Gene and protein expression profiles of anti- and pro-apoptotic actions of dopamine, R-apomorphine, green tea polyphenol (-)-epigallocatechine-3-gallate, and melatonin.

Significant evidence has been provided to support the hypothesis that oxidant stress may be responsible for degeneration of dopaminergic neurons in the substantia nigra pars compacta in Parkinson's disease. Dopamine (DA), R-apomorphine (R-APO), green tea polyphenol (-)-epigallocatechine-3-gallate (EGCG), and melatonin are neuroprotective and radical scavenger compounds. The aim of this study was to establish the mechanism of the concentration-dependent neuroprotective and pro-apoptotic action of these drugs via gene expression and protein determination.

Neuromelanin and its interaction with iron as a potential risk factor for dopaminergic neurodegeneration underlying Parkinson's disease.

Neuromelanin (NM) is a granular, dark brown pigment produced in some but not all of the dopaminergic neurons of the human substantia nigra (SN). In Parkinson's disease (PD) the pigmented dopaminergic neurons of the SN degenerate, suggesting that this process is related to the presence of NM. As yet it is unknown whether NM in the parkinsonian brain differs from that found in healthy tissue and thus may fulfil a different role within this tissue.

A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson's disease.

Degeneration of cholinergic cortical neurons is one of the main reasons for the cognitive deficit in dementia of the Alzheimer type (AD) and in dementia with Lewy bodies (DLB). Many subjects with AD and DLB have extrapyramidal dysfunction and depression resulting from degeneration of dopaminergic, noradrenergic and serotoninergic neurons. We prepared a novel drug, TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate), with both cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activity, as potential treatment of AD and DLB.

Early and late molecular events in neurodegeneration and neuroprotection in Parkinson's disease MPTP model as assessed by cDNA microarray; the role of iron.

Possible cell death mechanisms for pars compacta nigro-striatal dopamine neurons in Parkinson's disease include oxidative stress, inflammatory processes, nitric oxide iron accumulation, glutamate toxicity and diminished neurotrophic factor responses. There is a notion that Parkinson's disease is not a single disorder but a syndrome that can be initiated by several factors. Because of limitations of biochemical methods in the global analysis of neuronal death, a full picture of events has not been established.

Using cDNA microarray to assess Parkinson's disease models and the effects of neuroprotective drugs.

The remarkable progress made by molecular biology and molecular genetics during the past decade, and the advent of the novel tools of genomics and proteomics, are expected to reveal differential expression profiles of thousands of genes and proteins involved in the degeneration of dopamine-containing cells in Parkinson's disease and allow more focused treatments according to individual genotypes. Of particular interest is the application of microarrays in drug discovery and design to identify 'fingerprints' as potential candidate targets for drug intervention. The major microarray findings relevant to Parkinson's disease and its neurotoxin-induced animal and cell models will be discussed, with particular reference to the neuroprotective therapeutic potential that could arise from the development of drugs 'a la carte'.

Anti-apoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor.

The anti Parkinson drug, rasagiline [R-(+)-N-propargyl-1-aminoindan], an inhibitor of type B monoamine oxidase, has been shown to suppress apoptosis induced by neurotoxins and oxidative stress. A series of novel propargylaminoindans with a carbamate moiety to inhibit cholinesterase were developed from phamacophore of rasagiline to protect or rescue deteriorated neurons in Alzheimer's and Lewy Body disease and provide a beneficial effect on the cognitive deficits. Rasagiline analogues were found to protect dopaminergic SH-SY5Y cells against apoptosis induced by peroxynitrite donor.

Neuroprotection and neurorescue against Abeta toxicity and PKC-dependent release of nonamyloidogenic soluble precursor protein by green tea polyphenol (-)-epigallocatechin-3-gallate.

Green tea extract and its main polyphenol constituent (-)-epigallocatechin-3-gallate (EGCG) possess potent neuroprotective activity in cell culture and mice model of Parkinson's disease. The central hypothesis guiding this study is that EGCG may play an important role in amyloid precursor protein (APP) secretion and protection against toxicity induced by beta-amyloid (Abeta). The present study shows that EGCG enhances (approximately 6-fold) the release of the non-amyloidogenic soluble form of the amyloid precursor protein (sAPPalpha) into the conditioned media of human SH-SY5Y neuroblastoma and rat pheochromocytoma PC12 cells.

cDNA gene expression profile homology of antioxidants and their antiapoptotic and proapoptotic activities in human neuroblastoma cells.

Antioxidants have concentration-dependent neuroprotective and proapoptotic activities in models of Parkinson's disease. The aim of our study was to determine gene-protein pathways of the antioxidants, dopamine (DA), R-apomorphine (R-APO), melatonin, and green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG), in neuroblastoma cells, using a customized cDNA microarray and quantitative reverse transcriptase-polymerase chain reaction gene expression techniques. We demonstrate a concentration-dependent correlation between these compounds and modulation of cell survival/cell death-related gene pathways.

