ubiquinone and Parkinsonian-Disorders

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the core symptoms such as bradykinesia, resting tremor, rigidity and postural instability. Currently, pharmacotherapy and surgical approaches for the treatments of PD can only improve the neurological symptoms. Therefore, to search neuroprotective therapies using pharmacological and nonpharmacological approaches could be important to delay the progression of pathogenesis in PD. Coenzyme Q10 (CoQ10) is a component of the electron transport chain as well as an important antioxidant in mitochondrial and lipid membranes. The central role of CoQ10 in two areas implicated in the pathogenesis of PD, mitochondrial dysfunction and oxidative damages, suggest that it may be useful for treatment to slow the progression of PD. The neuroprotective effect of CoQ10 has been reported in several in vivo and in vitro models of neurodegenerative disorders. Although CoQ10 attenuated the toxin-induced reduction of dopamine content and tyrosine hydroxylase-immunoreactive neurons in the striatum of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model, it is still unknown how this nutrition affects the mitochondrial function. We demonstrated that oral administration of CoQ10 significantly attenuated the loss of dopaminergic nerve terminals induced by MPTP treatment. Furthermore, our experimental data indicate that an inhibition of mitochondrial cytochrome c release is one of the primary targets for CoQ10 and may lead to a potent neuroprotection.

Topics: Animals; Disease Progression; Dopaminergic Neurons; Mice; Mitochondria; Parkinsonian Disorders; Ubiquinone

Topics: Animals; Cardenolides; Disease Models, Animal; Female; Fish Proteins; Gene Expression; Locomotion; Male; Mitochondria; Neuroprotective Agents; Organophosphorus Compounds; Parkinson Disease; Parkinsonian Disorders; Rotenone; Synucleins; Ubiquinone; Zebrafish

Parkinson's disease is a neurodegenerative disorder, and no treatment has been yet established to prevent disease progression. Coenzyme Q10, an antioxidant, has been considered a promising neuroprotective agent; however, conventional oral administration provides limited efficacy due to its very low bioavailability. In this study, we hypothesised that continuous, intrastriatal administration of a low dose of Coenzyme Q10 could effectively prevent dopaminergic neuron degeneration. To this end, a Parkinson's disease rat model induced by 6-hydroxydopamine was established, and the treatment was applied a week before the full establishment of this disease model. Behavioural tests showed a dramatically decreased number of asymmetric rotations in the intrastriatal Coenzyme Q10 group compared with the no treatment group. Rats with intrastriatal Coenzyme Q10 exposure also exhibited a larger number of dopaminergic neurons, higher expression of neurogenetic and angiogenetic factors, and less inflammation, and the effects were more prominent than those of orally administered Coenzyme Q10, although the dose of intrastriatal Coenzyme Q10 was 17,000-times lower than that of orally-administered Coenzyme Q10. Therefore, continuous, intrastriatal delivery of Coenzyme Q10, especially when combined with implantable devices for convection-enhanced delivery or deep brain stimulation, can be an effective strategy to prevent neurodegeneration in Parkinson's disease.

Topics: Administration, Oral; Animals; Apomorphine; Corpus Striatum; Dopaminergic Neurons; Dose-Response Relationship, Drug; Down-Regulation; Inflammation; Infusion Pumps, Implantable; Infusions, Parenteral; Male; Neovascularization, Physiologic; Neurogenesis; Neuroprotective Agents; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha; Tyrosine 3-Monooxygenase; Ubiquinone

Background The physiopathologies of many neurologic diseases are characterized by related biochemical dysfunctions that could be explored as drug targets. This study evaluated the effect of a methanol leaf extract of Antiaris africana (MEA) on critical bioindices of Parkinsonism and related neurologic dysfunctions in rats with rotenone-induced neurotoxicity. Methods Animals were administered 50 or 100 mg/kg MEA for 14 consecutive days. Rotenone (1.5 mg/kg) was administered three times per day on days 13 and 14. Coenzyme Q10 (5 mg/kg) was the reference drug. Complex I activity, dopamine level, activities of acetylcholinesterase, myeloperoxidase, Na+/K+ ATPase and glutamine synthetase, as well as oxidative stress indices were evaluated at the end of the period of treatment. Results Rotenone-intoxicated group showed disruption of complex 1 activity, dopamine level, and glutamine synthetase activity with negative alterations to activities of acetylcholinesterase, myeloperoxidase, and Na+/K+ ATPase as well as heightened cerebral oxidative stress. MEA restored brain mitochondria functionality, mitigated altered neurochemical integrity, and ameliorated cerebral oxidative stress occasioned by rotenone neurotoxicity. The activity of A. Africana was comparable with that of 5 mg/kg coenzyme Q10. Conclusions These results indicated that A. africana displayed therapeutic potential against Parkinsonism and related neurologic dysfunctions and support its ethnobotanical use for the treatment of neurologic disorders.

