Neuroprotective Agents For Parkinson's Disease Research Articles

Central and Enteric Neuroprotective Effects by Eucommia ulmoides Extracts on Neurodegeneration in Rotenone-induced Parkinsonian Mouse.

Parkinson's disease (PD) is a progressive neurodegenerative disease of both the central and peripheral / enteric nervous systems. Oxidative stress and neuroinflammation are associated with the pathogenesis of PD, suggesting that anti-oxidative and anti-inflammatory compounds could be neuroprotective agents for PD. Eucommia ulmoides (EU) is a traditional herbal medicine which exerts neuroprotective effects by anti-inflammatory and anti-oxidative properties. Our previous study showed that treatment with chlorogenic acid, a component of EU, protected against neurodegeneration in the central and enteric nervous systems in a PD model. In this study, we examined the effects of EU extract (EUE) administration on dopaminergic neurodegeneration, glial response and α-synuclein expression in the substantia nigra pars compacta (SNpc), and intestinal enteric neurodegeneration in low-dose rotenone-induced PD model mice. Daily oral administration of EUE ameliorated dopaminergic neurodegeneration and α-synuclein accumulation in the SNpc. EUE treatment inhibited rotenone-induced decreases in the number of total astrocytes and in those expressing the antioxidant molecule metallothionein. EUE also prevented rotenone-induced microglial activation. Furthermore, EUE treatment exerted protective effects against intestinal neuronal loss in the PD model. These results suggest that EU exerts neuroprotective effects in the central and enteric nervous systems of rotenone-induced parkinsonism mice, in part by glial modification.

Central and Enteric Neuroprotective Effects by Eucommia ulmoides Extracts on Neurodegeneration in Rotenone-induced Parkinsonian Mouse.

Parkinson's disease (PD) is a progressive neurodegenerative disease of both the central and peripheral / enteric nervous systems. Oxidative stress and neuroinflammation are associated with the pathogenesis of PD, suggesting that anti-oxidative and anti-inflammatory compounds could be neuroprotective agents for PD. Eucommia ulmoides (EU) is a traditional herbal medicine which exerts neuroprotective effects by anti-inflammatory and anti-oxidative properties. Our previous study showed that treatment with chlorogenic acid, a component of EU, protected against neurodegeneration in the central and enteric nervous systems in a PD model. In this study, we examined the effects of EU extract (EUE) administration on dopaminergic neurodegeneration, glial response and α-synuclein expression in the substantia nigra pars compacta (SNpc), and intestinal enteric neurodegeneration in low-dose rotenone-induced PD model mice. Daily oral administration of EUE ameliorated dopaminergic neurodegeneration and α-synuclein accumulation in the SNpc. EUE treatment inhibited rotenone-induced decreases in the number of total astrocytes and in those expressing the antioxidant molecule metallothionein. EUE also prevented rotenone-induced microglial activation. Furthermore, EUE treatment exerted protective effects against intestinal neuronal loss in the PD model. These results suggest that EU exerts neuroprotective effects in the central and enteric nervous systems of rotenone-induced parkinsonism mice, in part by glial modification.

In vitro neuroprotective potential of Clivia miniata and Nerine humilis (Amaryllidaceae) in MPP+-induced neuronal toxicity in SH-SY5Y neuroblastoma cells

Parkinson's disease (PD) is one of the most common neurodegenerative diseases (NDD) and mainly affects the ageing population. A significant feature of PD pathogenesis is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta part of the midbrain in affected persons. This neuronal loss occurs partly due to the increased generation of reactive oxygen species (ROS) in the mitochondrial and the depletion of adenosine triphosphate (ATP) in affected neurons. In this study, the methanolic extracts of Clivia miniata (CME) and Nerine humilis (NHE) belonging to the plant family Amaryllidaceae, were investigated for their neuroprotective potential in MPP+-induced neurotoxicity in SH-SY5Y neuroblastoma cells. Cell viability was determined using the 3-(4,5-dimethyithiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays and cell morphology was analysed using light microscopy. Furthermore, the effects of the extracts on apoptosis and ATP production were investigated using caspase 3/7 apoptosis kit and the Promega Mitochondrial ToxGlo ATP assay kit respectively. Additionally, the antioxidant contents of extracts were evaluated using routine laboratory procedures. The results show that pre-treatment of cells with the extracts at 2 and 4 μg/mL concentrations improved cell viability as well as cell morphology by inhibiting the toxicity induced by MPP+. The extracts also improved ATP levels in cells and attenuated the apoptosis induced by MPP+. Furthermore, antioxidant assays showed that both extracts had low antioxidant activity. Findings from this study indicate that CME and NHE may be promising as neuroprotective agents for PD and warrant further investigation to determine the bioactive components of the plants that may be responsible for the observed effects.

