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1.
Cell Death Differ ; 23(2): 333-46, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26206088

ABSTRACT

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase and its dysregulation is implicated in neurodegenerative diseases. Likewise, C-terminus of Hsc70-interacting protein (CHIP) is linked to neurological disorders, serving as an E3 ubiquitin ligase for targeting damaged or toxic proteins for proteasomal degradation. Here, we demonstrate that CHIP is a novel substrate for Cdk5. Cdk5 phosphorylates CHIP at Ser20 via direct binding to a highly charged domain of CHIP. Co-immunoprecipitation and ubiquitination assays reveal that Cdk5-mediated phosphorylation disrupts the interaction between CHIP and truncated apoptosis-inducing factor (tAIF) without affecting CHIP's E3 ligase activity, resulting in the inhibition of CHIP-mediated degradation of tAIF. Lentiviral transduction assay shows that knockdown of Cdk5 or overexpression of CHIP(S20A), but not CHIP(WT), attenuates tAIF-mediated neuronal cell death induced by hydrogen peroxide. Thus, we conclude that Cdk5-mediated phosphorylation of CHIP negatively regulates its neuroprotective function, thereby contributing to neuronal cell death progression following neurotoxic stimuli.


Subject(s)
Apoptosis Inducing Factor/physiology , Apoptosis , Cyclin-Dependent Kinase 5/physiology , Neurons/physiology , Ubiquitin-Protein Ligases/metabolism , Animals , Cyclin-Dependent Kinase 5/chemistry , Hydrogen Peroxide/pharmacology , Male , Mice, Transgenic , Neurons/drug effects , Phosphorylation , Proteasome Endopeptidase Complex/metabolism , Proteolysis , Ubiquitin-Protein Ligases/chemistry , Ubiquitination
2.
Behav Brain Res ; 232(1): 252-63, 2012 Jun 15.
Article in English | MEDLINE | ID: mdl-22561126

ABSTRACT

Explanations and models of cooperation usually focus on the economics of an individual's invested effort and outcomes while down-playing social dimensions of naturally occurring cooperation. This study examined whether cooperative and individual behaviors differ in monoaminergic function in a manner that may explain the reported 'bias for cooperation' even under conditions where no immediate economic gains exist. Cooperation, represented by pairs of rats reinforced for coordinated shuttles within a shared chamber (COOP), was compared with rats shuttling for reinforcements individually (IND), and behaviorally naïve rats (NAïVE). Following training, the hypothalamus and striata were sampled and the activity patterns of the noradrenergic, serotonergic and dopaminergic systems were assessed using HPLC analyses. By matching the proportions of reinforced individual shuttles for COOP and IND rats the economic differences of invested effort (shuttles) and outcomes (obtained reinforcements) were neutralized. Nevertheless, differences were evident in monoaminergic functions. In comparison with IND rats, COOP rats showed significantly higher hypothalamic norepinephrine levels and exhibited a trend toward higher striatal serotonin levels. Differences in levels of dopaminergic metabolites were restricted to the right striatum; compared to IND rats, COOP rats exhibited significantly higher levels of HVA, whereas NAÏVE rats exhibited significantly higher DOPAC levels. Since economic differences between cooperative and individual shuttling were neutralized, the results demonstrate a relationship between social cooperation and a distinct activity pattern in brain mechanisms that were related with arousal, goal directed behaviors and motivation and further highlight the key role of social behaviors in the reported 'bias for cooperation'.


Subject(s)
Biogenic Monoamines/physiology , Cooperative Behavior , Corpus Striatum/physiology , Hypothalamus/physiology , Individuality , Social Behavior , Animals , Biogenic Monoamines/metabolism , Chromatography, High Pressure Liquid , Conditioning, Operant , Corpus Striatum/metabolism , Data Interpretation, Statistical , Electrochemistry , Hypothalamus/metabolism , Male , Orchiectomy , Rats , Rats, Wistar , Reinforcement, Psychology , Saccharin , Social Environment
3.
Mini Rev Med Chem ; 12(5): 364-70, 2012 May.
Article in English | MEDLINE | ID: mdl-22303968

ABSTRACT

Chelators hold great promise as disease-modifying drugs for Alzheimer's therapy, and recent research efforts have focused on designing multi-target chelators with increased targeting and efficacy through rational drug design. In this review, we discuss our research studies on the rational design of new multi-target chelators with the potential not only to simultaneously modulate several disease-related targets, but also contain features designed to improve the BBB permeability, increase the brain targeting, and minimize potential side effects. These new chelators include neuroprotective chelators with brain selective monoamine oxidase (MAO) A/B inhibitory activity, acetylcholinesterase (AChE) inhibitors with site-activated chelating and neurogenesis activity, and AChE-MAO A/B inhibitors with site-activated chelating and neurogenesis activity.


