phenanthrenes and Parkinson-Disease

Topics: Alzheimer Disease; Animals; Diterpenes; Epoxy Compounds; Humans; Medicine, Chinese Traditional; Molecular Conformation; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease; Pentacyclic Triterpenes; Phenanthrenes; Phytotherapy; Tripterygium; Triterpenes

Parkinson's disease (PD) is a type of motor system disorder that results from the progressive loss of dopaminergic (DAergic) neurons in the substantia nigra (SN) of the midbrain. It is one of the most common neurodegenerative disorders, with an incidence that is second only to Alzheimer's disease (AD). Although replacement of dopamine can temporarily alleviate the symptoms of PD patients, it can not prevent the progression of the disease. Increasing evidence has suggested that neuroinflammation significantly contributes to the progress of PD. Therefore, anti-inflammatory therapy could represent a promising neuroprotective intervention with the potential to delay or prevent onset of the disease. This review summarizes several novel potential agents/candidates that might open new avenues for the treatment of PD. In addition to possessing demonstrated anti-inflammatory activities that operate through different molecular mechanisms, these agents exert neuroprotective effects by enhancing the production of neurotrophic factors or interfering with the apoptosis of neurons.

Topics: Animals; Anti-Inflammatory Agents; Brain; Cytoprotection; Diterpenes; Encephalitis; Epoxy Compounds; Glatiramer Acetate; Humans; Microglia; Minocycline; Neuroprotective Agents; Parkinson Disease; Peptides; Phenanthrenes

In China, it has been estimated that there are more than 2.0 million people suffering from Parkinson's disease, which is currently becoming one of the most common chronic neurodegenerative disorders during recent years. For many years, scientists have struggled to find new therapeutic approaches for this disease. Since 1994, our research group led by Drs. Ji-Sheng Han and Xiao-Min Wang of Neuroscience Research Institute, Peking University has developed several prospective treatment strategies for the disease. These studies cover the traditional Chinese medicine-herbal formula or acupuncture, and modern technologies such as gene therapy or stem cell replacement therapy, and have achieved some original results. It hopes that these data may be beneficial for the research development and for the future clinical utility for treatment of Parkinson's disease.

Topics: Animals; Diterpenes; Electroacupuncture; Epoxy Compounds; Genetic Therapy; Glutamate Decarboxylase; Humans; Medicine, Chinese Traditional; Parkinson Disease; Phenanthrenes; Stem Cell Transplantation

Parkinson's disease (PD) is a degenerative neurological disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) of the brain. The loss of the dopaminergic projection from the SNpc deprives the striatum of dopamine and results in a myriad of motor signs, including tremor, rigidity and ataxia. Although the stimulus for the initiation of the degenerative process is not understood, 80% of the dopaminergic neurons in the SNpc must be lost before the clinical symptoms of the disease are observed. This suggests that the degenerative process is initiated many years before clinical presentation of the disease. The neurodegeneration observed in PD is accompanied by inflammatory processes, and it has been suggested that anti-inflammatory drugs may be useful in slowing disease progression once the clinical signs of PD have been observed. This review summarizes and evaluates the progress that has been made in this area of research since 2006.

Topics: Animals; Anti-Inflammatory Agents; Benzoates; Bridged-Ring Compounds; Diterpenes; Drug Evaluation, Preclinical; Glucosides; Humans; Inflammation; Monoterpenes; Parkinson Disease; Phenanthrenes; Purines

Cryptotanshinone (CTN) has shown its neuroprotective and anti-inflammatory qualities in non-genetic mouse model of Alzheimer's disease. According to bioinformatics analysis, CTN and Signal Transducer and Activator of Transcription 3 (STAT3) may interact to form a drug-target network. This study was conducted to identify the role of CTN-STAT3 interaction in Parkinson's disease (PD). PD model was established with MMP

Topics: 1-Methyl-4-phenylpyridinium; Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Humans; Mice; Neuroblastoma; Oxidative Stress; Parkinson Disease; Phenanthrenes; STAT3 Transcription Factor

Parkinson's disease (PD) is a well-known age-related neurodegenerative disease. Considering the vital importance of disease modeling based on reprogramming technology, we adopted direct reprogramming to human-induced neuronal progenitor cells (hiNPCs) for in vitro assessment of potential therapeutics. In this study, we investigated the neuroprotective effects of cryptotanshinone (CTN), which has been reported to have antioxidant properties, through PD patient-derived hiNPCs (PD-iNPCs) model with induced oxidative stress and cell death by the proteasome inhibitor MG132. A cytotoxicity assay showed that CTN possesses anti-apoptotic properties in PD-hiNPCs. CTN treatment significantly reduced cellular apoptosis through mitochondrial restoration, such as the reduction in mitochondrial reactive oxygen species and increments of mitochondrial membrane potential. These effects of CTN are mediated via the nuclear factor erythroid 2-related factor 2 (NRF2) pathway in PD-hiNPCs. Consequently, CTN could be a potential antioxidant reagent for preventing disease-related pathological phenotypes of PD.