A novel iron (II) preferring dopamine agonist chelator D-607 significantly suppresses α-syn- and MPTP-induced toxicities in vivo

Here, we report the characterization of a novel hybrid D2/D3 agonist and iron (II) specific chelator, D-607, as a multi-target-directed ligand against Parkinson's disease (PD). In our previously published report, we showed that D-607 is a potent agonist of dopamine (DA) D2/D3 receptors, exhibits efficacy in a reserpinized PD animal model and preferentially chelates to iron (II). As further evidence of its potential as a neuroprotective agent in PD, the present study reveals D-607 to be protective in neuronal PC12 cells against 6-OHDA toxicity. In an in vivo Drosophila melanogaster model expressing a disease-causing variant of α-synuclein (α-Syn) protein in fly eyes, the compound was found to significantly suppress toxicity compared to controls, concomitant with reduced levels of aggregated α-Syn. Furthermore, D-607 was able to rescue DAergic neurons from MPTP toxicity in mice, a well-known PD neurotoxicity model, following both sub-chronic and chronic MPTP administration. Mechanistic studies indicated that possible protection of mitochondria, up-regulation of hypoxia-inducible factor, reduction in formation of α-Syn aggregates and antioxidant activity may underlie the observed neuroprotection effects. These observations strongly suggest that D-607 has potential as a promising multifunctional lead molecule for viable symptomatic and disease-modifying therapy for PD.

Selective VIP Receptor Agonists Facilitate Immune Transformation for Dopaminergic Neuroprotection in MPTP-Intoxicated Mice.

Vasoactive intestinal peptide receptor 2 can elicit immune transformation in a model of Parkinson's disease (PD). Such immunomodulatory capabilities can lead to neuroprotection by attenuating microglial activation and by slowing degradation of neuronal cell bodies and termini in MPTP-intoxicated mice. The protective mechanism arises from altering a Th1/Th2 immune cytokine response into an anti-inflammatory and neuronal sparing profile. These results are directly applicable for the development of novel PD therapies.

Curcumin's neuroprotective efficacy in Drosophila model of idiopathic Parkinson's disease is phase specific: implication of its therapeutic effectiveness.

Selective degeneration of dopaminergic neurons in the substantia nigra underlies the basic motor impairments of Parkinson's disease (PD). Curcumin has been used for centuries in traditional medicines in India. Our aim is to understand the efficacy of genotropic drug curcumin as a neuroprotective agent in PD. Analysis of different developmental stages in model organisms revealed that they are characterized by different patterns of gene expression which is similar to that of developmental stages of human. Genotropic drugs would be effective only during those life cycle stages for which their target molecules are available. Hence there exists a possibility that targets of genotropic compounds such as curcumin may not be present in all life stages. However, no reports are available in PD models illustrating the efficacy of curcumin in later phases of adult life. This is important because this is the period during which late-onset disorders such as idiopathic PD set in. To understand this paradigm, we tested the protective efficacy of curcumin in different growth stages (early, late health stage, and transition phase) in adult Drosophila flies. Results showed that it can rescue the motor defects during early stages of life but is ineffective at later phases. This observation was substantiated with the finding that curcumin treatment could replenish depleted brain dopamine levels in the PD model only during early stages of life cycle, clearly suggesting its limitation as a therapeutic agent in late-onset neurodegenerative disorders such as PD.

