The Therapeutic Implications of Tea Polyphenols against Dopamine (DA) Neuron Degeneration in Parkinson’s Disease (PD)

Abstract

: Accumulative evidence indicated that the pathologically accumulated metal ions (iron species and Mn3+) and abnormally up-regulated monoamine oxidase B (MAOB) activity induced oxidation of endogenous dopamine (DA) can lead to mitochondria impairment, lysosome dysfunction, proteasome inhibition, and selective DA neuron vulnerability, which is implicated in the pathogenesis of Parkinson’s disease (PD). The DA oxidation can generate deleterious reactive oxygen species (ROS) and highly reactive DA quinones (DAQ) to induce DA-related toxicity, which can be alleviated by DA oxidation suppressors, ROS scavengers, DAQ quenchers, and MAOB inhibitors. On the other hand, the nuclear factor erythroid 2-related factor 2 (Nrf2)-Keap1 and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) anti-oxidative and proliferative signaling pathways play roles in anti-oxidative cell defense and mitochondria biogenesis, which is implicated in DA neuron protections. Therefore, agents with capabilities to suppress DA-related toxicity including inhibition of DA oxidation, scavenge of ROS, detoxification of DAQ, inhibition of MAOB, and modulations of anti-oxidative signaling pathways can be protective to DA neurons. Accumulative evidence shows that tea or coffee consumptions and smoking are related to deceased PD prevalence with unknown mechanisms. In this study, we investigate the protective capabilities of tea polyphenols and other PD relevant agents to inhibit DA-related toxicity and protect against environmental or genetic factors induced DA neuron degeneration in vitro and in vivo. We find that tea polyphenols can significantly suppress DA-related toxicity to protect DA neurons. The tea polyphenols can protect DA neurons via inhibition of DA oxidation, conjugation with DAQ, scavenge of ROS, inhibition of MAOB, and modulations of Nrf2-Keap1 and PGC-1α anti-oxidative signaling pathways. The tea polyphenols with more phenolic hydroxyl groups and ring structures have stronger protective functions. The protective capabilities of tea polyphenols is further strengthened by evidence that phenolic hydroxyl groups can directly conjugate with DAQ. However, GSH and other sulfhydyl groups containing agents have weaker capabilities to abrogate DA oxidation, detoxify ROS and DAQ and inhibit MAOB; whereas nicotine (NICO) and caffeine (CAF) can only modulate Nrf2-Keap1 and PGC-1α pathways to protect DA neurons weakly. The tea polyphenols are identified to protect against overexpression of mutant A30P α-synuclein (α-syn) induced DA neuron degeneration and PD-like symptoms in transgenic Drosophila. Based on achievements from current studies, the excellent and versatile protective capabilities of tea polyphenols are highlighted, which will contribute and benefit to future anti-PD therapy.

Flavonoids and Mitochondria: Activation of Cytoprotective Pathways?

“…Enzymes involved in this regulation of cellular redox status and protection against oxidative damage include glutathione-S-transferase (GST), hemeoxygenase 1 (HO-1) and NADPH:quinone oxidoreductase 1 (NQO1). The antioxidant properties of flavonoids have also been shown to improve cell survival in cerebral I/R injury [123], colistin-induced nephrotoxicity [124], chronic inflammatory diseases [125] and Parkinson's disease [126]. In addition, flavonoids have also been shown to modulate cellular endogenous levels of antioxidants by influencing the activity of enzymes responsible for glutathione synthesis (e.g., glutathione reductase) and antioxidant enzymes (glutathione peroxidase, superoxide dismutase, and catalase) [127,128].…”

Design of enamides as new selective monoamine oxidase-B inhibitors

“…[ 15 ] The deterioration of dopaminergic neurons and subsequent DA depletion in basal ganglia influence the generation and execution of voluntary movements that can culminate in the motor disorders associated with PD. [ 16 ] DA oxidation can be catalysed by abnormally high MAO‐B activity and results in free radical production, lysosome dysfunction, mitochondrial impairment, neuroinflammation, protein aggregation and DA‐associated neuron susceptibility, and the accumulation of these events has been implicated in the pathogenesis of PD. [ 17 ] Interestingly, the neurotoxic effects of the active metabolite 1‐methyl‐4‐phenylpyridinium ion (MPP + ) produced from 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) by MAO‐B have been associated with PD, and the selective inhibition of MAO‐B has been reported to block this conversion and suggested to have neuroprotective effects in PD.…”

Natural and Synthetic Derivatives of Hydroxycinnamic Acid Modulating the Pathological Transformation of Amyloidogenic Proteins

“…The combination of nuclear magnetic resonance, circular dichroism spectroscopy, and electron microscopy methods has demonstrated that in the presence of polyphenolic compounds, the assembly of α-synuclein oligomers and fibrils is destabilized due to the presence of aromatic and hydroxyl groups on the phenyl ring of the ligands [ 161 ]. This is supported by the notion that the number of hydroxyl groups influences the potency of fibrillation inhibition by tea polyphenols [ 162 ]. Presumably, the aromatic rings of polyphenols can interact with the monomeric and oligomeric forms of α-synuclein sterically inhibiting further protein aggregation [ 163 ].…”