Subject(s)
Acetylcholinesterase/metabolism , Amyloid beta-Peptides/metabolism , Antioxidants/pharmacology , Chelating Agents/pharmacology , Hypoxia-Inducible Factor 1/metabolism , Monoamine Oxidase/metabolism , Alzheimer Disease/drug therapy , Animals , Antioxidants/chemistry , Antioxidants/metabolism , Chelating Agents/chemistry , Chelating Agents/metabolism , Humans
4.
Neuroscience ; 189: 345-58, 2011 Aug 25.
Article in English | MEDLINE | ID: mdl-21570450

ABSTRACT

The novel multifunctional brain permeable iron, chelator M30 [5-(N-methyl-N-propargyaminomethyl)-8-hydroxyquinoline] was shown to possess neuroprotective 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. In the present study, we demonstrate that systemic chronic administration of M30 resulted in up-regulation of hypoxia-inducible factor (HIF)-1α protein levels in various brain regions (e.g. cortex, striatum, and hippocampus) and spinal cord of adult mice. Real-time RT-PCR revealed that M30 differentially induced HIF-1α-dependent target genes, including vascular endothelial growth factor (VEGF), erythropoietin (EPO), enolase-1, transferrin receptor (TfR), heme oxygenase-1 (HO-1), inducible nitric oxide synthase (iNOS), and glucose transporter (GLUT)-1. In addition, mRNA expression levels of the growth factors, brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GDNF) and three antioxidant enzymes (catalase, superoxide dismutase (SOD)-1, and glutathione peroxidase (GPx)) were up-regulated by M30 treatment in a brain-region-dependent manner. Signal transduction immunoblotting studies revealed that M30 induced a differential enhanced phosphorylation of protein kinase C (PKC), mitogen-activated protein kinase (MAPK)/ERK kinase (MEK), protein kinase B (PKB/Akt), and glycogen synthase kinase-3ß (GSK-3ß). Together, these results suggest that the multifunctional iron chelator M30 can up-regulate a number of neuroprotective-adaptive mechanisms and pro-survival signaling pathways in the brain that might function as important therapeutic targets for the drug in the context of neurodegenerative disease therapy.


Subject(s)
Brain/drug effects , Hydroxyquinolines/pharmacology , Iron Chelating Agents/pharmacology , Neuroprotective Agents/pharmacology , Animals , Antioxidants/metabolism , Brain/metabolism , Gene Expression Profiling , Hypoxia-Inducible Factor 1, alpha Subunit/physiology , Liver/metabolism , Mice , Myocardium/metabolism , Nerve Growth Factors/metabolism , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Spinal Cord/metabolism
5.
Curr Alzheimer Res ; 7(4): 300-6, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20043814

ABSTRACT

Based on a multimodal drug design paradigm, we have synthesized a multifunctional non-toxic, brain permeable iron chelator, M30, possessing the neuroprotective propargylamine moiety of the anti-Parkinsonian drug, rasagiline (Azilect) and antioxidant-iron chelator moiety of an 8-hydroxyquinoline derivative of our iron chelator, VK28. M30 was recently found to confer potential neuroprotective effects in vitro and in various preclinical neurodegenerative models and regulate the levels and processing of the Alzheimer's amyloid precursor protein and its toxic amyloidogenic derivative, Abeta. Here, we show that M30 activates the hypoxia-inducible factor (HIF)-1alpha signaling pathway, thus promoting HIF-1alpha mRNA and protein expression levels, as well as increasing transcription of HIF-1alpha-dependent genes, including vascular endothelial growth factor, erythropoietin, enolase-1, p21 and tyrosine hydroxylase in rat primary cortical cells. In addition, M30 also increased the expression levels of the transcripts of brain derived neurotrophic factor (BDNF) and growth-associated protein-43 (GAP-43). Regarding aspects of relevance to Alzheimer's disease (AD), western blotting analysis of glycogen synthase kinase- 3beta (GSK-3beta) signaling pathway revealed that M30 enhanced the levels of phospho-AKT (Ser473) and phospho- GSK-3beta (Ser9) and attenuated Tau phosphorylation. M30 was also shown to protect cultured cortical neurons against Abeta(25-35) toxicity. All these multimodal pharmacological activities of M30 might be beneficial for its potent efficacy in the prevention and treatment of neurodegenerative conditions, such as Parkinson's disease and AD in which oxidative stress and iron-mediated toxicity are involved.