Complementary & alternative management of Parkinson's disease: an evidence-based review of eastern influenced practices.

The prevalence of Parkinson’s disease (PD) appears to be lower in Asia compared to the Western world. It is unclear if this is related to the ubiquitous use of traditional medicine in Eastern healthcare, but the use of complementary and alternative medicine (CAM) modalities in countries like Korea may be as high as 76%. Among patients with PD, herbal medicines, health supplement foods, and acupuncture are interventions which are increasingly used throughout the world. Countries like Korea, China, India, and Japan have long embraced and incorporated traditional medicine into modern management of conditions such as PD, but research into various CAM modalities remains in its infancy limiting evidence-based recommendations for many treatments. We reviewed the literature on CAM treatments for PD, focusing on mind-body interventions and natural products. Based on evidence limited to randomized-controlled trials we found that mind-body interventions are generally effective forms of physical activity that are likely to foster good adherence and may reduce disability associated with PD. Based on the current data, modalities like Tai Chi and dance are safe and beneficial in PD, but better studies are needed to assess the effects of other frequently used modalities such as yoga and acupuncture. Furthermore, despite centuries of experience using medicinal herbs and plants in Eastern countries, and despite substantial preclinical data on the beneficial effects of nutritional antioxidants as neuroprotective agents in PD, there is insufficient clinical evidence that any vitamin, food additive, or supplement, can improve motor function or delay disease progression in PD.

Delayed gastric emptying in Parkinson's disease

Gastrointestinal symptoms are evident in all stages of Parkinson's disease (PD). Most of the gastrointestinal abnormalities associated with PD are attributable to impaired motility. At the level of the stomach, this results in delayed gastric emptying. The etiology of delayed gastric emptying in PD is probably multifactorial but is at least partly related to Lewy pathology in the enteric nervous system and discrete brainstem nuclei. Delayed gastric emptying occurs in both early and advanced PD but is underdetected in routine clinical practice. Recognition of delayed gastric emptying is important because it can cause an array of upper gastrointestinal symptoms, but additionally it has important implications for the absorption and action of levodopa. Delayed gastric emptying contributes significantly to response fluctuations seen in people on long-term l-dopa therapy. Neurohormonal aspects of the brain-gut axis are pertinent to discussions regarding the pathophysiology of delayed gastric emptying in PD and are also hypothesized to contribute to the pathogenesis of PD itself. Ghrelin is a gastric-derived hormone with potential as a therapeutic agent for delayed gastric emptying and also as a novel neuroprotective agent in PD. Recent findings relating to ghrelin in the context of PD and gastric emptying are considered. This article highlights the pathological abnormalities that may account for delayed gastric emptying in PD. It also considers the wider relevance of abnormal gastric pathology to our current understanding of the etiology of PD.

Ascorbate prevents cell death from prolonged exposure to glutamate in an in vitro model of human dopaminergic neurons

Ascorbate (vitamin C) is a nonenzymatic antioxidant highly concentrated in the brain. In addition to mediating redox balance, ascorbate is linked to glutamate neurotransmission in the striatum, where it renders neuroprotection against excessive glutamate stimulation. Oxidative stress and glutamatergic overactivity are key biochemical features accompanying the loss of dopaminergic neurons in the substantia nigra that characterizes Parkinson's disease (PD). At present, it is not clear whether antiglutamate agents and ascorbate might be neuroprotective agents for PD. Thus, we tested whether ascorbate can prevent cell death from prolonged exposure to glutamate using dopaminergic neurons of human origin. To this purpose, dopamine-like neurons were obtained by differentiation of SH-SY5Y cells and then cultured for 4 days without antioxidant (antiaging) protection to evaluate glutamate toxicity and ascorbate protection as a model system of potential factors contributing to dopaminergic neuron death in PD. Glutamate dose dependently induced toxicity in dopaminergic cells largely by the stimulation of AMPA and metabotropic receptors and to a lesser extent by N-methyl-D-aspartate and kainate receptors. At relatively physiological levels of extracellular concentration, ascorbate protected cells against glutamate excitotoxicity. This neuroprotection apparently relies on the inhibition of oxidative stress, because ascorbate prevented the pro-oxidant action of the scavenging molecule quercetin, which occurred over the course of prolonged exposure, as is also seen with glutamate. Our findings show the relevance of ascorbate as a neuroprotective agent and emphasize an often underappreciated role of oxidative stress in glutamate excitotoxicity. Occurrence of a glutamate-ascorbate link in dopaminergic neurons may explain previous contradictions regarding their putative role in PD.