Topics: Acetylcholinesterase; Animals; Antiaris; Dopamine; Glutamate-Ammonia Ligase; Male; Mitochondria; Nervous System Diseases; Neuroprotective Agents; Oxidative Stress; Parkinsonian Disorders; Peroxidase; Plant Extracts; Rats; Rats, Wistar; Rotenone; Sodium-Potassium-Exchanging ATPase; Ubiquinone

Prions are proteins that adopt alternative conformations that become self-propagating; the PrP(Sc) prion causes the rare human disorder Creutzfeldt-Jakob disease (CJD). We report here that multiple system atrophy (MSA) is caused by a different human prion composed of the α-synuclein protein. MSA is a slowly evolving disorder characterized by progressive loss of autonomic nervous system function and often signs of parkinsonism; the neuropathological hallmark of MSA is glial cytoplasmic inclusions consisting of filaments of α-synuclein. To determine whether human α-synuclein forms prions, we examined 14 human brain homogenates for transmission to cultured human embryonic kidney (HEK) cells expressing full-length, mutant human α-synuclein fused to yellow fluorescent protein (α-syn140*A53T-YFP) and TgM83(+/-) mice expressing α-synuclein (A53T). The TgM83(+/-) mice that were hemizygous for the mutant transgene did not develop spontaneous illness; in contrast, the TgM83(+/+) mice that were homozygous developed neurological dysfunction. Brain extracts from 14 MSA cases all transmitted neurodegeneration to TgM83(+/-) mice after incubation periods of ∼120 d, which was accompanied by deposition of α-synuclein within neuronal cell bodies and axons. All of the MSA extracts also induced aggregation of α-syn*A53T-YFP in cultured cells, whereas none of six Parkinson's disease (PD) extracts or a control sample did so. Our findings argue that MSA is caused by a unique strain of α-synuclein prions, which is different from the putative prions causing PD and from those causing spontaneous neurodegeneration in TgM83(+/+) mice. Remarkably, α-synuclein is the first new human prion to be identified, to our knowledge, since the discovery a half century ago that CJD was transmissible.

Topics: Aged; alpha-Synuclein; Animals; Brain; Exons; Female; HEK293 Cells; Humans; Immunohistochemistry; Male; Mice; Mice, Transgenic; Microscopy, Fluorescence; Middle Aged; Multiple System Atrophy; Neurodegenerative Diseases; Parkinsonian Disorders; Phosphorylation; Polymorphism, Single Nucleotide; Prions; Ubiquinone

Topics: Aged; Amino Acid Substitution; AMP Deaminase; Atorvastatin; Biopsy; Causality; Creatine Kinase, MM Form; Exercise Tolerance; Female; Heptanoic Acids; Homozygote; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Liver-Specific Organic Anion Transporter 1; Mitochondria, Muscle; Models, Genetic; Muscle, Skeletal; Mutation, Missense; Myalgia; Organic Anion Transporters; Parkinsonian Disorders; Point Mutation; Polymorphism, Single Nucleotide; Purine-Pyrimidine Metabolism, Inborn Errors; Pyrroles; Ubiquinone

Parkinson's disease (PD) is marked by widespread neurodegeneration in the brain in addition to a selective yet prominent and progressive loss of nigrostriatal dopaminergic neurons. Of the multiple theories suggested in the pathogenesis of PD, mitochondrial dysfunction takes a center stage in both sporadic and familial forms of illness. Deficits in mitochondrial functions due to impaired bioenergetics, aging associated increased generation of reactive oxygen species, damage to mitochondrial DNA, impaired calcium buffering, and alterations in mitochondrial morphology may contribute to improper functioning of the CNS leading to neurodegeneration. These mitochondrial alterations suggest that a potential target worth exploring for neuroprotective therapies are the ones that can preserve mitochondrial functions in PD. Here, we provide a recent update on potential drugs that are known to block mitochondrial dysfunctions in various experimental models and those that are currently under clinical trials for PD. We also review novel mitochondrial survival pathways that provide hope and promise for innovative neuroprotective therapies in the future that can be explored as possible therapeutic intervention for PD pathogenesis.

