Planta Med 2019; 85(17): 1351-1362
DOI: 10.1055/a-1013-7686
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Pharmacogenetics of Atremorine-Induced Neuroprotection and Dopamine Response in Parkinsonʼs Disease

Ramón Cacabelos
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain
,
Iván Carrera
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain
,
Ramón Alejo
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain
,
Lucía Fernández-Novoa
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain
,
Pablo Cacabelos
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain
,
Lola Corzo
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain
,
Susana Rodríguez
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain
,
Margarita Alcaraz
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain
,
Iván Tellado
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain
,
Natalia Cacabelos
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain
,
Rocío Pego
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain
,
Juan C. Carril
EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, Bergondo, Corunna, Spain
› Author Affiliations
Further Information

Publication History

received 11 June 2019
revised 02 September 2019

accepted 15 September 2019

Publication Date:
26 September 2019 (online)

Abstract

Atremorine is a novel bioproduct with neuroprotective effects on dopaminergic neurons and a natural L-DOPA donor in Parkinsonʼs disease (PD). In the present study, we show the effects of a single dose of Atremorine (5 g, p. o.) on plasma dopamine (DA) response and brain function in PD (n = 183) and the influence that pathogenic (LRRK2), metabolic (CYP2D5, CYP2C9, CYP2C19, CYP3A5, NAT2), transporter (ABCB1), pleiotropic (APOE), and detoxifying genes (CYP1B1, GSTT1, GSTP1, GSTM1, SOD2) involved in the pharmacogenetic network exerts on Atremorine-induced DA response. Over 90% of PD patients at diagnosis show plasma DA levels below 20 pg/mL. Atremorine induces DA synthesis causing a significant increase in plasma DA levels 1 h after administration in practically 100% of patients. Females tend to show lower basal DA levels than males and the response of DA to Atremorine is stronger in males than in females. Atremorine-induced DA response is pharmacogenotype-specific and lasts from 6 – 12 h depending upon the pharmacogenetic profile of each patient. Genetic variants in pathogenic genes, metabolic genes, and genes involved in the detoxification processes affect the response of DA to Atremorine in a genotype-specific manner. Atremorine or any of its bioactive components can cross the blood-brain barrier and improve brain function and motor function, as revealed by the reduction in slow wave activity in brain mapping and psychometric assessment, respectively. Atremorine is a selective neuroprotective agent for dopaminergic neurons with prophylactic and therapeutic potential in PD.