Attenuation of methamphetamine induced dopaminergic neurotoxicity by flupirtine: microdialysis study on dopamine release and free radical generation.

Flupirtine is a triaminopyridine derived centrally acting analgetic, which has been found to display neuroprotective effects in models of excitotoxic cell damage, global, and focal ischemia, but no direct interaction with any component of the N-methyl-D-aspartate (NMDA) and glutamate triggered Ca(2+)-channel. Additionally flupirtine shows potent antioxidant effects in isolated mitochondria and cell culture. Work in models of monoamine depletion and neuroleptic induced catalepsy in rats suggests a interaction of flupirtine with the dopaminergic neurotransmitter system as well.

Pharmacological properties of the anti-Parkinson drug rasagiline; modification of endogenous brain amines, reserpine reversal, serotonergic and dopaminergic behaviours.

Rasagiline [N-propargyl-1R(+)-aminoindan; TVP1012] is a potent irreversible monoamine oxidase (MAO) inhibitor with selectivity for type B of the enzyme, which is being developed for treatment of Parkinson's disease. In this study we examined effects of rasagiline on CNS monoamine levels, modification of behavioural response to L-tryptophan, fluoxetine and L-DOPA, and reversal of reserpine syndrome. Reserpine-induced ptosis was reversed by rasagiline at doses above 2 mg x kg(-1) i.

Early and late gene changes in MPTP mice model of Parkinson's disease employing cDNA microarray.

Recently, we reported specific brain gene expression changes in the chronic MPTP model inthe late stage of degeneration, employing cDNA expression array, which indicate a "domino" cascade of events involved in neuronal cell death. In an attempt to elucidate early gene expression profile in the region of the substantia nigra (SN) and the striatum of acute MPTP-treated mice (3-24 h), we elected a restricted number of genes affected by the long-term MPTP treatment, and their expression was examined. Specifically, we detected alterations in the expression of genes implicated in oxidative-stress, inflammatory processes, signal transduction and glutamate toxicity.

Novel dual inhibitors of AChE and MAO derived from hydroxy aminoindan and phenethylamine as potential treatment for Alzheimer's disease.

Carbamate derivatives of N-propargylaminoindans (Series I) and N-propargylphenethylamines (Series II) were synthesized via multistep procedures from the corresponding hydroxy precursors. The respective rasagiline- and selegiline-related series were designed to combine inhibitory activities of both acetylcholine esterase (AChE) and monoamine oxidase (MAO) by virtue of their carbamoyl and propargylamine pharmacophores. Each compound was tested for these activities in vitro in order to find molecules with similar potencies against each enzyme.

Limited potentiation of blood pressure response to oral tyramine by brain-selective monoamine oxidase A-B inhibitor, TV-3326 in conscious rabbits.

TV-3326 is a novel cholinesterase inhibitor that produces irreversible brain-selective inhibition of monoamine oxidase (MAO)-A and B and has antidepressant-like activity in rats after chronic oral administration. This study determined whether TV-3326 would cause less potentiation than other irreversible MAO-inhibitors of the blood pressure (BP) response to oral tyramine in conscious rabbits. Dose-response curves were established for the increase in BP induced by tyramine (5-200 mg/kg) administered orally via a naso-pharyngeal tube.

The effects of iron deficiency and iron and zinc supplementation on rat hippocampus ferritin.

Iron deficiency (ID), the most prevalent nutritional disorder in the world, impairs cognition in early development. The involvement of hippocampus in cognition has prompted investigation into distribution of the iron storage protein ferritin (FER) in rat hippocampus. (a) In normal rats, FER positive cells appeared first in lateral CA3 and hilus of dentate gyrus and then spread over the entire mossy fiber (MF) system.

Mitochondrial permeability transition mediates apoptosis induced by N-methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl-2 and rasagiline, N-propargyl-1(R)-aminoindan.

The role of mitochondrial permeability transition (PT) in apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol [NM(R)Sal], was studied by use of dopaminergic neuroblastoma SH-SY5Y cells. NM(R)Sal reduced mitochondrial membrane potential, DeltaPsim, in the early phase of apoptosis, which was not suppressed by a pan-caspase inhibitor, but was antagonized by Bcl-2 and cyclosporin A, suggesting the involvement of the PT in NM(R)Sal-induced loss of DeltaPsim. NM(R)Sal-induced apoptosis was completely inhibited not only by Bcl-2 and a pan-caspase inhibitor, but also by cyclosporin A, suggesting the essential role of the PT in NM(R)Sal-induced apoptosis.

Involvement of MAP kinase in the regulation of amyloid precursor protein processing by novel cholinesterase inhibitors derived from rasagiline.