Subject(s)
Alzheimer Disease/drug therapy , Chelating Agents/pharmacology , Hydroxyquinolines/pharmacology , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Neurons/metabolism , Neurons/pathology , Neuroprotective Agents/pharmacology , Up-Regulation/drug effects , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Animals , Cells, Cultured , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Chelating Agents/therapeutic use , Drug Delivery Systems , Hydroxyquinolines/therapeutic use , Hypoxia-Inducible Factor 1, alpha Subunit/agonists , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Neurons/drug effects , Neuroprotective Agents/therapeutic use , Rats , Rats, Sprague-Dawley
6.
Neurotox Res ; 14(1): 45-56, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18790724

ABSTRACT

While iron deficiency is not perceived as a life threatening disorder, it is the most prevalent nutritional abnormality in the world, and a better understanding of modes and sites of action, can help devise better treatment programs for those who suffer from it. Nowhere is this more important than in infants and children that make up the bulk of iron deficiency in society. Although the effects of iron deficiency have been extensively studied in systemic organs, until very recently little attention was paid to its effects on brain function. The studies of Oski at Johns Hopkin Medical School in 1974, demonstrating the impairment of learning in young school children with iron deficiency, prompted us to study its relevance to brain biochemistry and function in an animal model of iron deficiency. Indeed, rats made iron deficient have lowered brain iron and impaired behaviours including learning. This can become irreversible especially in newborns, even after long-term iron supplementation. We have shown that in this condition it is the brain striatal dopaminergic-opiate system which becomes defective, resulting in alterations in circadian behaviours, cognitive impairment and neurochemical changes closely associated with them. More recently we have extended these studies and have established that cognitive impairment may be closely associated with neuroanatomical damage and zinc metabolism in the hippocampus due to iron deficiency, and which may result from abnormal cholinergic function. The hippocampus is the focus of many studies today, since this brain structure has high zinc concentration and is highly involved in many forms of cognitive deficits as a consequence of cholinergic deficiency and has achieved prominence because of dementia in ageing and Alzheimer's disease. Thus, it is now apparent that cognitive impairment may not be attributed to a single neurotransmitter, but rather, alterations and interactions of several systems in different brain regions. In animal models of iron deficiency it is apparent that dopaminergic interaction with the opiate system and cholinergic neurotransmission may be defective.


Subject(s)
Brain Diseases/complications , Cognition Disorders , Corpus Striatum/physiopathology , Hippocampus/physiopathology , Iron Metabolism Disorders/complications , Neurodegenerative Diseases , Animals , Cognition Disorders/etiology , Cognition Disorders/pathology , Corpus Striatum/metabolism , Hippocampus/metabolism , Humans , Iron Metabolism Disorders/classification , Neurodegenerative Diseases/etiology , Neurodegenerative Diseases/pathology
7.
Parkinsonism Relat Disord ; 14 Suppl 2: S88-91, 2008.
Article in English | MEDLINE | ID: mdl-18585078

ABSTRACT

Parkinson's disease (PD) is thought to be associated with oxidative stress mechanisms, as well as with glutamate receptor abnormalities, ubiquitin-proteasome dysfunction, inflammatory and cytokine activation, dysfunction in neurotrophic factors, damage to mitochondria, cytoskeletal abnormalities, synaptic dysfunction and activation of apoptotic pathways. To investigate these hypotheses, many researchers have applied molecular biology techniques to the study of neuronal cell death in these conditions. In this article, we discuss recent findings of gene expression in PD that may elucidate the usage of specific new biomarkers for sporadic PD and point to novel drug developments.


