Neuroprotective and neurorestorative potential of propargylamine derivatives in ageing: focus on mitochondrial targets.

The mitochondrial theory of ageing proposes that accumulation of damage to mitochondrial function and DNA mutation lead to ageing of humans and animals. It has been suggested that mitochondria play dynamic roles in regulating synaptogenesis and morphological/functional responses of synaptic activity, and thus, deteriorating of mitochondrial function (e.g., deficits of the mitochondrial respiratory enzymes, reduced calcium influx, increased accumulation of mitochondrial DNA defects/apoptotic proteins and impairment of mitochondrial membrane potential) can lead to severe neuronal energy deficit, and in the long run, to modifications in neuronal synapses and neurodegeneration in the ageing brain. Hence, considering the mechanisms by which mitochondrial impairment can lead to neuronal death, the development of neuroprotective molecules that target various mitochondrial pathogenic processes can be effective in the treatment of ageing and age-related neurodegenerative diseases. This review addresses several aspects of the neuroprotective effects of propargylamine derivatives (e.g., the monoamine oxidase-B inhibitors, selegiline and rasagiline and the multifunctional drugs, ladostigil, M30 and VAR10303) in ageing with a special focus on mitochondrial molecular protective mechanisms.

Lithium's gene expression profile, relevance to neuroprotection A cDNA microarray study.

Lithium can prevent 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) dopaminergic neurotoxicity in mice. This is attributed to induced antioxidant and antiapoptotic state, which among other factors results from induction of Bcl-2 and reduction of Bax, however, cDNA microarray reveals that this represents only one cascade of lithium targets. From analyzing the gene expression profile of lithium, we are able to point out candidate genes that might be involved in the antioxidant and neuroprotective properties of lithium. Among these are, the cAMP response element binding (CREB) protein, extracellular signal-regulated kinase (ERK), both CREB and ERK-part of the mitogen-activated kinase pathway-were upregulated by lithium, downregulated by MPTP, and maintained in mice fed with lithium chloride (LiCl) supplemented diet and treated with MPTP. Our positive control included tyrosine hydroxylase which both its mRNA and protein levels were independently measured, in addition to Bcl-2 protein levels. Other important genes which were similarly regulated are plasma glutathione peroxidase precursor (GSHPX-P), protein kinase C alpha type, insulin-like growth factor binding protein 4 precursor, and interferon regulatory factor. In addition, some genes were oppositely regulated, i.e., downregulated by lithium, upregulated by MPTP, and maintained in mice fed with LiCl supplemented diet and treated with MPTP, among these genes were basic fibroblast growth factor receptor 1 precursor, inhibin alpha subunit, glutamate receptor subunit zeta 1 precursor (NMD-R1), postsynaptic density protein-95 which together with NMD-R1 can form an apoptotic promoting complex. The discussed targets represent part of genes altered by chronic lithium. In fact lithium affected the expressions of more than 50 genes among these were basic transcription factors, transcription activators, cell signaling proteins, cell adhesion proteins, oncogenes and tumor suppressors, intracellular transducers, survival and death genes, and cyclins, here we discuss the relevance of these changes to lithium's reported neuroprotective properties.

Effects of novel neuroprotective and neurorestorative multifunctional drugs on iron chelation and glucose metabolism.

Iron accumulation and iron-related oxidative stress are involved in several pathological conditions and provide a rationale for the development of iron chelators as novel promising therapeutic strategies. Thus, we have recently synthesized multifunctional non-toxic, brain permeable iron chelating compounds, M30 and HLA20, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelating moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we examined the hepatic regulatory effects of these novel compounds using two experimental approaches: chelation activity and glucose metabolism parameters. The present study demonstrated that M30 and HLA20 significantly decreased intracellular iron content and reduced ferritin expression levels in iron-loaded hepatoma Hep3B cells. In electron microscopy analysis, M30 was shown to reduce the electron-dense deposits of siderosomes by ~30 %, as well as down-regulate cytosolic ferritin particles observed in iron-overloaded cells. In vivo studies demonstrated that M30 administration (1 mg/kg, P.O. three times a week) reduced hepatic ferritin levels; increased hepatic insulin receptor and glucose transporter-1 levels and improved glucose tolerance in C57BL/6 mice and in a mouse model of type-2 diabetes, the ob/ob (leptin(-/-)). The results clearly indicate that the novel multifunctional drugs, especially M30, display significant capacity of chelating intracellular iron and regulating glucose metabolism parameters. Such effects can have therapeutic significance in conditions with abnormal local or systemic iron metabolism, including neurological diseases.

