Low dosage of rasagiline and epigallocatechin gallate synergistically restored the nigrostriatal axis in MPTP-induced parkinsonism.

Background: The anti-Parkinson monoamine oxidase B inhibitor rasagiline appears to be the first neuroprotective disease-modifying therapy in early-stage Parkinson's disease (PD).

Objective: Using a polypharmacy paradigm, we tested whether the distinct neuroprotective pharmacological profile of rasagiline would complement that of (-)-epigallocatechin-3-gallate (EGCG), the main antioxidant/iron chelator polyphenol constituent of green tea, and restore the neuronal loss and molecular targets damaged in animal parkinsonism.

Methods/results: We show by high-performance liquid chromatography, immunohistochemistry and Western blot analyses that the combination of rasagiline and EGCG, at subliminal doses which have no profound protective effect, acts synergistically to restore the nigrostriatal axis in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice.

A sporadic Parkinson disease model via silencing of the ubiquitin-proteasome/E3 ligase component SKP1A.

The aim of this study was to develop a new model of sporadic Parkinson disease (PD) based on silencing of the SKP1A gene, a component of the ubiquitin-proteasome/E3 ligase complex, Skp1, Cullin 1, F-box protein, which was found to be highly decreased in the substantia nigra of sporadic PD patients. Initially, an embryonic mouse substantia nigra-derived cell line (SN4741 cells) was infected with short hairpin RNA lentiviruses encoding the murine transcript of the SKP1A gene or with scrambled vector. SKP1A silencing resulted in increased susceptibility to neuronal damages induced by the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium ion and serum starvation, in parallel with a decline in the expression of the dopaminergic markers, dopamine transporter and vesicular monoamine transporter-2.

Simultaneous manipulation of multiple brain targets by green tea catechins: a potential neuroprotective strategy for Alzheimer and Parkinson diseases.

Current therapeutic approaches for Alzheimer and Parkinson disease (AD and PD, respectively) are merely symptomatic, intended for the treatment of symptoms, but offer only partial benefit, without any disease-modifying activity. Novel promising strategies suggest the use of antiinflammatory drugs, antioxidants, iron-complexing molecules, neurotrophic factor delivery, inhibitors of the amyloid precursor protein (APP)-processing secretases, gamma and beta (that generate the amyloid-beta peptides, Abeta), anti-Abeta aggregation molecules, the interference with lipid cholesterol metabolism and naturally occurring plant flavonoids to potentially reverse the course of the diseases. Human epidemiological and new animal data suggest that tea drinking may decrease the incidence of dementia, AD, and PD.

Cell signaling pathways and iron chelation in the neurorestorative activity of green tea polyphenols: special reference to epigallocatechin gallate (EGCG).

Although much progress has been made in understanding the pathogenesis of Alzheimer's disease (AD), the current therapeutic approaches are merely symptomatic, intended for the treatment of cognitive symptoms, such as disturbances in memory and perception. Novel promising strategies suggest the use of anti-inflammatory drugs, antioxidants including natural occurring plant flavonoids, iron-complexing molecules, neurotrophic factor delivery, inhibitors of the amyloid-beta protein precursor processing secretases, gamma and beta, that generate amyloid-beta peptides and the interference with lipid and cholesterol metabolism. Human epidemiological and new animal data suggest that tea drinking may decrease the incidence of dementia, AD and Parkinson's disease.

Targeting multiple neurodegenerative diseases etiologies with multimodal-acting green tea catechins.

Green tea is currently considered a source of dietary constituents endowed with biological and pharmacological activities relevant to human health. Human epidemiological and new animal data suggest that the pharmacological benefits of tea drinking may help to protect the brain as we age. Indeed, tea consumption is inversely correlated with the incidence of dementia and Alzheimer's and Parkinson's diseases.

Neurorescue activity, APP regulation and amyloid-beta peptide reduction by novel multi-functional brain permeable iron- chelating- antioxidants, M-30 and green tea polyphenol, EGCG.

Accumulation of iron at sites where neurons degenerate in Parkinson's disease (PD) and Alzheimer's disease (AD) is thought to have a major role in oxidative stress induced process of neurodegeneration. The novel non-toxic lipophilic brain- permeable iron chelators, VK-28 (5- [4- (2- hydroxyethyl) piperazine-1-ylmethyl]- quinoline- 8- ol) and its multi-functional derivative, M-30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline), as well as the main polyphenol constituent of green tea (-)-epigallocatechin-3-gallate (EGCG), which possesses iron metal chelating, radical scavenging and neuroprotective properties, offer potential therapeutic benefits for these diseases. M-30 and EGCG decreased apoptosis of human SH-SY5Y neuroblastoma cells in a neurorescue, serum deprivation model, via multiple protection mechanisms including: reduction of the pro-apoptotic proteins, Bad and Bax, reduction of apoptosis-associated Ser139 phosphorylated H2A.

Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the treatment of neurodegenerative disorders.

Neurodegeneration in Parkinson's, Alzheimer's, or other neurodegenerative diseases appears to be multifactorial, where a complex set of toxic reactions, including oxidative stress (OS), inflammation, reduced expression of trophic factors, and accumulation of protein aggregates, lead to the demise of neurons. One of the prominent pathological features is the abnormal accumulation of iron on top of the dying neurons and in the surrounding microglia. The capacity of free iron to enhance and promote the generation of toxic reactive oxygen radicals has been discussed numerous times.

Multifunctional activities of green tea catechins in neuroprotection. Modulation of cell survival genes, iron-dependent oxidative stress and PKC signaling pathway.

Many lines of evidence suggest that oxidative stress resulting in reactive oxygen species (ROS) generation and inflammation play a pivotal role in the age-associated cognitive decline and neuronal loss in neurodegenerative diseases including Alzheimer's (AD), Parkinson's (PD) and Huntington's diseases. One cardinal chemical pathology observed in these disorders is the accumulation of iron at sites where the neurons die. The buildup of an iron gradient in conjunction with ROS (superoxide, hydroxyl radical and nitric oxide) are thought to constitute a major trigger in neuronal toxicity and demise in all these diseases.

Green tea polyphenol (-)-epigallocatechin-3-gallate protects rat PC12 cells from apoptosis induced by serum withdrawal independent of P13-Akt pathway.

Our recent studies have demonstrated that green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) exerts neuroprotective/neurorescue effects against B-amyloid toxicity and protects neuronal cells from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinium ion (MPP+) and 6-hydroxydopamine in vitro, or from N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP-) induced nigral dopaminergic neuronal loss in mice. In the present study, we report that EGCG (0.1 and 1 microM) significantly protects rat pheochromocytoma PC12 cells from apoptosis induced by serum support withdrawal, suggesting that EGCG may play a role in the growth of PC12 cells, where it stimulates survival-promoting pathways.