Neuroprotective effects of probenecid in a transgenic animal model of Huntington's disease.
Huntington's disease (HD) is an autosomal dominantly inherited disorder, caused by an expanded polyglutamine region of a protein called huntingtin. The excitotoxicity, oxidative damage and altered membrane transport may have an important role in the pathogenesis of HD. Probenecid is a non-selective inhibitor of multidrug resistance-associated proteins, but it also inhibits organic anion transporters. In this study, we examined the effects of probenecid on the survival, behaviour and immunohistochemical changes in the N171-82Q transgenic mouse model of HD. After probenecid administration, the duration of survival improved by 35%. The motor activity was significantly ameliorated as compared with the control transgenic group. Probenecid treatment significantly reduced the neuronal loss and the number of neuronal intranuclear aggregates. These results suggest that probenecid may exert a neuroprotective effect by increasing the membrane transport of protective compounds, and/or inhibiting the toxic compounds.
Vamos
Eniko
E
Department of Neurology, Albert Szent-Gyorgyi Clinical Centre, University of Szeged, Szeged, Hungary.
Voros
Krisztina
K
Zadori
Denes
D
Vecsei
Laszlo
L
Klivenyi
Peter
P
D000367:Age Factors; D000818:Animals; D002452:Cell Count; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D053208:Kaplan-Meier Estimate; D007736:Kynurenic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011339:Probenecid / Q000494:pharmacology / Q000627:therapeutic use*; D018709:Statistics, Nonparametric; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D007736:Kynurenic Acid; D011339:Probenecid