Glycogen Synthase Kinase-3 Inhibitors as Potent Therapeutic Agents for the Treatment of Parkinson Disease.

Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. Because the current therapies only lead to temporary, limited improvement and have severe side effects, new approaches to treat PD need to be developed. To discover new targets for potential therapeutic intervention, a chemical genetic approach involving the use of small molecules as pharmacological tools has been implemented. First, a screening of an in-house chemical library on a well-established cellular model of PD was done followed by a detailed pharmacological analysis of the hits. Here, we report the results found for the small heterocyclic derivative called SC001, which after different enzymatic assays was revealed to be a new glycogen synthase kinase-3 (GSK-3) inhibitor with IC(50) = 3.38 ± 0.08 μM. To confirm that GSK-3 could be a good target for PD, the evaluation of a set of structurally diverse GSK-3 inhibitors as neuroprotective agents for PD was performed. Results show that inhibitors of GSK-3 have neuroprotective effects in vitro representing a new pharmacological option for the disease-modifying treatment of PD. Furthermore, we show that SC001 is able to cross the blood-brain barrier, protects dopaminergic neurons, and reduces microglia activation in in vivo models of Parkinson disease, being a good candidate for further drug development.

Melatonin as a Neuroprotective Agent in the Rodent Models of Parkinson’s Disease: Is it All Set to Irrefutable Clinical Translation?

Parkinson's disease (PD), a neurodegenerative disorder, is characterized by the selective degeneration of the nigrostriatal dopaminergic neurons, continuing or permanent deficiency of dopamine, accretion of an abnormal form of alpha synuclein in the adjacent neurons, and dysregulation of ubiquitin proteasomal system, mitochondrial metabolism, permeability and integrity, and cellular apoptosis resulting in rigidity, bradykinesia, resting tremor, and postural instability. Melatonin, an indoleamine produced almost in all the organisms, has anti-inflammatory, anti-apoptotic, and anti-oxidant nature. Experimental studies employing 1-methyl 4-phenyl 1, 2, 3, 6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), methamphetamine, rotenone, and maneb and paraquat models have shown an enormous potential of melatonin in amelioration of the symptomatic features of PD. Although a few reviews published previously have described the multifaceted efficacy of melatonin against MPTP and 6-OHDA rodent models, due to development and validation of the newer models as well as the extensive studies on the usage of melatonin in entrenched PD models, it is worthwhile to bring up to date note on the usage of melatonin as a neuroprotective agent in PD. This article presents an update on the usage and applications of melatonin in PD models along with incongruous observations. The impending implications in the clinics, success, limitations, and future prospective have also been discussed in this article.

Transgenic expression and activation of PGC-1α protect dopaminergic neurons in the MPTP mouse model of Parkinson’s disease

Mitochondrial dysfunction and oxidative stress occur in Parkinson's disease (PD), but little is known about the molecular mechanisms controlling these events. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) is a transcriptional coactivator that is a master regulator of oxidative stress and mitochondrial metabolism. We show here that transgenic mice overexpressing PGC-1α in dopaminergic neurons are resistant against cell degeneration induced by the neurotoxin MPTP. The increase in neuronal viability was accompanied by elevated levels of mitochondrial antioxidants SOD2 and Trx2 in the substantia nigra of transgenic mice. PGC-1α overexpression also protected against MPTP-induced striatal loss of dopamine, and mitochondria from PGC-1α transgenic mice showed an increased respiratory control ratio compared with wild-type animals. To modulate PGC-1α, we employed the small molecular compound, resveratrol (RSV) that protected dopaminergic neurons against the MPTP-induced cell degeneration almost to the same extent as after PGC-1α overexpression. As studied in vitro, RSV activated PGC-1α in dopaminergic SN4741 cells via the deacetylase SIRT1, and enhanced PGC-1α gene transcription with increases in SOD2 and Trx2. Taken together, the results reveal an important function of PGC-1α in dopaminergic neurons to combat oxidative stress and increase neuronal viability. RSV and other compounds acting via SIRT1/PGC-1α may prove useful as neuroprotective agents in PD and possibly in other neurological disorders.