Novel therapeutic approach for neurodegenerative pathologies: multitarget iron-chelating drugs regulating hypoxia-inducible factor 1 signal transduction pathway.

Our novel multimodal brain-permeable iron-chelating compounds M30 and HLA20 were demonstrated to possess neuroprotective/neurorescue activities in vitro and in vivo against several insults applicable to various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Neuroprotection by iron chelators has been widely recognized with respect to their ability to prevent reactive oxygen species generation in the Fenton reaction by sequestering redox-active iron. An additional neuroprotective mechanism of iron-chelating compounds is associated with their ability to regulate the transcriptional activator hypoxia-inducible factor 1 (HIF-1). HIF-1 is a 'master switch' being an important physiological response mechanism, likely enhancing neuroprotective compensatory pathways involved in many physiological processes within the brain. This mini-review will discuss the multifunctional mechanisms of action of the drugs, M30 and HLA20 in preclinical models of neurodegeneration with a specific emphasis on their ability to activate the HIF-1 signal transduction pathway.

Iron-chelating backbone coupled with monoamine oxidase inhibitory moiety as novel pluripotential therapeutic agents for Alzheimer's disease: a tribute to Moussa Youdim.

It is for these authors a great privilege to dedicate this review article to Moussa Youdim, who is one of the most imperative pharmacologists and pioneer investigators in the search and development of novel therapeutics for neurodegenerative diseases. 40 years ago, Moussa Youdim has started studying brain iron, catecholamine receptor and monoamine oxidase (MAO)-A and -B functions. Although Moussa Youdim succeeded in exploring the novel anti-Parkinsonian, selective MAO-B inhibitor drug, rasagiline (Azilect, Teva Pharmaceutical Co.), he did not stop searching for superior therapeutic approaches for neurodegenerative disorders. To date, Moussa Youdim and his research group are designing and synthesizing pluripotential drug candidates possessing diverse pharmacological properties that can act on multiple targets and pathological features ascribed to Parkinson's disease, Alzheimer's disease (AD) and amyotrophic lateral sclerosis. One such example is the multimodal non-toxic, brain-permeable iron-chelating compound, M30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline), which amalgamates the propargyl moiety of rasagiline with the backbone of the potent iron chelator, VK28. This review discusses the multiple effects of several leading compounds of this series, concerning their neuroprotective/neurorestorative molecular mechanisms in vivo and in vitro, with a special focus on the pathological features ascribed to AD, including antioxidant and iron chelating activities, regulation of amyloid precursor protein and amyloid ß peptide expression processing, activation of pro-survival signaling pathways and regulation of cell cycle and neurite outgrowth.

The neuroprotective mechanism of 1-(R)-aminoindan, the major metabolite of the anti-parkinsonian drug rasagiline.

The anti-parkinsonian drug, rasagiline [N-propargyl-1-(R)-aminoindan; Azilect(R)], is a secondary cyclic benzylamine and indane derivative, which provides irreversible, potent monoamine oxidase-B (MAO-B) inhibition and possesses neuroprotective and neurorestorative activities. A prospective clinical trial has shown that rasagiline confers significant symptomatic improvement and demonstrated alterations in Parkinson's disease progression. Rasagiline is primarily metabolized by hepatic cytochrome P-450 to form its major metabolite, 1-(R)-aminoindan, a non-amphetamine, weak reversible MAO-B inhibitor compound. Recent studies indicated the potential neuroprotective effect of 1-(R)-aminoindan, suggesting that it may contribute to the overall neuroprotective and antiapoptotic effects of its parent compound, rasagiline. This review article briefly highlights the molecular mechanisms underlying the neuroprotective properties of the active metabolite of rasagiline, 1-(R)-aminoindan, supporting the valuable potential of rasagiline for disease modification.

