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

Ramón Cacabelos; Iván Carrera; Ramón Alejo; Lucía Fernández-Novoa; Pablo Cacabelos; Lola Corzo; Susana Rodríguez; Margarita Alcaraz; Iván Tellado; Natalia Cacabelos; Rocío Pego; Juan C. Carril

doi:10.1055/a-1013-7686

Planta Medica, Inhaltsverzeichnis

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

Authors

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

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.

Key words

atremorine - metabolic genes - pathogenic genes - Parkinsonʼs disease - pharmacogenetics - Vicia faba - leguminosae

Volltext

Referenzen

References
1 Hirsch L, Jette N, Frolkis A, Steeves T, Pringsheim T. The incidence of Parkinsonʼs disease: a systematic review and meta-analysis. Neuroepidemiology 2016; 46: 292-300
2 Savica R, Grossardt BR, Bower JH, Ahlskog JE, Rocca WA. Time trends in the incidence of Parkinson disease. JAMA Neurol 2016; 73: 981-989
3 Pringsheim T, Jette N, Frolkis A, Steeves TD. The prevalence of Parkinsonʼs disease: a systematic review and meta-analysis. Mov Disord 2014; 29: 1583-1590
4 Riedel O, Bitters D, Amann U, Garbe E, Langner I. Estimating the prevalence of Parkinsonʼs disease (PD) and proportions of patients with associated dementia and depression among the older adults based on secondary claims data. Int J Geriatr Psychiatry 2016; 31: 938-943
5 Moisan F, Kab S, Mohamed F, Canonico M, Le Guern M, Quintin C, Carcaillon L, Nicolau J, Duport N, Singh-Manoux A, Boussac-Zarebska M, Elbaz A. Parkinson disease male-to-female ratios increase with age: French nationwide study and meta-analysis. J Neurol Neurosurg Psychiatry 2016; 87: 952-957
6 Cacabelos R. Parkinsonʼs disease: from pathogenesis to pharmacogenomics. Int J Mol Sci 2017; 18: 551
7 Hauser RA. Levodopa: past, present, and future. Eur Neurol 2009; 62: 1-8
8 Ludin HP. The L-DOPA story: translational neuroscience ante verbum. Clin Translational Neurosci 2018;
9 Cacabelos R. World Guide for Drug Use and Pharmacogenomics. Corunna: EuroEspes Publishing; 2012
10 Cacabelos R. Pharmacogenomics of Alzheimerʼs and Parkinsonʼs diseases. Neurosci Lett 2018;
11 Pahwa R, Lyons KE. Levodopa-related wearing-off in Parkinsonʼs disease: identification and management. Curr Med Res Opin 2009; 25: 841-849
12 Haaxma CA, Horstink MW, Zijlmans JC, Lemmens WA, Bloem BR, Borm GF. Risk of disabling response fluctuations and dyskinesias for dopamine agonists versus levodopa in Parkinsonʼs disease. J Parkinsons Dis 2015; 5: 847-853
13 Cacabelos R. E-PodoFavalin-15999. Bioactive extract obtained from Vicia faba and its use in the treatment and/or prevention of neurodegenerative diseases. European Patent 300188737, Application number: EP16382138.2; March 19; 2016
14 Romero A, Parada E, González-Lafuente L, Farré-Alins V, Ramos E, Cacabelos R, Egea J. Neuroprotective effects of E-PodoFavalin-15999 (Atremroine^®). CNS Neurosci Ther 2017; 23: 450-452
15 Carrera I, Fernández-Novoa L, Sampedro C, Cacabelos R. Neuroprotective effect of Atremorine in an experimental model of Parkinsonʼs disease. Curr Pharm Des 2017; 23: 1-12
16 Carrera I, Fernandez-Novoa L, Sampedro C, Tarasov VV, Aliev G, Cacabelos R. Dopaminergic neuroprotection with Atremorine in Parkinsonʼs disease. Curr Med Chem 2018; 25: 5372-5388
17 Carrera I, Cacabelos R. Current drugs and potential future neuroprotective compounds for Parkinsonʼs disease. Curr Neuropharmacol 2019; 17: 295-306
18 Cacabelos R, Fernández-Novoa L, Alejo R, Corzo L, Alcaraz M, Nebril L, Cacabelos P, Fraile C, Carrera I, Carril JC. E-PodoFavalin-15999 (Atremorine^®)-induced dopamine response in Parkinsonʼs disease: pharmacogenetics-related effects. J Genomic Med Pharmacogenomics 2016; 1: 1-26
19 Cacabelos R, Fernández-Novoa L, Alejo R, Corzo L, Rodríguez S, Alcaraz M, Nebril L, Cacabelos P, Fraile C, Carrera I, Carril JC. E-PodoFavalin-15999 (Atremorine^®)-induced neurotransmitter and hormonal response in Parkinsonʼs disease. J Explor Res Pharmacol 2016; 1: 1-12
20 Cacabelos R, Cacabelos P, Torrellas C, Tellado I, Carril JC. Pharmacogenomics of Alzheimerʼs disease: novel therapeutic strategies for drug development. Methods Mol Biol 2014; 1175: 323-556