Topics: Case-Control Studies; Cell Line; Cellular Reprogramming; Gene Expression Regulation; Humans; Induced Pluripotent Stem Cells; Leupeptins; Mitochondria; Neuroprotective Agents; Oxidative Stress; Parkinson Disease; Phenanthrenes

Metabotropic glutamate receptor (mGlu)

Topics: Animals; Cell Line; Disease Models, Animal; Diterpenes; Dopaminergic Neurons; Epoxy Compounds; Inflammation; Interleukin-1beta; Lipopolysaccharides; Macrophage Activation; Male; Mice; Microglia; Nitric Oxide; Nitric Oxide Synthase Type II; Parkinson Disease; Phenanthrenes; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Signal Transduction; Transcriptional Activation; Tumor Necrosis Factor-alpha; Up-Regulation

Dopamine-mediated neurotransmission plays an important role in relevant psychiatric and neurological disorders. Nowadays, there is an enormous interest in the development of new drugs acting at the dopamine receptors (DR) as potential new targets for the treatment of schizophrenia or Parkinson's disease. Previous studies have revealed that isoquinoline compounds such as tetrahydroisoquinolines (THIQs) can behave as selective D2 dopaminergic alkaloids. In the present study we have synthesized five aporphine compounds and five phenanthrene alkaloids and evaluated their potential dopaminergic activity. Binding studies on rat striatal membranes were used to evaluate their affinity and selectivity towards D1 and D2 DR. Phenanthrene type alkaloids, in particular the 3,4-dihydroxy- and 3,4-methylenedioxy derivatives, displayed high selectivity towards D2 DR. Therefore, they are potential candidates to be used in the treatment of schizophrenia (antagonists) or Parkinson's disease (agonists) due to their scarce D1 DR-associated side effects.

Topics: Alkaloids; Animals; Corpus Striatum; Humans; Parkinson Disease; Phenanthrenes; Rats; Receptors, Dopamine D2; Schizophrenia

Treatments based on pharmacological inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) have been suggested for a broad variety of human disorders, including Parkinson's disease (PD). The neuroprotective effects underlying the efficacy of PARP-1 inhibitors in PD models suggest a role for PARP-1 in neurodegeneration. In this study, we assessed the efficacy of PARP-1 inhibition in two distinct PD models. First, we tested a panel of small molecule PARP-1 inhibitors in alpha-synuclein (aSyn) cytotoxicity assay, where we observed compound-dependent ameliorating effects. Next, we tested the same panel in primary ventral mesencephalic neuronal cultures, treated with MPP(+). Dopaminergic neurons, the primary cells affected in PD, were selected and subjected to analysis. A significant ameliorating effect was achieved only with a highly potent PARP-1 inhibitor. Our data implicates aberrant PARP-1 function in different pathways of neurodegeneration. Further, our results suggest a rationale for the development of highly potent, bio-available, brain-penetrable PARP-1 inhibitors to provide therapeutic benefits for Parkinson's patients.

Topics: 1-Methyl-4-phenylpyridinium; alpha-Synuclein; Cell Nucleus; Cell Survival; Cells, Cultured; Cytoplasm; Dopamine; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Molecular Structure; Neurons; Neuroprotective Agents; Parkinson Disease; Phenanthrenes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors

To study whether the immunosuppressant tripchlorolide (T4) exerts neuroprotective effect on dopaminergic neurons.. A rat model of Parkinson's disease (PD) was set up by transection of the medial forebrain bundle (MFB) with a wire knife. The rotational behavior, HPLC-ECD, tyrosine hydroxylase (TH) immunocytochemistry, ELISA methods were used to evaluate the influence on the dopaminergic neurons following T4 treatment.. T4 treatment was shown to effectively attenuate the rotational behavior challenged by amphetamine (2.5 mg.kg-1, i.p.) in the PD rats. T4 markedly prevented the decrease of dopamine content in the striatum and the loss of dopaminergic neurons in the substantia nigra pars compacta. T4 was found to suppress the abnormal increase of TNF-alpha and IL-2 level in brain tissues of PD rats after MFB transection.. The evidence that the immunosuppressive Chinese herb extract T4 possesses neuroprotective activities on the dopaminergic neurons in PD rats was presented. The underlying mechanism of T4 may be relevant to its immunosuppressive activity.