Metallocorroles as cytoprotective agents against oxidative and nitrative stress in cellular models of neurodegeneration.

Water-soluble iron, and manganese(III) complexes of corroles and porphyrins were examined with regard to their neuroprotective/neurorescue activities by using various neuronal cytotoxic models of oxidative and nitrative stress. The present study demonstrates that the metallocorroles significantly protect human neuroblastoma SH-SY5Y and mouse motor neuron-neuroblastoma fusion NSC-34 cell lines against neurotoxicity induced by either the peroxynitrite donor 3-morpholinosydnonimine or the parkinsonism-related neurotoxin 6-hydroxydopamine. The neuronal survival effect is further reflected by the prevention of 3-morpholinosydnonimine-induced protein nitration, inhibition of caspase 3 activation, as well as attenuation of 6-hydroxydopamine-mediated decrease in growth associated protein-43 levels. The iron(III) corrole, but not manganese (III) corrole, also significantly promotes neuronal survival of hydrogen peroxide (H(2)O(2))-impaired SH-SY5Y and NSC-34 cells. A substantial superiority of the metallocorroles relative to the corresponding porphyrin complexes is revealed in all examined aspects. These results highlight the large potential of corrole complexes as novel agents for therapeutic approaches in degenerative disorders of the central and peripheral nervous systems, where oxidative and nitrative stresses are involved.

The novel multifunctional, iron-chelating drugs M30 and HLA20 protect pancreatic beta-cell lines from oxidative stress damage.

Increasing evidence suggests that oxidative stress (OS)-induced pancreatic beta-cell impairments is involved in diabetes and diabetic complications. Our group has recently synthesized two multifunctional nontoxic, lipophilic, iron-chelating drugs, 5-{N-methyl-N-propargylaminomethyl}-8-hydroxyquinoline (M30) and 5-{4-propargylpiperazin-1-ylmethyl}-8-hydroxyquinoline (HLA20), for the treatment of various OS-mediated pathogeneses. These compounds contain the N-propargylamine cytoprotective moiety of the antiparkinsonian drug rasagiline (Azilect) and the iron-complexing component 8-hydroxyquinoline. The aim of this research was to evaluate the protective effect of the multifunctional iron-chelating drugs on rat insulin-producing pancreatic beta-cells (INS-1E and RINm) against OS-induced cytotoxicity. We found that M30 and HLA20 markedly and dose-dependently inhibited H(2)O(2)-induced cytotoxicity, associated with decreased intracellular reactive oxygen species formation and increased catalase activity. In accordance, the catalase inhibitor 3-amino-1,2,4-triazol blocked the protective action of M30 against H(2)O(2)-induced damage. Both compounds significantly increased the levels of the iron-responsive protein transferrin receptor indicating their iron-chelating effect. Further mechanistic studies showed that M30 and HLA20 attenuated H(2)O(2)-induced mitochondrial membrane potential loss, decreased the release of cytochrome c into the cytoplasm, and inhibited the activation of caspase-3, suggesting that these drugs may produce cytoprotective effects via the preservation of mitochondrial function. These results indicate that the novel drugs, M30 and HLA20 display significant cytoprotective activity against OS-induced cytotoxicity in insulin producing beta-cells, which might be of therapeutic use in the treatment of diabetes mellitus.

Neuroprotective and neuritogenic activities of novel multimodal iron-chelating drugs in motor-neuron-like NSC-34 cells and transgenic mouse model of amyotrophic lateral sclerosis.