Topics: Animals; Creatine; Humans; Mitochondria; Parkinsonian Disorders; Ubiquinone

The objective of this study was to assess the neuroprotective effects of a mitochondria-targeted antioxidant, Mito-Q(10), the coenzyme-Q analog attached to a triphenylphosphonium cation that targets the antioxidant to mitochondria, in experimental models of Parkinson's disease (PD). Primary mesencephalic neuronal cells and cultured dopaminergic cells were treated with 1-methyl-4-phenylpyridinium (MPP(+)), an active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and mice were used for testing the efficacy of Mito-Q(10). MPP(+) treatment caused a dose-dependent loss of tyrosine hydroxylase and membrane potential and an increase in caspase-3 activation in dopaminergic cells, which were reversed by Mito-Q(10). MPTP treatment induced a loss of striatal dopamine and its metabolites, inactivation of mitochondrial aconitase in the substantia nigra, and a loss of locomotor activity in mice. Treatment with Mito-Q(10) significantly inhibited both MPP(+)- and MPTP-induced neurotoxicity in cell culture and mouse models. Collectively, these results indicate that mitochondrial targeting of antioxidants is a promising neuroprotective strategy in this preclinical mouse model of PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Cells, Cultured; Cytoprotection; Disease Models, Animal; Dopamine; Drug Delivery Systems; Drug Evaluation, Preclinical; Male; Mice; Mitochondria; Neurons; Neuroprotective Agents; Neurotoxins; Organophosphorus Compounds; Osmolar Concentration; Parkinsonian Disorders; Rats; Ubiquinone

Parkinson's disease (PD) is the most common movement disorder. Extrapyramidal motor symptoms stem from the degeneration of the dopaminergic pathways in patient brain. Current treatments for PD are symptomatic, alleviating disease symptoms without reversing or retarding disease progression. Although the cause of PD remains unknown, several pathogenic factors have been identified, which cause dopaminergic neuron (DN) death in the substantia nigra (SN). These include oxidative stress, mitochondrial dysfunction, inflammation and excitotoxicity. Manipulation of these factors may allow the development of disease-modifying treatment strategies to slow neuronal death. Inhibition of DJ-1A, the Drosophila homologue of the familial PD gene DJ-1, leads to oxidative stress, mitochondrial dysfunction, and DN loss, making fly DJ-1A model an excellent in vivo system to test for compounds with therapeutic potential.. In the present study, a Drosophila DJ-1A model of PD was used to test potential neuroprotective drugs. The drugs applied are the Chinese herb celastrol, the antibiotic minocycline, the bioenergetic amine coenzyme Q10 (coQ10), and the glutamate antagonist 2,3-dihydroxy-6-nitro-7-sulphamoylbenzo[f]-quinoxaline (NBQX). All of these drugs target pathogenic processes implicated in PD, thus constitute mechanism-based treatment strategies. We show that celastrol and minocycline, both having antioxidant and anti-inflammatory properties, confer potent dopaminergic neuroprotection in Drosophila DJ-1A model, while coQ10 shows no protective effect. NBQX exerts differential effects on cell survival and brain dopamine content: it protects against DN loss but fails to restore brain dopamine level.. The present study further validates Drosophila as a valuable model for preclinical testing of drugs with therapeutic potential for neurodegenerative diseases. The lower cost and amenability to high throughput testing make Drosophila PD models effective in vivo tools for screening novel therapeutic compounds. If our findings can be further validated in mammalian PD models, they would implicate drugs combining antioxidant and anti-inflammatory properties as strong therapeutic candidates for mechanism-based PD treatment.