Two novel neuroprotective cholinesterase (ChE) inhibitors, TV3326, (N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate, and TV3279, (N-propargyl-(3S) aminoindan-5-yl)-ethyl methyl carbamate, were derived from rasagiline for the treatment of Alzheimer's disease (AD). TV3326 also inhibits monoamine oxidase (MAO)-A and -B, whereas its S-isomer, TV3279, lacks MAO inhibitory activity. The action of these drugs in the regulation of amyloid precursor protein (APP) processing, using rat PC12 and human SH-SY5Y neuroblastoma cells, was examined.

Influence of neuromelanin on oxidative pathways within the human substantia nigra.

Neuromelanin (NM) is a dark-coloured pigment produced in the dopaminergic neurons of the human substantia nigra (SN). The function of NM within the pigmented neurons is unknown but other melanins are believed to play a protective role via attenuation of free radical damage. Experimental evidence suggests that NM may also exhibit this characteristic, possibly by directly inactivating free radical species or via its ability to chelate transition metals, such as iron.

Non-steroidal anti-inflammatory drugs stimulate secretion of non-amyloidogenic precursor protein.

Chronic inflammatory processes are associated with the pathophysiology of Alzheimer's disease (AD), and it has been proposed that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk for AD. Here we report that various NSAIDs, such as the cyclooxygenase inhibitors, nimesulide, ibuprofen and indomethacin, as well as thalidomide (Thal) and its non-teratogenic analogue, supidimide, significantly stimulated the secretion of the non-amyloidogenic alpha-secretase form of the soluble amyloid precursor protein (sAPP alpha) into the conditioned media of SH-SY5Y neuroblastoma and PC12 cells. These NSAIDs markedly reduced the levels of the cellular APP holoprotein, further accelerating non-amyloidogenic processes.

Involvement of protein kinase C activation and cell survival/ cell cycle genes in green tea polyphenol (-)-epigallocatechin 3-gallate neuroprotective action.

Studies from our laboratory have demonstrated that the major green tea polyphenol, (-)-epigallocatechin 3-gallate (EGCG), exerts potent neuroprotective actions in the mice model of Parkinson's disease. These studies were extended to neuronal cell culture employing the parkinsonism-inducing neurotoxin, 6-hydroxydopamine (6-OHDA). Pretreatment with EGCG (0.

An anti-Parkinson's disease drug, N-propargyl-1(R)-aminoindan (rasagiline), enhances expression of anti-apoptotic bcl-2 in human dopaminergic SH-SY5Y cells.

N-Propargyl-1(R)-aminoindan (rasagiline) is now under phase III clinical trials for Parkinson's disease (PD), and it rescues dopamine neurons from cell death in animal and cellular models of PD. Recently, we proved that rasagiline protected dopaminergic SH-SY5Y cells against apoptosis induced by a dopaminergic neurotoxin, N-methyl(R)salsolinol, and the mechanism was clarified to be due to suppression of death signal transduction in mitochondria. In this paper, the effects of rasagiline on the levels of anti-apoptotic bcl-2 gene family were studied.

Novel neuroprotective anti-Alzheimer drugs with anti-depressant activity derived from the anti-Parkinson drug, rasagiline.

A number of studies have shown that the selective monoamine oxidase (MAO)-B inhibitor l-selegiline has neuroprotective activities in several cell culture systems and in vivo. The suggestion has been made that the propargyl moiety in this molecule may have some intrinsic neuroprotective activity not related to its ability to bind covalently to MAO B and inhibit it. We have therefore developed a number of novel drugs based on rasagiline (N-propargyl-1R-(+)-aminoindan), a potent anti-Parkinson-propargyl-containing MAO-B inhibitor drug with structural resemblance to selegiline, for the treatment of Alzheimer's disease.

Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate].

Rasagiline (N-propargyl-1-(R)-aminoindan) is a selective, irreversible monoamine oxidase B (MAO B) inhibitor which has been developed as an anti-Parkinson drug. In controlled monotherapy and as adjunct to L-dopa it has shown anti-Parkinson activity. In cell culture (PC-12 and neuroblastoma SH-SY5Y cells) it exhibits neuroprotective and anti-apoptotic activity against several neurotoxins (SIN-1, MPTP, 6-hydroxydopamine and N-methyl-(R)-salsolinol) and ischemia.

Rat striatal monoamine oxidase-B inhibition by l-deprenyl and rasagiline: its relationship to 2-phenylethylamine-induced stereotypy and Parkinson's disease.

Rats were injected intraperitoneally with varying doses of l-deprenyl (selegiline) followed 2h later by 30 mg kg(-1) 2-phenylethylamine (PEA), administered in the same way, and the stereotypic behavioural response elicited was assessed. l-Deprenyl alone at doses of up to 5 mg kg(-1) caused no significant behavioural response. Administration of PEA without prior l-deprenyl treatment resulted in only a modest increase in stereotypic behaviour and this was not significantly enhanced by the prior administration 1 mg kg(-1) l-deprenyl.