Subject(s)
Genomics/methods , Parkinson Disease/genetics , Parkinson Disease/metabolism , Gene Expression , Humans , Models, Biological , Parkinson Disease/pathology , Substantia Nigra/metabolism
8.
J Neural Transm (Vienna) ; 114(11): 1443-54, 2007.
Article in English | MEDLINE | ID: mdl-17576515

ABSTRACT

Treating primary 'negative symptoms' of schizophrenia with a combination of a typical antipsychotic and a selective serotonin reuptake inhibitor, is more effective than with antipsychotic alone and is similar to the effect of the atypical antipsychotic, clozapine. The mechanism of this treatment combination is unknown and may involve changes in dopaminergic and serotonin systems. We studied dopamine and serotonin metabolism in different rat brain areas at 1.5 and 24 h after the last dosage of chronic treatment (30 days), with haloperidol plus fluvoxamine, each drug alone, and clozapine. Haloperidol-fluvoxamine combination, haloperidol, and clozapine treatments increased striatal and frontal cortex dopamine turnover and reduced striatal tyrosine hydroxylase activity at 1.5 h. At 24 h both dopamine turnover and tyrosine hydroxylase activity were reduced. Thus, in chronically treated animals, release of striatal dopamine increases following a drug pulse and returns to baseline by 24 h. Serotonin and 5-hydroxyindoleacetic acid concentrations were decreased at 1.5 h in haloperidol-fluvoxamine and clozapine groups and returned to normal levels by 24 h. A limited behavioral assessment showed that treatment with haloperidol plus fluvoxamine reduced motor activity compared to haloperidol, and increased sniffing compared to haloperidol, fluvoxamine and clozapine. These findings indicate that combining antipsychotic with SSRI results in specific changes in dopaminergic and serotonergic systems and in behavior. The possibility that these may be relevant to the mechanism underlying the clinical effectiveness of augmentation treatment warrant further study.


Subject(s)
Dopamine Antagonists/pharmacology , Dopamine/metabolism , Fluvoxamine/pharmacology , Haloperidol/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Serotonin/metabolism , Animals , Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Body Weight/drug effects , Brain/drug effects , Brain/metabolism , Clozapine/pharmacology , Dopamine Antagonists/blood , Drug Interactions , Fluvoxamine/blood , Haloperidol/blood , Immunohistochemistry , Male , Motor Activity/drug effects , Neostriatum/drug effects , Neostriatum/metabolism , Rats , Rats, Sprague-Dawley , Selective Serotonin Reuptake Inhibitors/blood , Tyrosine 3-Monooxygenase/metabolism
9.
J Neural Transm (Vienna) ; 114(2): 205-9, 2007 Feb.
Article in English | MEDLINE | ID: mdl-16736232

ABSTRACT

In MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and 6-hydroxydopamine induced dopaminergic neurotoxicity and Parkinson's disease iron accumulates in substantia nigra pars compacta which has been suggested to participate in oxidative stress induced neurodegeneration. Pretreatment with iron chelators desferal, clioquinol, VK-28 and M30 are neuroprotective in both models. To determine the specificity of chelation neuroprotective activity we have examined the effect of D-penicillamine, a relatively specific copper chelator, in the mice model of MPTP-induced dopamine depletion. Our studies show that D-penicillamine, employed for removal of copper in Wilson disease is relatively weak in preventing dopaminergic neurotoxicity induced by MPTP, as compared to iron chelators previously studied. The results indicate that for prevention of MPTP-induced dopamine depletion and dopamine neurodegeneration, iron rather than copper chelation may be more effective and specific.


Subject(s)
Corpus Striatum/drug effects , Dopamine Agents/toxicity , Dopamine/metabolism , Nerve Degeneration/prevention & control , Neuroprotective Agents/pharmacology , Penicillamine/pharmacology , Acetylcysteine/pharmacology , Animals , Chelating Agents/pharmacology , Chromatography, High Pressure Liquid , Corpus Striatum/metabolism , Iron/metabolism , MPTP Poisoning , Male , Mice , Mice, Inbred C57BL , Salicylic Acid/pharmacology
10.
Br J Pharmacol ; 149(6): 647-56, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17016505

