RGFP109, a histone deacetylase inhibitor attenuates L-DOPA-induced dyskinesia in the MPTP-lesioned marmoset: a proof-of-concept study.
BACKGROUND
l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID) are a complication of chronic dopamine replacement therapy in Parkinson's disease (PD). Recent studies have suggested that the mechanisms underlying development and expression of LID in PD may involve epigenetic changes that include deacetylation of striatal histone proteins. We hypothesised that inhibition of histone deacetylase, the enzyme responsible of histone deacetylation, would alleviate LID.


METHODS
Four female common marmoset (Callithrix jacchus) were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Following stabilisation of the parkinsonian phenotype, marmosets were primed to exhibit dyskinesia with chronic administration of L-DOPA. We then investigated the effects of the brain-penetrant histone deacetylase inhibitor, RGFP109 (30 mg/kg p.o. once daily for 6 days), on LID and L-DOPA anti-parkinsonian efficacy.


RESULTS
RGFP109 had no acute effects on dyskinesia after single or 6 days once-daily treatment (both P > 0.05). However, one week following cessation of RGFP109, dyskinesia and duration of ON-time with disabling dyskinesia were reduced by 37% and 50%, respectively (both P < 0.05), compared to that seen previously with L-DOPA alone. There was no change in anti-parkinsonian actions of, or ON-time duration afforded by, L-DOPA (P > 0.05).


CONCLUSIONS
Histone deacetylation inhibition may represent a novel approach to reverse established LID in PD and improve quality of the anti-parkinsonian benefit provided by L-DOPA.
Division of Brain, Imaging & Behaviour, Systems Neuroscience, Toronto Western Research Institute, 399 Bathurst Street, MP-12-303, Toronto, ON M5T2S8, Canada. tom.johnston@uhnresearch.ca
Tom H
TH
Johnston
Philippe
P
Huot
Sammie
S
Damude
Susan H
SH
Fox
Steven W
SW
Jones
James R
JR
Rusche
Jonathan M
JM
Brotchie
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D002144:Callithrix; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D007980:Levodopa / Q000009:adverse effects; D020734:Parkinsonian Disorders / Q000188:drug therapy*
D000978:Antiparkinson Agents; D056572:Histone Deacetylase Inhibitors; D007980:Levodopa