Edaravone guards dopamine neurons in a rotenone model for Parkinson's disease.
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ABSTRACT:
SUBMITTER: Xiong N
PROVIDER: S-EPMC3108992 | biostudies-literature | 2011
REPOSITORIES: biostudies-literature
Publications
Edaravone guards dopamine neurons in a rotenone model for Parkinson's disease.
Xiong Nian N Xiong Jing J Khare Ghanshyam G Chen Chunnuan C Huang Jinsha J Zhao Ying Y Zhang Zhentao Z Qiao Xian X Feng Yuan Y Reesaul Harrish H Zhang Yongxue Y Sun Shenggang S Lin Zhicheng Z Wang Tao T
PloS one 20110603 6
3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), an effective free radical scavenger, provides neuroprotection in stroke models and patients. In this study, we investigated its neuroprotective effects in a chronic rotenone rat model for Parkinson's disease. Here we showed that a five-week treatment with edaravone abolished rotenone's activity to induce catalepsy, damage mitochondria and degenerate dopamine neurons in the midbrain of rotenone-treated rats. This abolishment was attributable at lea ...[more]
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Project description:Parkinson's disease, which is the one of the most common neurodegenerative movement disorder, is characterized by a progressive loss of dopamine containing neurons. The mechanisms underlying disease initiation and development are not well understood and causative therapies are currently not available. To elucidate the molecular processes during early stages of Parkinson's disease, we utilized a Drosophila model. To induce Parkinson's disease-like phenotypes, we treated flies with the pesticide rotenone and isolated dopamine producing neurons of animals that were at an early disease stage. Transcriptomic analyses revealed that gene ontologies associated with regulation of cell death and neuronal functions were significantly enriched. Moreover, the activities of the MAPK/EGFR- and TGF-β signaling pathways were enhanced, while the Wnt pathway was dampened. In order to evaluate the role of Wnt signaling for survival of dopaminergic neurons in the disease model, we rescued the reduced Wnt signaling activity by ectopic overexpression of armadillo/β-catenin. This intervention rescued the rotenone induced movement impairments in the Drosophila model. Taken together, this initial study showed a highly relevant role of Wnt signaling for dopamine producing neurons during pathogenesis in Parkinson's disease and it implies that interfering with this pathway might by a suitable therapeutic option for the future.
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Project description:Parkinson's disease (PD) often displays a strong unilateral predominance in arising symptoms. PD is correlated with dopamine neuron (DAN) degeneration in the substantia nigra pars compacta (SNPC), and in many patients, DANs appear to be affected more severely on one hemisphere than the other. The reason for this asymmetric onset is far from being understood. Drosophila melanogaster has proven its merit to model molecular and cellular aspects of the development of PD. However, the cellular hallmark of the asymmetric degeneration of DANs in PD has not yet been described in Drosophila. We ectopically express human α-synuclein (hα-syn) together with presynaptically targeted syt::HA in single DANs that innervate the Antler (ATL), a symmetric neuropil located in the dorsomedial protocerebrum. We find that expression of hα-syn in DANs innervating the ATL yields asymmetric depletion of synaptic connectivity. Our study represents the first example of unilateral predominance in an invertebrate model of PD and will pave the way to the investigation of unilateral predominance in the development of neurodegenerative diseases in the genetically versatile invertebrate model Drosophila.
