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

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.

A Systematic Review of Parkinson’s Disease Pharmacogenomics: Is There Time for Translation into the Clinics?

“…SNCA gene encodes the protein α-synuclein, now considered a central player in the pathogenesis of PD due to its aggregation into Lewy-bodies. SNP's in the SNCA gene are consistently linked to an increased risk of developing PD in GWAS studies in both familial and even sporadic PD [95]. In cases of autosomal dominant mutations, there is a solid L-dopa and classical PD treatment response, albeit with early cognitive and mental problems, akin to GBA mutations [108].…”

Vicia plants—A comprehensive review on chemical composition and phytopharmacology

“…Of note that atremorine (E‐PodoFavalin‐1599929), a processed extract of V. faba with an increased L‐dopa concentration (2%, w/w), is proposed as dopaminergic neuroprotectant and L‐dopa donor (Cacabelos, 2016; Cacabelos et al, 2019). This substance has been tested in a small subset of Parkinson's patients with promising results (it could magnify the response of dopamine to conventional antiparkinsonian agents), but its clinical use is still premature (Cacabelos et al, 2016).…”

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“…In vivo studies showed that AtreMorine (i) protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration; (ii) inhibits MPTP-induced microglia activation and neurotoxicity in the substantia nigra; and (iii) improves motor function in mice with MPTP-induced neurodegeneration ( Figure 12) [62] (Table 7).…”

“…A recent study reported that AtreMorine-induced dopamine response is pharmacogenotype-specific and lasts from six to 12 hours, depending upon the pharmacogenetic profile of each patient (environmental factors, nutrition, and co-administration of different drugs may also modify this response). Genetic variants in pathogenic genes (APOE, LRRK2), metabolic genes (CYP2D6, CYP2C9, CYP3A5, NAT2) and detoxification genes (CYP1B1, GSTP1, SOD2) influence the response of dopamine to AtreMorine [65] (Table 7). Table 7.…”