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1.
FASEB J ; 34(5): 6570-6581, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32246801

RESUMO

Dysfunction of the circadian rhythm is one of most common nonmotor symptoms in Parkinson's disease (PD), but the molecular role of the circadian rhythm in PD is unclear. We here showed that inactivation of brain and muscle ARNT-like 1 (BMAL1) in 1-methyl-4-phenyl-1,2,4,5-tetrahydropyridine (MPTP)-treated mice resulted in obvious motor functional deficit, loss of dopaminergic neurons (DANs) in the substantia nigra pars compacta (SNpc), decrease of dopamine (DA) transmitter, and increased activation of microglia and astrocytes in the striatum. Time on the rotarod or calorie consumption, and food and water intake were reduced in the Bmal1-/- mice after MPTP treatment, suggesting that absence of Bmal1 may exacerbate circadian and PD motor function. We observed a significant reduction of DANs (~35%) in the SNpc, the tyrosine hydroxylase protein level in the striatum (~60%), the DA (~22%), and 3,4-dihydroxyphenylacetic acid content (~29%), respectively, in MPTP-treated Bmal1-/- mice. Loss of Bmal1 aggravated the inflammatory reaction both in vivo and in vitro. These findings suggest that BMAL1 may play an essential role in the survival of DANs and maintain normal function of the DA signaling pathway via regulating microglia-mediated neuroinflammation in the brain.

2.
Adv Exp Med Biol ; 1206: 221-236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31776988

RESUMO

Epigenetics refers to reversible and hereditary changes in gene expression without alterations in DNA sequences, such as DNA methylation, histone modification and chromatin remodelling. It was first proposed by Waddington in the book Introduction to Modern Genetics in 1939. Autophagy includes at least four processes: autophagy induction, autophagosome formation, autophagosome fusion with lysosomes and lysosomal degradation of cytoplasmic components. The whole process is complex and dynamic, and involves at least 30 autophagy-related proteins. This degradative machinery is regulated by multiple signal molecules. Autophagy was once considered to be a cytoplasmic event; however, in recent years, emerging evidence suggests that nuclear components (transcription factors, histone modification, microRNAs, etc.) also play an important role in autophagy regulation (Baek and Kim 2017). Among them, epigenetic regulation of autophagy has gained much attention. The epigenetic machinery can not only modify autophagy-related genes but also affect some signal molecule genes that regulate autophagy, thus impacting their transcription and subsequent autophagy. This chapter focuses on the role and recent progress in autophagy regulation by DNA methylation and histone modifications. The role of non-coding RNAs such as microRNA in autophagy regulation will be covered in other chapters.


Assuntos
Autofagia , Metilação de DNA , Epigênese Genética , Código das Histonas , Animais , Autofagia/genética , Humanos
3.
Neurotoxicology ; 73: 175-182, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30978411

RESUMO

Olfactory impairment is an early feature of patients with Parkinson's disease (PD). Retrospective epidemiological studies reported lower scores on the University of Pennsylvania Smell Identification Test (UPSIT) in non-smokers than smokers with PD and showed an inverse correlation between susceptibility to PD and a person's history of smoking. But the mechanisms by which cigarettes affect olfaction in PD are not fully understood. So we investigated the effect of nicotine on the olfactory function in 1-methyl-4-phenyl-1, 2, 3, 6 tetrahydropyridine (MPTP)-treated mice. We observed that nicotine improved locomotor activity and protection against dopaminergic neuron loss in the midbrain in MPTP-treated mice. Compared to controls, MPTP-treated mice showed a deficit of odor discrimination and odor detection, which were alleviated by nicotine treatment. But no significant changes were found in olfactory memory in MPTP-treated mice. Moreover, we detected a marked decrease of Choline acetyltransferase (ChAT) expression in the olfactory bulb (OB) in MPTP-treated mice, which was also attenuated by nicotine administration. In addition, nicotine ameliorated the loss of cholinergic neurons and dopaminergic innervation in the horizontal limb of the diagonal band (HDB), which is the primary origin of cholinergic input to the OB. Our results suggested that nicotine could improve the olfactory impairment by protecting cholinergic systems in the OB of MPTP-treated mice. And nicotine protection of cholinergic systems in the OB is relevant to attenuating dopaminergic neuron loss in the midbrain and HDB.

4.
Physiol Plant ; 167(4): 564-584, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30561011

RESUMO

Abrupt drought-flood alternation (T1) is a meteorological disaster that frequently occurs during summer in southern China and the Yangtze river basin, often causing a significant loss of rice production. In this study, the response mechanism of yield decline under abrupt drought-flood alternation stress at the panicle differentiation stage was analyzed by looking at the metabolome, proteome as well as yield and physiological and biochemical indexes. The results showed that drought and flood stress caused a decrease in the yield of rice at the panicle differentiation stage, and abrupt drought-flood alternation stress created a synergistic effect for the reduction of yield. The main reason for the decrease of yield per plant under abrupt drought-flood alternation was the decrease of seed setting rate. Compared with CK0 (no drought and no flood), the net photosynthetic rate and soluble sugar content of T1 decreased significantly and its hydrogen peroxidase, superoxide dismutase, peroxidase activity increased significantly. The identified differential metabolites and differentially expressed proteins indicated that photosynthesis metabolism, energy metabolism pathway and reactive oxygen species response have changed strongly under abrupt drought-flood alteration stress, which are factors that leads to the rice grain yield reduction.