Neuroprotection and imaging studies in Parkinson's disease

The most challenging issue when testing putative neuroprotective agents for Parkinson's disease (PD) in clinical trials is the assessment of the effect of the treatment on the neurodegenerative process. By measuring changes in symptoms severity, clinical rating scales represent an important tool to rate the progression of the disease. However, the rating of clinical symptoms is dependent on the examiner and the neuroprotective effect can be masked by the symptomatic effect of the therapy. 18 f-dopa PET and 123 I-β-CIT SPECT have been shown to be able to monitor the progressive loss of presynaptic nigrostriatal projections in PD and have been used as surrogate biomarkers of disease in several recent clinical trials. In this article the value of imaging as a biomarker for testing neuroprotective agents in PD is reviewed.

Neuroprotection in Parkinson's disease

A major focus in Parkinson's disease (PD) research is to produce drugs or other interventions that can slow or stop clinical progression. This should include an effect on both motor and non-motor symptoms and so target dopaminergic and non-dopaminergic pathways. It is logical to assume that the best chance of developing such therapies will be based on forming a better understanding of the aetiology and pathogenesis of PD and to identify critical molecular targets. There have been great advances in finding different genetic causes and risk factors for PD, but less so in the discovery of environmental contributions. The separate genetic causes still share common pathways to cell dysfunction and death, and these interconnect at several levels. Despite the major advances in genetics and PD pathogenesis, we still do not have good models of PD that can be used with confidence to accurately predict the effect of drugs on disease progression. Clinical trial design and study population selection are also areas that represent significant challenges to testing any putative neuro-protective agent. Several drugs have attracted attention as potential neuroprotective agents in PD. There are numerous studies demonstrating beneficial effects in the laboratory, but clinical efficacy for neuroprotection remains unproven.

Neuroimaging in Parkinson's Disease

In this review, the potential role of positron emission tomography and single photon emission computed tomography as biological markers for diagnosing and following the progression of Parkinson's disease (PD) is discussed. Their value for assessing the efficacy of putative neuroprotective agents in PD and for revealing the pharmacological changes underlying the symptomatology and complications of this disorder is also considered. It is concluded that in the future functional imaging will provide a valuable adjunct to clinical assessment when judging the efficacy of putative neuroprotective approaches to PD.

Minocycline: neuroprotective mechanisms in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by cardinal features of tremor, bradykinesia, rigidity and postural instability. In addition to the motor symptoms patients experience cognitive decline eventually resulting in severe disability. Pathologically PD is characterized by neurodegeneration in the substantia nigra pars compacta (SNc) with intracytoplasmic inclusions known as Lewy bodies. In addition to the SNc there is neurodegeneration in other areas including cerebral cortex, raphe nuclei, locus ceruleus, nucleus basalis of meynert, cranial nerves and autonomic nervous system. Recent evidence supports the role of inflammation in Parkinson's disease. Apoptosis has been shown to be one of the pathways of cell death in PD. Minocycline, a tetracycline derivative is a caspase inhibitor, and also inhibits the inducible nitric oxide synthase which are important for apoptotic cell death. Furthermore, Minocycline has been shown to block microglial activation of 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonism animal models and protect against nigrostriatal dopaminergic neurodegeneration. In this review, we present the current experimental evidence for the potential use of tetracycline derivative, minocycline, as a neuroprotective agent in PD.

