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Parkinson's disease therapy with Istradefylline and blood biomarkers of epigenetics
Author(s) -
Kanzato Naomi,
Nakachi Kou,
Naka Taro,
Mochizuki Satsuki,
Miyamae Yuka,
Okada Yasunori
Publication year - 2020
Publication title -
neurology and clinical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2049-4173
DOI - 10.1111/ncn3.12415
Subject(s) - medicine , epigenetics , dyskinesia , biomarker , disease , dna methylation , oncology , bioinformatics , parkinson's disease , gene expression , gene , biochemistry , chemistry , biology
Abstract Background Istradefylline (IST), an adenosine A 2A receptor antagonist, has been used since 2013 in Japan as an adjunctive therapy to levodopa (L‐DOPA) for patients with Parkinson's disease (PD). The long‐term use of IST as an adjunct to L‐DOPA (IST‐LD) was herein investigated to clarify the cooperative potential to keep motor functions, and an epigenetic modification for disease‐specific up‐regulated A 2A R signals. Methods The cohort comprising 62 PD patients with diurnal variations in motor function were treated with IST‐LD for 36 months, and clinical and biomarker parameters were evaluated. One monozygotic twin pair with juvenile PD and eight healthy control (HC) subjects were recruited for analyses of epigenetic biomarkers with peripheral blood lymphocyte (PBL): the A 2A R protein (A 2A R‐p), A 2A R mRNA (A 2A R‐m), and DNA methylation of the ADORA2A (Chr22q11.23) and DRD1 (Chr5q35.1) genes. Results IST‐LD partially reversed locomotive dysfunction and motor off time and did not promote the severe dyskinesia (LID) develop. A 2A R expression levels of the PBL were higher in IST‐naïve PD patients than in HC, which were associated with the effectiveness of IST‐LD and clinical global impression improvements. Intrinsic DNA demethylation of the ADORA2A gene were observed in juvenile monozygotic twin pair of the PD and IST‐naïve PD patients, which were reversed by IST‐LD at 12 months. Conclusions IST‐LD was cooperative for long term to preserve motor execution controls and global daily activities improvement, through the canonical pharmacodynamics of inhibiting A 2A R signaling, and also via the epigenetic modification on the ADORA2A gene.