Oral uridine pro-drug PN401 is neuroprotective in the R6/2 and N171-82Q mouse models of Huntington's disease.
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.
Saydoff
Joel A
JA
Neuroscience Research, Wellstat Therapeutics Corporation, 930 Clopper Road, Gaithersburg, MD 20878, USA. jsaydoff@wellstattherapeutics.com
Garcia
Rolando A G
RA
Browne
Susan E
SE
Liu
Liansheng
L
Sheng
Jin
J
Brenneman
Denise
D
Hu
Zhongyi
Z
Cardin
Sylvain
S
Gonzalez
Alexis
A
von Borstel
Reid W
RW
Gregorio
Jason
J
Burr
Holly
H
Beal
M Flint
MF
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
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