ABSTRACT

BACKGROUND AND PURPOSE: Postural hypotension is a common side-effect of L-DOPA treatment of Parkinson's disease, and may be potentiated when L-DOPA is combined with selegiline, a selective inhibitor of monoamine oxidase B (MAO-B). Rasagiline is a new, potent and selective MAO-B inhibitor, which does not possess the sympathomimetic effects of selegiline. We have studied the effects of these selective MAO inhibitors, L-DOPA and dopamine on the cardiovascular system of the rat. EXPERIMENTAL APPROACH: Blood pressure and heart rate was measured in conscious rats following acute or chronic administration of rasagiline, selegiline and L-DOPA, by comparison with the selective MAO-A inhibitor clorgyline, or the MAO-A/B inhibitor tranylcypromine. Cardiovascular responses, catecholamine release, and modification of pressor response to dopamine were studied in pithed rats. KEY RESULTS: In conscious rats neither rasagiline nor selegiline caused significant potentiation of the effects of L-DOPA (50, 100, 150 mg.kg(-1)) on blood pressure or heart rate at doses which selectively inhibited MAO-B, but L-DOPA responses were potentiated by clorgyline and tranylcypromine. In rats treated twice daily for 8 days with L-DOPA and carbidopa, selegiline (5 mg.kg(-1)) but not rasagiline (0.2 mg.kg(-1)) caused a significant hypotensive response to L-DOPA and carbidopa, although both drugs caused similar inhibition of MAO-A and MAO-B. In pithed rats, selegiline but not rasagiline increased catecholamine release and heart rate, and potentiated dopamine pressor response at MAO-B selective dose. CONCLUSIONS AND IMPLICATIONS: The different responses to the two MAO-B inhibitors may be explained by the amine releasing effect of amphetamine metabolites formed from selegiline.


Subject(s)
Blood Pressure/drug effects , Heart Rate/drug effects , Levodopa/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/drug effects , Animals , Male , Rats , Rats, Sprague-Dawley
11.
J Neural Transm Suppl ; (70): 133-42, 2006.
Article in English | MEDLINE | ID: mdl-17017520

ABSTRACT

Histopathological, biochemical and in vivo brain imaging techniques, such as magnetic resonance imaging and transcranial sonography, revealed a consistent increase of substantia nigra (SN) iron in Parkinson's disease (PD). Increased iron deposits in the SN may have genetic and non-genetic causes. There are several rare movement disorders associated with neurodegeneration, and genetic abnormalities in iron regulation resulting in iron deposition in the brain. Non-genetic causes of increased SN iron may be the result of a disturbed or open blood-brain-barrier, local changes in the normal iron-regulatory systems, intraneuronal transportation of iron from iron-rich area into the SN and release of iron from intracellular iron storage molecules. Major iron stores are ferritin and haemosiderin in glial cells as well as neuromelanin in neurons. Age- and disease dependent overload of iron storage proteins may result in iron release upon reduction. Consequently, the low molecular weight chelatable iron complexes may trigger redox reactions leading to damage of biomolecules. Additionally, upon neurodegeneration there is strong microglial activation which can be another source of high iron concentrations in the brain.


Subject(s)
Iron/metabolism , Parkinson Disease/metabolism , Substantia Nigra/metabolism , Animals , Brain Chemistry/physiology , Homeostasis , Humans
12.
J Neural Transm Suppl ; (70): 447-56, 2006.
Article in English | MEDLINE | ID: mdl-17017567

ABSTRACT

Iron and monoamine oxidase activity are increased in brain of Parkinson's disease (PD). They are associated with autoxidation and oxidative deamination of dopamine by MAO resulting in the generation of reactive oxygen species and the onset of oxidative stress to induce neurodegeneration. Iron chelators (desferal, Vk-28 and clioquinol) but not copper chelators have been shown to be neuroprotective in the 6-hydroxydoapmine and MPTP models of Parkinson's disease (PD), as are monoamine oxidase B inhibitors such as selegiline and rasagiline. These findings prompted the development of multifunctional anti PD drugs possessing iron chelating phamacophore of VK-28 and the propargylamine MAO inhibitory activity of rasagiline. M30 is a potent iron chelator, radical scavenger and brain selective irreversible MAO-A and B inhibitor, with little inhibition of peripheral MAO. It has neuroprotective activity in in vitro and in vivo models of PD and unlike selective MAO-B inhibitors it increases brain dopamine, serotonin and noradrenaline. These findings indicate beside its anti PD action, it may also possess antidepressant activity, similar to selective MAO-A and nonselective MAO inhibitors. These properties make it an ideal anti PD drug for which it is being developed.