21 Cacabelos R, Carril JC, Cacabelos P, Teijido O, Goldgaber D. Pharmacogenomics of Alzheimerʼs disease: genetic determinants of phenotypic variation and therapeutic outcome. J Genomic Med Pharmacogenomics 2016; 1: 151-209
22 Cacabelos R, Cacabelos N, Carril JC. The role of pharmacogenomics in adverse drug reactions. Expert Rev Clin Pharmacol 2019; 12: 407-442
23 He X, Zhang Y, Chen J, Xie C, Gan R, Yang R, Wang L, Nie K, Wang L. The patterns of EEG changes in early-onset Parkinsonʼs disease patients. Int J Neurosci 2017; 127: 1028-1035
24 Barcelon E, Mukaino T, Yokoyama J, Uehara T, Ogata K, Kira JI, Tobimatsu S. Grand total EEG score can differentiate Parkinsonʼs disease from Parkinson-related disorders. Front Neurol 2019; 10: 398
25 Iyer KK, Au TR, Angwin AJ, Copland DA, Dissanayaka NNW. Source activity during emotion processing and its relationship to cognitive impairment in Parkinsonʼs disease. J Affect Disord 2019; 253: 327-335
26 Tinkhauser G, Pogosyan A, Tan H, Herz DM, Kühn AA, Brown P. Beta burst dynamics in Parkinsonʼs disease OFF and ON dopaminergic medication. Brain 2017; 140: 2968-2981
27 Miller AM, Miocinovic S, Swann NC, Rajagopalan S, Darevsky D, Gilron R, de Hemptinne C, Ostrem JL, Starr PA. Effect of levodopa on electroencephalographic biomarkers of the parkinsonian state. J Neurophysiol 2019; 122: 290-299
28 Canuet L, Tellado I, Couceiro V, Fraile C, Fernández-Novoa L, Ishii R, Takeda M, Cacabelos R. Resting-state network disruption and APOE genotype in Alzheimerʼs disease: a lagged functional connectivity study. PLoS One 2012; 7: e46289
29 Michels L, Muthuraman M, Anwar AR, Kollias S, Leh SE, Riese F, Unschuld PG, Siniatchkin M, Gietl AF, Hock C. Changes of functional and directed resting-state connectivity are associated with neuronal oscillations, apoE Genotype and amyloid deposition in mild cognitive impairment. Front Aging Neurosci 2017; 9: 304
30 Cacabelos R, Torrellas C, Teijido O, Carril JC. Pharmacogenetic considerations in the treatment of Alzheimerʼs disease. Pharmacogenomics 2016; 17: 1041-1074
31 Gandhi PN, Wang X, Zhu X, Chen SG, Wilson-Delfosse AL. The Roc domain of leucine-rich repeat kinase 2 is sufficient for interaction with microtubules. J Neurosci Res 2008; 86: 1711-1720
32 Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci U S A 2005; 102: 18676-18681
33 Gorostidi A, Ruiz-Martínez J, Lopez de Munain A, Alzualde A, Martí Massó JF. LRRK2 G2019S and R1441G mutations associated with Parkinsonʼs disease are common in the Basque country, but relative prevalence is determined by ethnicity. Neurogenetics 2009; 10: 157-159
34 Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, Kachergus J, Hulihan M, Uitti RJ, Calne DB, Stoessl AJ, Pfeiffer RF, Patenge N, Carbajal IC, Vieregge P, Asmus F, Muller-Myhsok B, Dickson DW, Meitinger T, Strom TM, Wszolek ZK, Gasser T. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004; 44: 601-607
35 Di Fonzo A, Rohe CF, Ferreira J, Chien HF, Vacca L, Stocchi F, Guedes L, Fabrizio E, Manfredi M, Vanacore N, Goldwurm S, Breedveld G, Sampaio C, Meco G, Barbosa E, Oostra BA, Bonifati V. Italian Parkinson Genetics Network. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinsonʼs disease. Lancet 2005; 365: 412-415
36 Kachergus J, Mata IF, Hulihan M, Taylor JP, Lincoln S, Aasly J, Gibson JM, Ross OA, Lynch T, Wiley J, Payami H, Nutt J, Maraganore DM, Czyzewski K, Styczynska M, Wszolek ZK, Farrer MJ, Toft M. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 2005; 76: 672-680
37 Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, Tagliati M, Hunt AL, Klein C, Henick B, Hailpern SM, Lipton RB, Soto-Valencia J, Risch N, Bressman SB. LRRK2 G2019S as a cause of Parkinsonʼs disease in Ashkenazi Jews. N Engl J Med 2006; 354: 424-425
38 Lee IS, Kim D. Polymorphic metabolism by functional alterations of human cytochrome P450 enzymes. Arch Pharm Res 2011; 34: 1799-1816
39 Xie HG, Kim RB, Wood AJ, Stein CM. Molecular basis of ethnic differences in drug disposition and response. Annu Rev Pharmacol Toxicol 2001; 41: 815-850
40 Isaza C, Henao J, Ramírez E, Cuesta F, Cacabelos R. Polymorphic variants of the beta-2-adrenergic receptor (ADRB2) gene and ADRB2-related propanolol-induced dyslipidemia in the Colombian population. Methods Find Exp Clin Pharmacol 2005; 27: 237-244