Novel therapeutic approaches for the treatment of neurodegenerative disorders comprise drug candidates designed specifically to act on multiple central nervous system targets. We have recently synthesized multifunctional, nontoxic, brain-permeable iron-chelating drugs, M30 and HLA20, possessing the N-propargylamine neuroprotective moiety of rasagiline (Azilect) and the iron-chelating moiety of VK28. The present study demonstrates that M30 and HLA20 possess a wide range of pharmacological activities in mouse NSC-34 motor neuron cells, including neuroprotective effects against hydrogen peroxide- and 3-morpholinosydnonimine-induced neurotoxicity, induction of differentiation, and up-regulation of hypoxia-inducible factor (HIF)-1alpha and HIF-target genes (enolase1 and vascular endothelial growth factor). Both compounds induced NSC-34 neuritogenesis, accompanied by a marked increase in the expression of brain-derived neurotrophic factor and growth-associated protein-43, which was inhibited by PD98059 and GF109203X, indicating the involvement of mitogen-activated protein kinase and protein kinase C pathways. A major finding was the ability of M30 to significantly extend the survival of G93A-SOD1 amyotrophic lateral sclerosis mice and delay the onset of the disease. These properties of the novel multimodal iron-chelating drugs possessing neuroprotective/neuritogenic activities may offer future therapeutic possibilities for motor neurodegenerative diseases.

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 detailed analysis revealed a complementary action of these drugs, differentially acting at MPTP-injured molecules/targets in the substantia nigra (SN): induction of brain-derived neurotrophic factor by rasagiline, increased membranal levels of the protein kinase C alpha-isoform by EGCG and a synergistic replenishment of their downstream effector, the serine/threonine kinase Akt/protein kinase B, suggesting that this kinase might represent one point of convergence of the distinct mechanisms of action of the drug cocktail. CONCLUSION: These results provide molecular evidence that activation of multiple brain targets by the combination of rasagiline and EGCG may synergistically contribute to the rescue of the dopamine neurons in the SN and replenishment of striatal dopamine. This may have important implications for rasagiline-treated PD patients who could further benefit from an adjunct administration of EGCG.

The novel cholinesterase-monoamine oxidase inhibitor and antioxidant, ladostigil, confers neuroprotection in neuroblastoma cells and aged rats.

The current therapeutic advance in which future drugs are designed to possess varied pharmacological properties and act on multiple targets has stimulated the development of the multimodal drug, ladostigil (TV3326; (N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate). Ladostigil combines neuroprotective effects with monoamine oxidase (MAO)-A and MAO-B and cholinesterase (ChE) inhibitory activities in a single molecule, as a potential treatment for Alzheimer's disease (AD) and Lewy body disease. In the present study, we demonstrate that ladostigil (10(-6)-10 muM) dose-dependently increased cell viability, associated with increased activity of catalase and glutathione reductase and decrease of intracellular reactive oxygen species production in a cytotoxic model of human SH-SY5Y neuroblastoma cells exposed to hydrogen peroxide (H(2)O(2)). In addition, ladostigil significantly upregulated mRNA levels of several antioxidant enzymes (catalase, NAD(P)H quinone oxidoreductase 1 and peroxiredoxin 1) in both H(2)O(2)-treated SH-SY5Y cells, as well as in the high-density human SK-N-SH neuroblastoma cultured apoptotic models. In vivo chronic treatment with ladostigil (1 mg/kg per os per day for 30 days) markedly upregulated mRNA expression levels of various enzymes involved in metabolism and oxidation processes in aged rat hippocampus. In addition to its unique combination of ChE and MAO enzyme inhibition, these results indicate that ladostigil displays neuroprotective activity against oxidative stress-induced cell apoptosis, which might be valuable for aging and age-associated neurodegenerative diseases.

Targeting multiple Alzheimer's disease etiologies with multimodal neuroprotective and neurorestorative iron chelators.