Subject(s)
Hydroxyquinolines/therapeutic use , Iron Chelating Agents/therapeutic use , Monoamine Oxidase Inhibitors/therapeutic use , Neuroprotective Agents/therapeutic use , Parkinson Disease/drug therapy , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/antagonists & inhibitors , Animals , Brain/drug effects , Brain/enzymology , Dopamine/physiology , Dopamine Agents/toxicity , Humans , Synaptic Transmission/drug effects
13.
J Neural Transm Suppl ; (70): 457-65, 2006.
Article in English | MEDLINE | ID: mdl-17017568

ABSTRACT

Our recent studies aimed to elucidate the molecular and biochemical mechanism of actions of the novel anti-Parkinson's drug, rasagiline, an irreversible and selective monoamine oxidase (MAO)-B inhibitor and its propargyl moiety, propargylamine. In cell death models induced by serum withdrawal in rat PC12 cells and human SH-SY5Y neuroblastoma cells, both rasagiline and propargylamine exerted neuroprotective and neurorescue activities via multiple survival pathways, including: stimulation of protein kinase C (PKC) phosphorylation; up-regulation of protein and gene levels of PKCalpha, PKCepsilon and the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w; and up-regulation of the neurotrophic factors, BDNF and GDNF mRNAs. Rasagiline and propargylamine inhibited the cleavage and subsequent activation of pro-caspase-3 and poly ADP-ribose polymerase. Additionally, these compounds significantly down-regulated PKCgamma mRNA and decreased the level of the pro-apoptotic proteins, Bax, Bad, Bim and H2A.X. Rasagiline and propargylamine both regulated amyloid precursor protein (APP) processing towards the non-amyloidogenic pathway. These structure-activity studies have provided evidence that propargylamine promoted neuronal survival via neuroprotective/neurorescue pathways similar to that of rasagiline. In addition, recent study demonstrated that chronic low doses of rasagiline administered to mice subsequently to 1 methyl-4 phenyl 1,2,3,6 tetrahydropyridine (MPTP), rescued dopaminergic neurons in the substantia nigra pars compacta via activation of the Ras-PI3K-Akt survival pathway, suggesting that rasagiline may possess a disease modifying activity.


Subject(s)
Amyloid beta-Protein Precursor/metabolism , Indans/pharmacology , Neuroprotective Agents , Signal Transduction/physiology , Animals , Humans , Indans/chemistry , Pargyline/analogs & derivatives , Pargyline/pharmacology , Propylamines/pharmacology , Structure-Activity Relationship
14.
J Neurochem ; 97(2): 527-36, 2006 Apr.
Article in English | MEDLINE | ID: mdl-16539659

ABSTRACT

Brain iron dysregulation and its association with amyloid precursor protein (APP) plaque formation are implicated in Alzheimer's disease (AD) pathology and so iron chelation could be considered a rational therapeutic strategy for AD. Here we analyzed the effect of the main polyphenol constituent of green tea, (-)-epigallocatechin-3-gallate (EGCG), which possesses metal-chelating and radical-scavenging properties, on the regulation of the iron metabolism-related proteins APP and transferrin receptor (TfR). EGCG exhibited potent iron-chelating activity comparable to that of the prototype iron chelator desferrioxamine, and dose dependently (1-10 microm) increased TfR protein and mRNA levels in human SH-SY5Y neuroblastoma cells. Both the immature and full-length cellular holo-APP were significantly reduced by EGCG, as shown by two-dimensional gel electrophoresis, without altering APP mRNA levels, suggesting a post-transcriptional action. Indeed, EGCG suppressed the translation of a luciferase reporter gene fused to the APP mRNA 5'-untranslated region, encompassing the APP iron-responsive element. The finding that Fe(2)SO(4) reversed the action of EGCG on APP and TfR proteins reinforces the likelihood that these effects are mediated through modulation of the intracellular iron pool. Furthermore, EGCG reduced toxic beta-amyloid peptide generation in Chinese hamster ovary cells overexpressing the APP 'Swedish' mutation. Thus, the natural non-toxic brain-permeable EGCG may provide a potential therapeutic approach for AD and other iron-associated disorders.


Subject(s)
Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Catechin/analogs & derivatives , Gene Expression/drug effects , Iron/physiology , Neuroprotective Agents/pharmacology , Animals , Antigens, CD/metabolism , Blotting, Western/methods , CHO Cells , Catechin/pharmacology , Cell Line, Tumor , Cricetinae , Cricetulus , Deferoxamine/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Electrophoresis, Gel, Two-Dimensional/methods , Humans , Immunoprecipitation/methods , Iron Chelating Agents/pharmacology , Neuroblastoma , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Transferrin/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methods , Transfection/methods
15.
J Neural Transm (Vienna) ; 113(1): 21-32, 2006 Jan.
Article in English | MEDLINE | ID: mdl-15843867