Topics: Animals; Behavior, Animal; Brain; Corpus Striatum; Diterpenes; Dopamine; Drugs, Chinese Herbal; Interleukin-2; Male; Neurons; Neuroprotective Agents; Parkinson Disease; Phenanthrenes; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Cell models of neurodegenerative diseases (NDD) can involve expression of mutant nuclear genes associated with Mendelian forms of the diseases or effects of toxins believed to replicate essential disease features. Death produced by exposing neural cells to methylpyridinium ion (MPP(+)) or neurotoxic beta amyloid (BA) peptides is frequently used to study features of the sporadic, most prevalent forms of Parkinson's disease (PD) and Alzheimer's disease (AD), respectively. We examined in replicating SH-SY5Y human neuroblastoma cells the release of cytochrome C into cytoplasm, activation of caspases 9 and 3, and loss of calcein retention as markers of the "mitochondrial" pathway of cell death. Exposure to 5 mM MPP(+), which induces apoptotic cell death within 18-24 hr, released cytochrome C within 4 hr, activated caspases 9 and 3, and reduced calcein accumulation. BA 25-35 peptide produced more rapid and greater elevations of caspase 3 activity; no effects were observed with the nontoxic BA 35-25 reverse sequence. The dependence on mitochondrial transition pore (MTP) activity of MPP(+)-induced caspase activations was demonstrated by preincubation with bongkreckic acid, which blocked elevations of caspases 9 and 3. Stereoisomers of pramipexole (PPX), a free radical scavenger and inhibitor of MTP opening, inhibited caspase activation (MPP(+) and BA) and restored calcein accumulation (MPP(+)). Our results demonstrate that MPP(+) and BA can induce cell death through MTP-dependent activation of caspase cascades. PPX stereoisomers interfere with activation of these cell death pathways and may be useful clinically as neuroprotectants in PD and AD and related diseases.

Topics: 1-Methyl-4-phenylpyridinium; Alzheimer Disease; Amyloid beta-Peptides; Anti-Bacterial Agents; Aristolochic Acids; Benzothiazoles; Bongkrekic Acid; Brain; Caspase Inhibitors; Caspases; Cell Death; Dose-Response Relationship, Drug; Enzyme Inhibitors; Free Radical Scavengers; Humans; Neuroblastoma; Neurodegenerative Diseases; Neurons; Parkinson Disease; Peptide Fragments; Phenanthrenes; Pramipexole; Thiazoles; Tumor Cells, Cultured

Parkinson's disease (PD) is a major cause of age-related morbidity and mortality, present in nearly 1% of individuals at ages 70-79 and approximately 2.5% of individuals at age 85. L-DOPA (L-dihydroxyphenylalanine), which is metabolized to dopamine by dopa decarboxylase, is the primary therapy for PD, but may also contribute to disease progression. Association between mitochondrial dysfunction, monoamine oxidase (MAO) activity, and dopaminergic neurotoxicity has been repeatedly observed, but the mechanisms underlying selective dopaminergic neuron depletion in aging and neurodegenerative disorders remain unclear. We now report that 3,4-dihydroxyphenylacetaldehyde (DOPAL), the MAO metabolite of dopamine, is more cytotoxic in neuronally differentiated PC12 cells than dopamine and several of its metabolites. In isolated, energetically compromised mitochondria, physiological concentrations of DOPAL induced the permeability transition (PT), a trigger for cell death. Dopamine was > 1000-fold less potent. PT inhibitors protected both mitochondria and cells against DOPAL. Sensitivity to DOPAL was reduced > or = 30-fold in fully energized mitochondria, suggesting that mitochondrial respiration may increase resistance to PT induction by the endogenous DOPAL in the substantia nigra. These data provide a potential mechanism of action for L-DOPA-mediated neurotoxicity and suggest two potentially interactive mechanisms for the selective vulnerability of neurons exposed to dopamine.

Topics: 3,4-Dihydroxyphenylacetic Acid; 4-Aminobenzoic Acid; Aminobenzoates; Animals; Aristolochic Acids; Cell Death; Cell Differentiation; Cyclosporine; Dopamine; Dopamine Antagonists; Enzyme Inhibitors; Ion Channels; Male; Membrane Proteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Nerve Growth Factor; para-Aminobenzoates; Parkinson Disease; PC12 Cells; Phenanthrenes; Rats; Rats, Inbred F344; Respiration; Rotenone; Trifluoperazine; Uncoupling Agents