Iron and α-Synuclein in the Substantia Nigra of MPTP-Treated Mice: Effect of Neuroprotective Drugs R-Apomorphine and Green Tea Polyphenol (-)-Epigallocatechin-3-Gallate

Abstract

One of the prominent pathological features of Parkinson's disease (PD) is the abnormal accumulation of iron in the substantia nigra pars compacta (SNpc), in the reactive microglia, and in association with neuromelanin, within the melanin-containing dopamine (DA) neurons. Lewy body, the morphological hallmark of PD, is composed of lipids, redox-active iron, and aggregated alpha-synuclein, concentrating in its peripheral halo and ubiquitinated, hyperphosphorylated, neurofilament proteins. The capacity of free iron to enhance and promote the generation of toxic reactive oxygen radicals has been discussed numerous times. Recent observations, that iron induces aggregation of inert alpha-synuclein to toxic aggregates, have reinforced the critical role of iron in oxidative stress-induced pathogenesis of DA neuron degeneration and protein degradation via ubiquitination. N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and 6-hydroxydopamine-induced neurodegeneration in rodents and nonhuman primates is associated with increased presence of iron and alpha-synuclein in the SNpc. The accumulation of iron in MPTP-induced neurodegeneration has been linked to nitric oxide-dependent mechanism, resulting in degradation of prominent iron regulatory proteins by ubiquitination. Radical scavengers such as R-apomorphine and green tea catechin polyphenol (-)-epigallocatechin-3-gallate, as well as the recently developed brain-permeable VK-28 series derivative iron chelators, which are neuroprotective against these neurotoxins in mice and rats, prevent the accumulation of iron and alpha-synuclein in SNpc. This study supports the notion that a combination of iron chelation and antioxidant therapy, as emphasized on several occasions, might be a significant approach to neuroprotection in PD and other neurodegenerative diseases.

Neural effects of green tea extract on dorsolateral prefrontal cortex

“…1 Moreover, previous studies gave some indications of improving effects of green tea on cognitive function. 2,3 To date, two studies were published analyzing the association between green tea consumption and cognitive functioning in humans. The first study analyzed data from 1003 Japanese subjects (470 years), who gave information about the frequency of green tea consumption, whereas their cognitive function was evaluated by using the Mini-Mental State Examination test.…”

Pharmacological inhibition of neuronal NADPH oxidase protects against 1-methyl-4-phenylpyridinium (MPP+)-induced oxidative stress and apoptosis in mesencephalic dopaminergic neuronal cells

“…One of the well-recognized pathways responsible for generation of oxidative radicals is mitochondrial toxicity induced by accumulation of MPP + in the inner mitochondrial membrane, and the subsequent disruption of complex I in the electron transport chain (Cassarino et al, 1999;Fiskum et al, 2003;Kalivendi et al, 2003). Studies have also shown auto-oxidation of the neurotransmitter dopamine (Obata, 2002;Sidhu et al, 2004) or the interaction of MPP + with iron stores within the pigmented substantia nigra cells as possible sources of oxidative stress (Andersen, 2004;Mandel et al, 2004;Youdim et al, 2004;Mancuso et al, 2007).…”

Role of tea catechins in prevention of aging and age-related disorders

“…The Catechol like structure has been attributed to a neuroprtotective ability as it may competitively inhibit 1-methyl-4-phenylpyridinium (MPP + ) intake which prevents MPTP/MPP + induced damage (Pan et al, 2003). EGCG decreases bax expression, a proapoptotic gene (Levites et al, 2002;Mandel et al, 2004), responsible for the decrease in membrane potential in mitochondria by opening the mitochondrial mega-channel permeability transition pore (mPTP) which leads to cytochrome c release and cell death (Cory and Adams, 2002;Bernardi et al, 2001). This way, by maintaining mitochondrial integrity in nonrenewable cells like neurons, contributes to neuroprotection (Mandel et al, 2005).…”