ABSTRACT

Propargylamine derivatives, rasagiline and (-)deprenyl, are anti-Parkinson agents and protect neurons from cell death as shown by in vivo and in vitro experiments. The studies on the chemical structure-activity relationship proved that the propargyl moiety is essentially required for the neuroprotective function. In this paper, neuroprotective activity of free N-propargylamine was studied using SH-SY5Y cells expressing only type A monoamine oxidase (MAO) against apoptosis induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. N-Propargylamine prevented apoptosis, whereas N-methylpropargylamine and propiolaldehyde did not. N-Propargylamine stabilized mitochondrial membrane potential and induced anti-apoptotic Bcl-2 at 1 microM-10 nM. N-Propargylamine inhibited MAO-A in competition to substrate with the apparent K(i) value of 28 microM, which was significantly higher than the concentration required for neuroprotection. It indicates that MAO inhibition is not prerequisite for the protective function of N-propargylamine. The anti-apoptotic function of N-propargylamine is discussed in terms of neuroprotection by propargylamines in neurodegenerative diseases, including Parkinson's disease.


Subject(s)
Apoptosis Regulatory Proteins/biosynthesis , Apoptosis/drug effects , Mitochondrial Membranes/drug effects , Pargyline/analogs & derivatives , Propylamines/pharmacology , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Salsoline Alkaloids/toxicity , Tetrahydroisoquinolines/toxicity , Apoptosis/physiology , Apoptosis Regulatory Proteins/genetics , Apoptosis Regulatory Proteins/physiology , Dose-Response Relationship, Drug , Humans , Mitochondria/drug effects , Mitochondria/metabolism , Mitochondrial Membranes/metabolism , Neuroprotective Agents/pharmacology , Pargyline/pharmacology , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/physiology , Tumor Cells, Cultured
17.
J Neural Transm Suppl ; (71): 237-47, 2006.
Article in English | MEDLINE | ID: mdl-17447434

ABSTRACT

Iron closely regulates the expression of the Alzheimer's Amyloid Precursor Protein (APP) gene at the level of message translation by a pathway similar to iron control of the translation of the ferritin L- and H mRNAs by Iron-responsive Elements in their 5' untranslated regions (5'UTRs). Using transfection based assays in SH-SY5Y neuroblastoma cells we tested the relative efficiency by which iron, copper and zinc up-regulate IRE activity in the APP 5'UTR. Desferrioxamine (high affinity Fe3+ chelator), (ii) clioquinol (low affinity Fe/Cu/Zn chelator), (iii) piperazine-1 (oral Fe chelator), (iv) VK-28 (oral Fe chelator), were tested for their relative modulation of APP 5' UTR directed translation of a luciferase reporter gene. Iron chelation based therapeutic strategies for slowing the progression of Alzheimer's disease (and other neurological disorders that manifest iron imbalance) are discussed with regard to the relative neural toxic action of each chelator in SH-SY5Y cells and in H4 glioblastoma cells.


Subject(s)
Amyloid beta-Protein Precursor/metabolism , Iron Chelating Agents/pharmacology , Iron-Regulatory Proteins/metabolism , Protein Biosynthesis/drug effects , RNA, Messenger/metabolism , Untranslated Regions/metabolism , Amyloid beta-Protein Precursor/genetics , Cell Line, Tumor , Clioquinol/pharmacology , Deferoxamine/pharmacology , Dose-Response Relationship, Drug , Glioblastoma , Humans , Models, Molecular , Neuroblastoma , Transfection/methods , Untranslated Regions/genetics
18.
J Pept Res ; 66(4): 190-203, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16138857

ABSTRACT

A series of novel derivatives of neuropeptides with a metal-chelating moiety was synthesized and examined for various properties related to iron (Fe) chelation and neuroprotective action. All derivatives chelated Fe to form stable Fe complexes in water. Some strongly inhibited Fe-induced lipid peroxidation with an IC(50) value of about 12 microm. In PC12 cell culture, several compounds, at concentrations as low as 1 microm, attenuated serum-free stimulated cell death and improved cell survival by 20-35%. At this concentration, these analogs also protected against 6-hydroxydopamine (6-OHDA)-induced cell death, increasing cell viability by 20-30%. Electron paramagnetic resonance (EPR) studies indicated that besides being good Fe chelators, these analogs act as radical scavengers to directly scavenge hydroxyl radicals. Together, the data indicate that some of the analogs could be further developed as possible neuroprotective agents for treatment of neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's diseases, Friedreich's atxia, amyotrophic, and lateral sclerosis where Fe misregulation has been reported.


