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  • Genome-wide microarray analysis identifies a potential role for striatal retrograde endocannabinoid signaling in the pathogenesis of experimental L-DOPA-induced dyskinesia.

Genome-wide microarray analysis identifies a potential role for striatal retrograde endocannabinoid signaling in the pathogenesis of experimental L-DOPA-induced dyskinesia.

Synapse (New York, N.Y.) (2014-03-07)
Yong Wang, Qiao Jun Zhang, Hui Sheng Wang, Tao Wang, Jian Liu
ABSTRACT

l-3,4-Dihydroxyphenylalanine (L-DOPA) is the most widely used drug for the treatment of Parkinson's disease. Unfortunately, chronic administration of this dopamine precursor causes L-DOPA-induced dyskinesia (LID), which is a debilitating complication whose pathogenesis remains unclear. In this study, we compared gene expression profiles of sensorimotor striatum tissue derived from LID and non-LID 6-hydroxydopamine-lesioned rats treated with L-DOPA. Total RNA was amplified, transcribed and hybridized to Agilent Whole Rat Genome Oligo Microarray chips. Quantitative real-time reverse transcription PCR was conducted to validate the microarray data. We detected 382 upregulated genes and 115 downregulated genes in LID rats when compared with that of non-LID subjects with Significance Analysis for Microarrays software. The differentially expressed genes were mainly associated with postsynaptic cell membranes, synapses, and neurotransmitter receptors. Gene Set Analysis (GSA) software was used to identify differentially expressed gene ontology (GO) categories and pathways. The GSA found that "long-term depression" and "retrograde endocannabinoid signaling" pathways were downregulated, whereas a set of lipid metabolism-related GO categories and pathways were upregulated in LID rats compared with non-LID controls. Our study provides further experimental evidence to support the direct correlation between abnormal striatal synaptic plasticity and the induction of LID, and it suggests that the dysfunction of the retrograde endocannabinoid signaling system, a lipid-based neuromodulatory system, and the relevant alteration of the related lipid metabolism processes might play an important role in the pathogenesis of LID.

MATERIALS
Product Number
Brand
Product Description

Supelco
Levodopa, Pharmaceutical Secondary Standard; Certified Reference Material
Levodopa, European Pharmacopoeia (EP) Reference Standard
USP
Levodopa, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Hydrogen bromide, ReagentPlus®, ≥99%
Sigma-Aldrich
L-3,4-Dihydroxyphenylalanine methyl ester hydrochloride, solid
Sigma-Aldrich
Desipramine hydrochloride, ≥98% (TLC), powder
Sigma-Aldrich
Benserazide hydrochloride, ≥98% (HPLC), solid
Sigma-Aldrich
3,4-Dihydroxy-L-phenylalanine, ≥98% (TLC)
USP
Desipramine hydrochloride, United States Pharmacopeia (USP) Reference Standard
Sigma-Aldrich
Hydrobromic acid solution, 33 wt. % in acetic acid
Benserazide hydrochloride, European Pharmacopoeia (EP) Reference Standard
Desipramine hydrochloride, European Pharmacopoeia (EP) Reference Standard
Sigma-Aldrich
Hydrogen bromide solution, 33 wt. % in acetic acid
Sigma-Aldrich
Hydrobromic acid, reagent grade, 48%
Sigma-Aldrich
Hydrobromic acid, ACS reagent, 48%
Sigma-Aldrich
Hydrobromic acid, 48 wt. % in H2O, ≥99.99%