significantly increased cortical BDNF in both +/- and -/- mice, but PN401 did not affect striatal BDNF. These results suggest that PN401 may have beneficial effects in the treatment of neurodegenerative diseases such as HD.
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: Rolando A G
authors.initials: RA
authors.lastname: Garcia
authors.forename: Susan E
authors.initials: SE
authors.lastname: Browne
authors.forename: Liansheng
authors.initials: L
authors.lastname: Liu
authors.forename: Jin
authors.initials: J
authors.lastname: Sheng
authors.forename: Denise
authors.initials: D
authors.lastname: Brenneman
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Hu
authors.forename: Sylvain
authors.initials: S
authors.lastname: Cardin
authors.forename: Alexis
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Reid W
authors.initials: RW
authors.lastname: von Borstel
authors.forename: Jason
authors.initials: J
authors.lastname: Gregorio
authors.forename: Holly
authors.initials: H
authors.lastname: Burr
authors.forename: M Flint
authors.initials: MF
authors.lastname: Beal
mesh_terms: D000085:Acetates; D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy / Q000401:mortality / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000517:prevention & control*; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology*; D045442:Rotarod Performance Test; D014529:Uridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000085:Acetates; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D011355:Prodrugs; C000609666:uridine triacetate; D014529:Uridine