Topics: Age Factors; Animals; Animals, Genetically Modified; Anti-Inflammatory Agents; Antioxidants; Brain; Cell Count; Cell Survival; Chromatography, High Pressure Liquid; Dopamine; Drosophila; Drug Evaluation, Preclinical; Excitatory Amino Acid Antagonists; Immunohistochemistry; Neurons; Neuroprotective Agents; Oxidative Stress; Parkinsonian Disorders; Pentacyclic Triterpenes; Quinoxalines; Triterpenes; Ubiquinone

We studied the influence of antioxidants (trolox, melatonin and coenzyme Q10) on 6-hydroxydopamine-induced degeneration in the substantia nigra dopaminergic neurons from the left brain hemisphere. In rats, the level of unilateral degeneration of nigrostriatal dopaminergic system was estimated on the base of an intensity of rotation movements which were contralateral to denervated hemishere and resulted from systemic injections of a dopamine receptor agonist apomorphine. It has been shown that all tested antioxidants reduced a number of animals with apomorphine-induced behavioral asymmetry in a different degree: coenzyme Q10 reduced it twofold, trolox - fivefold and melatonin - sevenfold. We suggest that a neuroprotective effects of trolox, melatonin and coenzyme Q10 are associated with their ability to block the mitochondrial pore openings in the nervous cells under exploration, and this is the way to prevent apoptotic death. An oxidative stress has been proved to take part in the apoptosis in dopamine-producing neurons in the substantia nigra, and tested antioxidants have been shown to be effective in preventing neurodegeneration.

Topics: Animals; Antioxidants; Behavior, Animal; Chromans; Disease Models, Animal; Dopamine; Male; Melatonin; Neurons; Oxidative Stress; Oxidopamine; Parkinsonian Disorders; Rats; Rats, Inbred WKY; Substantia Nigra; Ubiquinone

Current treatment options for parkinsonism as a neurodegenerative disease are limited and still mainly symptomatic and lack significant disease-modifying effect. Understanding its molecular pathology and finding the cause of dopaminergic cell loss will lead to exploring therapies that could prevent and cure the disease. Mitochondrial dysfunction was found to stimulate releasing of reactive oxygen species (ROS) with subsequent induction of apoptotic neuronal cell death. The aim of the present study was to throw the light on the role of coenzyme Q10 with or without L-dopa in an experimental model of parkinsonism induced by rotenone in rats. The present work showed that rotenone (2.5 mg/kg/day i.p. for 60 days) induced a model of parkinsonism (group II) resembling the basic findings in human characterized by bradykinesia and rigidity manifested as an increase in catalepsy score (detected after 20 days with bad prognosis after 60 days) with marked decrease in striatal dopamine levels. This model confirmed the implication of mitochondrial-apoptotic pathway in the pathogenesis of parkinsonism as there was a decrease in levels of striatal complex I activity and ATP as well as extreme overexpression of the antiapoptotic protein Bcl-2, and also exhibited the role of coenzyme Q10 where its plasma and striatal levels were found to be decreased in comparison to the normal control rats (group I). This proposed pathogenesis was evidenced by the significant correlation between catalepsy score and the neurochemical parameters obtained in the current work. The treated groups started to receive the drug(s) after 20 days from induction of parkinsonism and continued to complete for 60 days. Oral administration of Co Q10 in a low dose 200 mg/kg/day (group III) or a high dose 600 mg/kg/day (group IV), resulted in amelioration of the mitochondrial induced apoptosis by dose-dependent restoration of striatal complex I activity, ATP levels with temperate increase in expression of Bcl-2 as well as decrease in catalepsy score. Although both low and high doses of Co Q10 resulted in significant increase in its plasma and striatal levels, but only the high dose was shown to reach the recommended therapeutic levels. As a current replacement therapy, oral administration of levodopa 10 mg/kg/day (group V), caused symptomatic improvement in the form of reduction of catalepsy score with restoration of striatal dopamine levels, but it did not show any significant effects on either striatal c

Topics: Adenosine Triphosphate; Analysis of Variance; Animals; Antiparkinson Agents; Behavior, Animal; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Levodopa; Mitochondria; NAD; Neurons; Parkinsonian Disorders; Proto-Oncogene Proteins c-bcl-2; Psychomotor Performance; Rats; Rotenone; Spectrophotometry; Ubiquinone; Ultrasonography; Vitamins