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Project description:Impaired mitochondrial function has been associated with the etiopathogenesis of Parkinson's disease (PD). Sustained inhibition of complex I produces mitochondrial dysfunction, which is related to oxidative injury and nigrostriatal dopamine (DA) neurodegeneration. This study aimed to identify disease-modifying treatments for PD. Unsubstituted phenothiazine (PTZ) is a small and uncharged aromatic imine that readily crosses the blood-brain barrier. PTZ lacks significant DA receptor-binding activity and, in the nanomolar range, exhibits protective effects via its potent free radical scavenging and anti-inflammatory activities. Given that DAergic neurons are highly vulnerable to oxidative damage and inflammation, we hypothesized that administration of PTZ might confer neuroprotection in different experimental models of PD. Our findings showed that PTZ rescues rotenone (ROT) toxicity in primary ventral midbrain neuronal cultures by preserving neuronal integrity and reducing protein thiol oxidation. Long-term treatment with PTZ improved animal weight, survival rate, and behavioral deficits in ROT-lesioned rats. PTZ protected DA content and fiber density in the striatum and DA neurons in the SN against the deleterious effects of ROT. Mitochondrial dysfunction, axonal impairment, oxidative insult, and inflammatory response were attenuated with PTZ therapy. Furthermore, we have provided a new insight into the molecular mechanism underlying the neuroprotective effects of PTZ.
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Project description:BackgroundTaste impairments are often accompanied by olfactory impairments in the early stage of Parkinson's disease (PD). The development of animal models is required to elucidate the mechanisms underlying taste impairments in PD.ObjectiveThis study was conducted to clarify whether the intranasal administration of rotenone causes taste impairments prior to motor deficits in mice.MethodsRotenone was administrated to the right nose of mice once a day for 1 or 4 week(s). In the 1-week group, taste, olfactory, and motor function was assessed before and after a 1-week recovery period following the rotenone administration. Motor function was also continuously examined in the 4-weeks group from 0 to 5 weeks. After a behavioral test, the number of catecholamine neurons (CA-Nos) was counted in the regions responsible for taste, olfactory, and motor function.Resultstaste and olfactory impairments were simultaneously observed without locomotor impairments in the 1-week group. The CA-Nos was significantly reduced in the olfactory bulb and nucleus of the solitary tract. In the 4-week group, locomotor impairments were observed from the third week, and a significant reduction in the CA-Nos was observed in the substantia nigra (SN) and ventral tegmental area (VTA) at the fifth week along with the weight loss.ConclusionThe intranasal administration of rotenone caused chemosensory and motor impairments in an administration time-period dependent manner. Since chemosensory impairments were expressed prior to the locomotor impairments followed by SN/VTA CA neurons loss, this rotenone administration model may contribute to the clarification of the prodromal symptoms of PD.
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Project description:BackgroundCognitive decline occurs frequently in Parkinson's disease (PD), which greatly decreases the quality of life of patients. However, the mechanisms remain to be investigated. Neuroinflammation mediated by overactivated microglia is a common pathological feature in multiple neurological disorders, including PD. This study is designed to explore the role of microglia in cognitive deficits by using a rotenone-induced mouse PD model.MethodsTo evaluate the role of microglia in rotenone-induced cognitive deficits, PLX3397, an inhibitor of colony-stimulating factor 1 receptor, and minocycline, a widely used antibiotic, were used to deplete or inactivate microglia, respectively. Cognitive performance of mice among groups was detected by Morris water maze, objective recognition, and passive avoidance tests. Neurodegeneration, synaptic loss, α-synuclein phosphorylation, glial activation, and apoptosis were determined by immunohistochemistry and Western blot or immunofluorescence staining. The gene expression of inflammatory factors and lipid peroxidation were further explored by using RT-PCR and ELISA kits, respectively.ResultsRotenone dose-dependently induced cognitive deficits in mice by showing decreased performance of rotenone-treated mice in the novel objective recognition, passive avoidance, and Morris water maze compared with that of vehicle controls. Rotenone-induced cognitive decline was associated with neurodegeneration, synaptic loss, and Ser129-phosphorylation of α-synuclein and microglial activation in the hippocampal and cortical regions of mice. A time course experiment revealed that rotenone-induced microglial activation preceded neurodegeneration. Interestingly, microglial depletion by PLX3397 or inactivation by minocycline significantly reduced neuronal damage and α-synuclein pathology as well as improved cognitive performance in rotenone-injected mice. Mechanistically, PLX3397 and minocycline attenuated rotenone-induced astroglial activation and production of cytotoxic factors in mice. Reduced lipid peroxidation was also observed in mice treated with combined PLX3397 or minocycline and rotenonee compared with rotenone alone group. Finally, microglial depletion or inactivation was found to mitigate rotenone-induced neuronal apoptosis.ConclusionsTaken together, our findings suggested that microglial activation contributes to cognitive impairments in a rotenone-induced mouse PD model via neuroinflammation, oxidative stress, and apoptosis, providing novel insight into the immunopathogensis of cognitive deficits in PD.