Dysregulation of brain iron homeostasis is central to early neuropathological events in Alzheimer's disease (AD), including oxidative stress, inflammatory processes, amyloid deposition, tau phosphorylation, and neuronal cell cycle regulatory failure, leading to apoptosis. Also, there is a direct link between iron metabolism and AD pathogenesis, demonstrated by the presence of an iron-responsive element in the 5' UTR of the amyloid precursor protein transcript. As a consequence of these findings, a new paradigm is emerging that includes the development of iron-chelating neuroprotective-neurorescue drugs with multimodal functions, acting at various pathological brain targets. This concept is challenging the widely held assumption that "silver bullet" agents are superior to "dirty drugs" in drug therapy for neurodegenerative diseases. At best, the so-called magic bullets exhibit moderate symptomatic activity without modifying the course of disease progression. The present review elaborates on conventional and novel therapeutic targets of various multifunctional iron-chelating drugs (e.g., chemically designed compounds; natural polyphenols) that address multiple central nervous system etiologies in AD, aimed at preventing or slowing disease evolution. A similar approach in drug design is being investigated for treatment of cancer, AIDS, cardiovascular diseases, and depression.

Genomic and proteomic study to survey the mechanism of action of the anti-Parkinson's disease drug, rasagiline compared with selegiline, in the rat midbrain.

The novel anti-Parkinson's disease (PD) drug, rasagiline (N-propargyl-1-(R)-aminoindan), is a second generation of irreversible selective inhibitor of monoamine oxidase-B follows selegiline. In light of the recent large clinical study (phase III ADAGIO) reporting benefits in PD patients, it has been suggested that rasagiline could be the first PD treatment to receive the label neuroprotective "disease-modifying" drug. Indeed, rasagiline has been shown to have a broad neuroprotective activity against a variety of neurotoxins in preclinical models of neurodegenerative diseases and in cultured neuronal cells. In the present study, we have investigated the status of various molecular and biochemical markers in the rat midbrain following chronic treatments with rasagiline and selegiline, using proteomic and genomic analyses. Our findings demonstrated significant molecular changes induced by both drugs, at the protein and transcriptional levels, associated with neuronal differentiation, cell survival and death pathways, metabolism/oxidation stress, signaling system, and biomarkers of neurodegenerative disorders, which may be reflected in the clinical studies.

Iron dysregulation in Alzheimer's disease: multimodal brain permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities as therapeutic agents.

Considering the multi-etiological character of Alzheimer's disease (AD), the current pharmacological approaches using drugs oriented towards a single molecular target possess limited ability to modify the course of the disease and thus, offer a partial benefit to the patient. In line with this concept, novel strategies include the use of a cocktail of several drugs and/or the development of a single molecule, possessing two or more active neuroprotective-neurorescue moieties that simultaneously manipulate multiple targets involved in AD pathology. A consistent observation in AD is a dysregulation of metal ions (Fe(2+), Cu(2+) and Zn(2+)) homeostasis and consequential induction of oxidative stress, associated with beta-amyloid aggregation and neurite plaque formation. In particular, iron has been demonstrated to modulate the Alzheimer's amyloid precursor holo-protein expression by a pathway similar to that of ferritin L-and H-mRNA translation through iron-responsive elements in their 5'UTRs. This review will discuss two separate scenarios concerning multiple therapy targets in AD, sharing in common the implementation of iron chelation activity: (i) novel multimodal brain-permeable iron chelating drugs, possessing neuroprotective-neurorescue and amyloid precursor protein-processing regulatory activities; (ii) natural plant polyphenols (flavonoids), such as green tea epigallocatechin gallate (EGCG) and curcumin, reported to have access to the brain and to possess multifunctional activities, such as metal chelation-radical scavenging, anti-inflammation and neuroprotection.

The neuroprotective mechanism of action of the multimodal drug ladostigil.