Coenzyme Q10 (CoQ10) is a promising agent for neuroprotection in neurodegenerative diseases. We tested the effects of various doses of two formulations of CoQ10 in food and found that administration in the diet resulted in significant protection against loss of dopamine (DA), which was accompanied by a marked increase in plasma concentrations of CoQ10. We further investigated the neuroprotective effects of CoQ10, reduced CoQ10 (ubiquinol), and CoQ10 emulsions in the (MPTP) model of Parkinson's disease (PD). We found neuroprotection against MPTP induced loss of DA using both CoQ10, and reduced CoQ10, which produced the largest increases in plasma concentrations. Lastly, we administered CoQ10 in the diet to test its effects in a chronic MPTP model induced by administration of MPTP by Alzet pump for 1 month. We found neuroprotective effects against DA depletion, loss of tyrosine hydroxylase neurons and induction of alpha-synuclein inclusions in the substantia nigra pars compacta. The finding that CoQ10 is effective in a chronic dosing model of MPTP toxicity, is of particular interest, as this may be more relevant to PD. These results provide further evidence that administration of CoQ10 is a promising therapeutic strategy for the treatment of PD.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animal Feed; Animals; Coenzymes; Disease Models, Animal; Dopamine; Drug Interactions; Male; Mice; Neurons; Neuroprotective Agents; Neurotoxins; Oxidation-Reduction; Parkinsonian Disorders; Ubiquinone; Vitamins

Incidence of Parkinson's disease is lower in women as compared with men. Although neuroprotective effect of estrogen is recognized, the underlying molecular mechanisms are unclear. MPTP (1-methyl-4-phenyl-1, 2, 3, 6, tetrahydro-pyridine), a neurotoxin that causes Parkinson's disease-like symptoms acts through inhibition of mitochondrial complex I. Administration of MPTP to male mice results in loss of dopaminergic neurons in substantia nigra, whereas female mice are unaffected. Oxidation of critical thiol groups by MPTP disrupts mitochondrial complex I, and up-regulation of glutaredoxin (a thiol disulfide oxidoreductase) is essential for recovery of complex I. Early events following MPTP exposure, such as increased AP1 transcription, loss of glutathione, and up-regulation of glutaredoxin mRNA is seen only in male mice, indicating that early response to neurotoxic insult does not occur in females. Pretreatment of female mice with ICI 182,780, estrogen receptor (ER) antagonist sensitizes them to MPTP-mediated complex I dysfunction. Constitutive expression of glutaredoxin is significantly higher in female mice as compared with males. ICI 182,780 down-regulates glutaredoxin activity in female mouse brain regions (midbrain and striatum), indicating that glutaredoxin expression is regulated through estrogen receptor signaling. Higher constitutive expression of glutaredoxin could potentially contribute to the neuroprotection seen in female mouse following exposure to neurotoxins, such as MPTP.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Corpus Striatum; Dopamine; Electron Transport Complex I; Estradiol; Estrogen Antagonists; Estrogens; Female; Fulvestrant; Glutaredoxins; Glutathione; Male; Mesencephalon; Mice; Mitochondria; Nerve Tissue Proteins; Neurotoxins; Oxidoreductases; Parkinsonian Disorders; Receptors, Estrogen; Sex Characteristics; Tyrosine 3-Monooxygenase; Ubiquinone

Parkinson's disease is characterized by dopamine cell loss of the substantia nigra. Parkinson's disease and the neurotoxin 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine may destroy dopamine neurons through oxidative stress. Coenzyme Q is a cofactor of mitochondrial uncoupling proteins that enhances state-4 respiration and eliminate superoxides. Here we report that short-term oral administration of coenzyme Q induces nigral mitochondrial uncoupling and prevents dopamine cell loss after 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine administration in monkeys.

Topics: Animals; Cell Count; Cell Respiration; Chlorocebus aethiops; Disease Models, Animal; Dopamine; Gene Expression; Ion Channels; Male; Membrane Transport Proteins; Mitochondria; Mitochondrial Proteins; Parkinsonian Disorders; Proteins; RNA, Messenger; Substantia Nigra; Ubiquinone; Uncoupling Agents; Uncoupling Protein 2