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Project description:Oral rotenone has been proposed as a model for Parkinson's disease (PD) in mice. To establish the model in our lab and study complex behavior we followed a published treatment regimen. C57BL/6 mice received 30 mg/kg body weight of rotenone once daily via oral administration for 4 and 8 weeks. Motor functions were assessed by RotaRod running. Immunofluorescence studies were used to analyze the morphology of dopaminergic neurons, the expression of alpha-Synuclein (α-Syn), and inflammatory gliosis or infiltration in the substantia nigra. Rotenone-treated mice did not gain body weight during treatment compared with about 4 g in vehicle-treated mice, which was however the only robust manifestation of drug treatment and suggested local gut damage. Rotenone-treated mice had no deficits in motor behavior, no loss or sign of degeneration of dopaminergic neurons, no α-Syn accumulation, and only mild microgliosis, the latter likely an indirect remote effect of rotenone-evoked gut dysbiosis. Searching for explanations for the model failure, we analyzed rotenone plasma concentrations via LC-MS/MS 2 h after administration of the last dose to assess bioavailability. Rotenone was not detectable in plasma at a lower limit of quantification of 2 ng/mL (5 nM), showing that oral rotenone had insufficient bioavailability to achieve sustained systemic drug levels in mice. Hence, oral rotenone caused local gastrointestinal toxicity evident as lack of weight gain but failed to evoke behavioral or biological correlates of PD within 8 weeks.
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Project description:Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid, play a crucial role in cytoprotection by attenuating oxidative stress, inflammation and apoptosis. EETs are rapidly metabolised in vivo by the soluble epoxide hydrolase (sEH). Increasing the half life of EETs by inhibiting the sEH enzyme is a novel strategy for neuroprotection. In the present study, sEH inhibitors APAU was screened in silico and further evaluated for their antiparkinson activity against rotenone (ROT) induced neurodegeneration in N27 dopaminergic cell line and Drosophila melanogaster model of Parkinson disease (PD). In the in vitro study cell viability (MTT and LDH release assay), oxidative stress parameters (total intracellular ROS, hydroperoxides, protein oxidation, lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidise, glutathione reductase, glutathione, total antioxidant status, mitochondrial complex-1activity and mitochondrial membrane potential), inflammatory markers (IL-6, COX-1 and COX-2), and apoptotic markers (JNK, phospho-JNK, c-jun, phospho-c-jun, pro and active caspase-3) were assessed to study the neuroprotective effects. In vivo activity of APAU was assessed in Drosophila melanogaster by measuring survival rate, negative geotaxis, oxidative stress parameters (total intracellular ROS, hydroperoxides, glutathione levels) were measured. Dopamine and its metabolites were estimated by LC-MS/MS analysis. In the in silico study the molecule, APAU showed good binding interaction at the active site of sEH (PDB: 1VJ5). In the in vitro study, APAU significantly attenuated ROT induced changes in oxidative, pro-inflammatory and apoptotic parameters. In the in vivo study, APAU significantly attenuates ROT induced changes in survival rate, negative geotaxis, oxidative stress, dopamine and its metabolites levels (p < 0.05). Our study, therefore, concludes that the molecule APAU, has significant neuroprotection benefits against rotenone induced Parkinsonism.
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