Neuroprotective strategies in Parkinson's disease : an update on progress.

In spite of the extensive studies performed on postmortem substantia nigra from Parkinson's disease patients, the aetiology of the disease has not yet been established. Nevertheless, these studies have demonstrated that, at the time of death, a cascade of events had been initiated that may contribute to the demise of the melanin-containing nigro-striatal dopamine neurons. These events include increased levels of iron and monoamine oxidase (MAO)-B activity, oxidative stress, inflammatory processes, glutamatergic excitotoxicity, nitric oxide synthesis, abnormal protein folding and aggregation, reduced expression of trophic factors, depletion of endogenous antioxidants such as reduced glutathione, and altered calcium homeostasis.

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.

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.

cDNA microarray to study gene expression of dopaminergic neurodegeneration and neuroprotection in MPTP and 6-hydroxydopamine models: implications for idiopathic Parkinson's disease.

cDNA microarray membranes comprising 1,200 different gene fragments have been employed to identify gene expression profile in MPTP-induced nigro striatal dopamine neurodegeneration and its protection with Rapomorphine. Both MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and R-apomorphine (R-APO) induced alterations in specific patterns of gene expression. MPTP altered the expression of 49 different genes involved in oxidative stress (oxidative stress-induced protein A 170, cytochrome P450 1A1 and Osp94), inflammation (cytotoxic cytokines, eg: IL-1, IL-6, TNF-alpha), protective cytokines (IL-10), glutamate receptors (NMDA but not AMPA receptors), neurotrophic factors (GDNF, EGF), nitric oxide synthase and transferrin receptor, as determined by microarray membrane hybridization.

Iron chelating, antioxidant and cytoprotective properties of dopamine receptor agonist; apomorphine.

There have been many attempts to discover neuroprotective drugs for the treatment of Parkinson's disease (PD). Many of these compounds either do not cross the blood brain barrier or are not very effective in the 6-hydroxydopamine or MPTP (N-methyl-4-phenyl-1,2,3,6-terahydropyridine) models of PD. We have examined several compounds including dopamine receptor agonist bromocritine, lisuride, pergolide and R-apomorphine for their neuroprotective action against the above neurotoxins in PC12 and dopamine neuroblastoma cell lines in culture and in vivo.

Apomorphine protects against MPTP-induced neurotoxicity in mice.

R-apomorphine is a potent radical scavenger and iron chelator. The neuroprotective property of R-apomorphine, a dopamine D1-D2 receptor agonist, has been studied in the MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease. Pretreatment with 5-10 mg/kg R-apomorphine administered subcutaneously in C57BL mice protects against MPTP (24 mg/kg administered intraperitoneally) induced loss of nigrostriatal dopamine neurons as indicated by striatal dopamine content, tyrosine hydroxylase content, and tyrosine hydroxylase activity.

Antioxidant properties of the triaminopyridine, flupirtine.

Flupirtine is a triaminopyridine-derived centrally acting analgesic, which interacts with mechanisms of noradrenergic pain modulation. Recently, it has been found to display neuroprotective effects in various models of excitotoxic cell damage, global and focal ischemia. Although this profile suggests that flupirtine acts as an antagonist of the N-methyl-D-aspartate (NMDA) and glutamate-triggered Ca2+ channel, there is no direct interaction with the receptor.

Apomorphine enantiomers protect cultured pheochromocytoma (PC12) cells from oxidative stress induced by H2O2 and 6-hydroxydopamine.

A significant body of evidence has been provided to support the hypothesis that oxidant stress may be responsible for the degeneration of dopaminergic neurons in the substantia nigra pars compacta in Parkinson's disease. Apomorphine, a dopamine D1/D2-receptor agonist in the clinical therapy of Parkinson's disease, has been found to be a potent antioxidant and to prevent free radical reaction in rat brain mitochondrial fraction. In this article we show that 1-10 microM of apomorphine protects rat pheochromocytoma (PC12) cells from the toxic effects of H2O2 (0.

Mechanism of 6-hydroxydopamine neurotoxicity.

The catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) has recently been found to be formed endogenously in patients suffering from Parkinson's disease. In this article, we highlight the latest findings on the biochemical mechanism of 6-OHDA toxicity. 6-OHDA has two ways of action: it easily forms free radicals and it is a potent inhibitor of the mitochondrial respiratory chain complexes I and IV.

Apomorphine is a highly potent free radical scavenger in rat brain mitochondrial fraction.

Ergoline-derived dopamine receptor agonists, like pergolide or bromocryptine, have recently attracted attention as potential neuroprotective drugs. The classical mixed type dopamine D1 and D2 receptor agonist apomorphine, although used clinically in the therapy of Parkinson's disease, has never been examined for any properties related to neuroprotection. In this paper, we examine the effects of 0.