Subject(s)
Chelating Agents/chemical synthesis , Neurodegenerative Diseases/drug therapy , Neuropeptides/chemical synthesis , Animals , Chelating Agents/pharmacology , Free Radical Scavengers/metabolism , Metals, Heavy/metabolism , Neurodegenerative Diseases/metabolism , Neuropeptides/metabolism , Neuropeptides/pharmacology , PC12 Cells , Rats
19.
J Neurochem ; 93(5): 1157-67, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15934936

ABSTRACT

Our previous studies have shown that the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) prevents neuronal cell death caused by several neurotoxins. The present study sought to determine the neuroprotective effect of EGCG when it is administered after the induction of cell damage ('neurorescue'). In an attempt to imitate a progressive mode of death, PC12 cells were initially subjected to serum-starvation conditions for a period of 1 or 3 days before administration of EGCG (0.1-10 microM) for up to 3 days. In spite of the high percentage of cell death, single or repetitive administration of EGCG (1 microM) significantly attenuated cell death. The neurorescue effect of EGCG was abolished by pre-treatment with the protein kinase C inhibitor GF109203X (2.5 microM), suggesting the involvement of the protein kinase C pathway in neurorescue by the drug. This is consistent with the rapid (15 min) translocation of the protein kinase C alpha isoform to the cell membrane in response to EGCG. The correlative neurite outgrowth activity of EGCG on PC12 cells may also contribute to its neurorescue effect. The present findings suggest that EGCG may have a positive impact on aging and neurodegenerative diseases to retard or perhaps even reverse the accelerated rate of neuronal degeneration.


Subject(s)
Catechin/analogs & derivatives , Catechin/pharmacology , Culture Media, Serum-Free/pharmacology , Flavonoids/pharmacology , Neurites/physiology , Neuroprotective Agents/pharmacology , PC12 Cells/drug effects , Phenols/pharmacology , Animals , Biological Transport/drug effects , Cell Death/drug effects , Cell Differentiation/drug effects , Cell Membrane/enzymology , Enzyme Activation/drug effects , Neurites/drug effects , PC12 Cells/enzymology , PC12 Cells/pathology , PC12 Cells/physiology , Polyphenols , Protein Kinase C/metabolism , Protein Kinase C/physiology , Protein Kinase C-alpha , Rats
20.
J Neural Transm (Vienna) ; 112(4): 519-37, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15666041

ABSTRACT

Patients with mild forms of dementia and age-related memory impairment have just begun to benefit from pharmacotherapy developed over the last several years. However, current approaches do not significantly modify the course of neurodegeneration or of the aging process, and they offer limited and transient benefit to many patients. The goal of this review is to summarize new potential approaches in which molecules have been developed expressly to target multiple brain systems for the treatment of memory and cognition impairment. Some of these approaches include the development of single molecular entities that combine activity as cholinesterase inhibitors, muscarinic cholinergic M2 receptor antagonists, nicotinic acetylcholine receptor agonists, alpha(2)-adrenergic agonists, or monoamine oxidase inhibitors. Many of the bi-functional compounds discussed have improved efficacy as cognitive enhancing agents and/or they offer potential for neuroprotection and disease modification. It is likely that syndromes such as Alzheimer's disease will require multiple drug therapy to address the varied pathological aspects of the disease. Even if the strategy of combining drugs with different therapeutic targets is workable, the development of multi-functional compounds will obviate the challenge of administering multiple single drug entities with potentially different degrees of bioavailability, pharmacokinetics, and metabolism. Also, the simplification of the therapeutic regimen for individuals with AD who have difficulty with compliance is important.


Subject(s)
Alzheimer Disease/drug therapy , Brain/drug effects , Neuroprotective Agents/pharmacology , Nootropic Agents/pharmacology , Parkinson Disease/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Animals , Brain/metabolism , Brain/physiopathology , Drug Design , Humans , Neuropharmacology/trends , Neuroprotective Agents/chemistry , Neurotransmitter Agents/agonists , Neurotransmitter Agents/antagonists & inhibitors , Nootropic Agents/chemistry , Parkinson Disease/metabolism , Parkinson Disease/physiopathology , Receptors, Neurotransmitter/agonists , Receptors, Neurotransmitter/antagonists & inhibitors
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