Bioenergetic approaches for neuroprotection in Parkinson's disease

There is considerable evidence suggesting that mitochondrial dysfunction and oxidative damage may play a role in the pathogenesis of Parkinson's disease (PD). This possibility has been strengthened by recent studies in animal models, which have shown that a selective inhibitor of complex I of the electron transport gene can produce an animal model that closely mimics both the biochemical and histopathological findings of PD. Several agents are available that can modulate cellular energy metabolism and that may exert antioxidative effects. There is substantial evidence that mitochondria are a major source of free radicals within the cell. These appear to be produced at both the iron-sulfur clusters of complex I as well as the ubiquinone site. Agents that have shown to be beneficial in animal models of PD include creatine, coenzyme Q(10), Ginkgo biloba, nicotinamide, and acetyl-L-carnitine. Creatine has been shown to be effective in several animal models of neurodegenerative diseases and currently is being evaluated in early stage trials in PD. Similarly, coenzyme Q(10) is also effective in animal models and has shown promising effects both in clinical trials of PD as well as in clinical trials in Huntington's disease and Friedreich's ataxia. Many other agents show good human tolerability. These agents therefore are promising candidates for further study as neuroprotective agents in PD.

Imaging end points for monitoring neuroprotection in Parkinson's disease.

In this review, the potential role of positron emission tomography and single-photon emission computed tomography as biological markers for following the progression of Parkinson's disease (PD) is discussed, and their value for assessing the efficacy of putative neuroprotective agents in PD is considered. It is concluded that functional imaging provides a valuable adjunct to clinical assessment when judging the efficacy of neuroprotective approaches to PD.

Monitoring neuroprotection and restorative therapies in Parkinson's disease with PET.

In this article the role of functional imaging (PET and SPECT) as a surrogate marker for following the progression of Parkinson's disease (PD) is discussed. The potential value of PET and SPECT for assessing the efficacy of putative neuroprotective agents in PD is considered and a review of 18F-dopa PET findings in transplantation trials involving implantation of human and procine fetal mesencephalic tissue is presented. It is concluded that functional imaging provides a valuable adjunct to clinical assessment when judging the efficacy of neuroprotective and restorative approaches to PD.

Selective MAO-A and B inhibitors, radical scavengers and nitric oxide synthase inhibitors in Parkinson's desease

In the absence of identification of either an endogenously or an exogenously derived dopaminergic neurotoxin, the most valid hypothesis currently envisaged for etiopathology of Parkinson's disease (PD) is selective oxidative stress (OS) in substantia nigra (SN). Although OS is not proven, a significant body of evidence from studies on animal and Parkinsonian brain neurochemistry supports it. This hypothesis is based on excessive formation of reactive oxygen species (O 2 and OH.) and demise of systems involved with scavenging or preventing the formation of such radicals from H 2O 2, generated as a consequence of dopamine oxidation (autoxidation and deamination). Since MAO (monoamine oxidase A and B are the major H 2O 2 generating enzymes in the SN much attention has been paid to their selective inhibitors as symptomatic and neuroprotective agents in PD. Attention should also be given to radical scavengers (e.g. iron chelators, lipid peroxidative inhibitors and Vitamin E derivatives) as therapeutic neuroprotective agents in PD. This is considered valid since a significant elevation of iron is known to occur selectively in SN zone compacta and within the remaining melanized dopamine neurons of Parkinsonian brains. Although all the mechanism of iron induced oxygen free radical formation is not fully known there is no doubt that it participates with H 2O 2 (Fenton chemistry) to generate cytotoxic hydroxyl radical (OH.) and induce tissue OS and neurodegeneration in 6-hydroxydopamine model of PD. The dramatic proliferation of reactive amoeboid macrophages and microglia seen in SN of PD brains together with OS is highly compatible with an inflammatory process, similar to what has been observed in Alzheimer's disease and multiple sclerosis brains. This has led us to examine the ability of reactive macrophages to produce oxygen free radicals in response to nitric oxide (NO) production. The latter radical has been implicated in the excitotoxicity of glutaminergic neurons innervating the striatum and SN. Indeed we have now observed that in reactive macrophages NO acts as a signal transducer of O 2 production which can synergize with dopamineoxidation.