The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of the multimodal drug, ladostigil (TV3326) ((N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate). Ladostigil combines neuroprotective effects with monoamine oxidase -A and -B and cholinesterase inhibitory activities in a single molecule, as a potential treatment for Alzheimer's disease (AD) and Lewy Body disease. Preclinical studies show that ladostigil has antidepressant and anti-AD activities and the clinical development is planned for these dementias. In this review, we discuss the multimodal effects of ladostigil in terms of neuroprotective molecular mechanism in vivo and in vitro, which include the amyloid precursor protein processing; activation of protein kinase C and mitogen-activated protein kinase pathways; regulation of the Bcl-2 family members; inhibition of cell death markers and up-regulation of neurotrophic factors. Altogether, these scientific findings make ladostigil a potentially valuable drug for the treatment of AD.

Physiological and pathological aspects of Abeta in iron homeostasis via 5'UTR in the APP mRNA and the therapeutic use of iron-chelators.

Many studies have highlighted the pathological involvement of iron accumulation and iron-related oxidative stress (OS) in Alzheimer's disease (AD). Iron was further demonstrated to modulate expression of the Alzheimer's amyloid precursor holo-protein (APP) by a mechanism similar to that of regulation of ferritin-L and -H mRNA translation through an iron-responsive element (IRE) in their 5' untranslated regions (UTRs). Here, we discuss two aspects of the link between iron and AD, in relation to the recently discovered IRE in the 5'UTR of APP mRNA. The first is the physiological aspect: a compensatory neuroprotective response of amyloid-beta protein (Abeta) in reducing iron-induced neurotoxicity. Thus, given that Abeta possesses iron chelation sites, it is hypothesized that OS-induced intracellular iron may stimulate APP holo-protein translation (via the APP 5'UTR) and subsequently the generation of its cleavage product, Abeta, as a compensatory response that eventually reduces OS. The second is the pathological aspect: iron chelating compounds target the APP 5'UTR and possess the capacity to reduce APP translation, and subsequently Abeta levels, and thus represent molecules with high potential in the development of drugs for the treatment of AD.

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. In particular, its main catechin polyphenol constituent (-)-epigallocatechin-3-gallate (EGCG) has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and animal models of neurological disorders. This review provides a detailed overview on the multimodal activities of green tea polyphenols with emphasis on their iron chelating, neurorescue/neuroregenerative and mitochondrial stabilization action.

The application of proteomics for studying the neurorescue activity of the polyphenol (-)-epigallocatechin-3-gallate.

Accumulating evidence suggests that oxidative stress resulting in reactive oxygen species generation plays a pivotal role in neurodegenerative diseases, supporting the realization of the use of radical scavengers, metal chelator agents, such as the natural polyphenols for therapy. In this study, we have focused on specific identification of proteins involved in the neurorescue activity of the green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG) in a progressive model of neuronal death, induced by long-term serum deprivation of human neuroblastoma SH-SY5Y cells. The study was designed in attempt to define biomarkers for the mechanism of action of EGCG, associated with its iron chelating properties and its ability to regulate metabolic energy balance and affect cell morphology. By using mass spectrometry analysis combined with gene expression technique, we have succeeded to identify such genes and proteins (e.g. ATP synthase mitochondrial F1 complex beta, protein kinase C epsilon, nerve vascular growth factor inducible precursor and hypoxia inducible factor-1 alpha). These results strengthen the notion that the diverse molecular signaling pathways participating in the neurorescue activity of EGCG render this multifunctional compound as potential agent to reduce risk of various neurodegenerative diseases.

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. In particular, its main catechin polyphenol constituent (-)-epigallocatechin-3-gallate has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and animal models of neurological disorders. The intense efforts dedicated in recent years to shed light on the molecular mechanisms participating in the brain protective action of green tea indicate that in addition to the known antioxidant activity of catechins, the modulation of signal transduction pathways, cell survival/death genes, and mitochondrial function all contribute significantly to the induction of neuron viability. Because of the multietiological character of neurodegenerative disease pathology, these natural compounds are receiving significant attention as therapeutic cytoprotective agents that simultaneously manipulate multiple desired targets in the central nervous system. This article elaborates on the multimodal activities of green tea polyphenols with emphasis on their recently described neurorescue/neuroregenerative and mitochondrial stabilization actions.