5.
Front Aging Neurosci ; 10: 378, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30515090

RESUMO

Neuroinflammation and autophagy dysfunction are closely related to the development of neurodegeneration such as Parkinson's disease (PD). However, the role of autophagy in microglia polarization and neuroinflammation is poorly understood. TNF-α, which is highly toxic to dopaminergic neurons, is implicated as a major mediator of neuroinflammation in PD. In this study, we found that TNF-α resulted in an impairment of autophagic flux in microglia. Concomitantly, an increase of M1 marker (iNOS/NO, IL-1ß, and IL-6) expression and reduction of M2 marker (Arginase1, Ym1/2, and IL-10) were observed in TNF-α challenged microglia. Upregulation of autophagy via serum deprivation or pharmacologic activators (rapamycin and resveratrol) promoted microglia polarization toward M2 phenotype, as evidenced by suppressed M1 and elevated M2 gene expression, while inhibition of autophagy with 3-MA or Atg5 siRNA consistently aggravated the M1 polarization induced by TNF-α. Moreover, Atg5 knockdown alone was sufficient to trigger microglia activation toward M1 status. More important, TNF-α stimulated microglia conditioned medium caused neurotoxicity when added to neuronal cells. The neurotoxicity was further aggravated when Atg5 knockdown in BV2 cells but alleviated when microglia pretreatment with rapamycin. Activation of AKT/mTOR signaling may contribute to the changes of autophagy and inflammation as the AKT specific inhibitor perifosine prevented the increase of LC3II (an autophagic marker) in TNF-α stimulated microglia. Taking together, our results demonstrate that TNF-α inhibits autophagy in microglia through AKT/mTOR signaling pathway, and autophagy enhancement can promote microglia polarization toward M2 phenotype and inflammation resolution.

6.
Brain Behav Immun ; 73: 603-614, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29981830

RESUMO

Neuroinflammation and excessive ß-amyloid1-42 (Aß1-42) generation contribute to the pathogenesis of Alzheimer's disease (AD). Emerging evidence has demonstrated that hydrogen sulfide (H2S), an endogenous gasotransmitter, produces therapeutic effects in AD; however, the underlying mechanisms remain largely elusive. In the present study, we investigated the effects of H2S on exogenous ATP-induced inflammation and Aß1-42 production in both BV-2 and primary cultured microglial cells and analyzed the potential mechanism(s) mediating these effects. Our results showed that NaHS, an H2S donor, inhibited exogenous ATP-stimulated inflammatory responses as manifested by the reduction of pro-inflammatory cytokines, ROS and activation of nuclear factor-κB (NF-κB) pathway. Furthermore, NaHS also suppressed the enhanced production of Aß1-42 induced by exogenous ATP, which is probably due to its inhibitory effect on exogenous ATP-boosted expression of amyloid precursor protein (APP) and activation of ß- and γ-secretase enzymes. Thereafter, we found that exogenous ATP-induced inflammation and Aß1-42 production requires the activation of signal transducer and activator of transcription 3 (STAT3) and cathepsin S (Cat S) as inhibition of the activity of either proteins attenuated the effect of exogenous ATP. Intriguingly, NaHS suppressed exogenous ATP-induced phosphorylation of STAT3 and the activation of Cat S. In addition, we observed that NaHS led to the persulfidation of Cat S at cysteine-25. Importantly, mutation of cysteine-25 into serine attenuated the activity of Cat S stimulated by exogenous ATP and subsequent inflammation and Aß1-42 production, indicating its involvement in H2S-mediated effect. Taken together, our data provide a novel understanding of H2S-mediated effect on neuroinflammation and Aß1-42 production by suppressing the activation of STAT3 and Cat S.


Assuntos
Sulfeto de Hidrogênio/farmacologia , Microglia/efeitos dos fármacos , Neuroimunomodulação/efeitos dos fármacos , Trifosfato de Adenosina/efeitos adversos , Trifosfato de Adenosina/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Catepsinas/efeitos dos fármacos , Catepsinas/fisiologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Células HEK293 , Humanos , Sulfeto de Hidrogênio/metabolismo , Inflamação , Camundongos , Fragmentos de Peptídeos/efeitos dos fármacos , Fragmentos de Peptídeos/metabolismo , Fosforilação , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/fisiologia , Transdução de Sinais/efeitos dos fármacos , Sulfetos/farmacologia
7.
Oxid Med Cell Longev ; 2018: 4854732, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29849897

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disease and is known to involve circadian dysfunction and oxidative stress. Although antioxidative defense is regulated by the molecular circadian clock, few studies have examined their function in PD and their regulation by silent information regulator 1 (SIRT1). We hypothesize that reduced antioxidative activity in models of PD results from dysfunction of the molecular circadian clock via the SIRT1 pathway. We treated rats and SH-SY5Y cells with 6-hydroxydopamine (6-OHDA) and measured the expression of core circadian clock and associated nuclear receptor genes using real-time quantitative PCR as well as levels of SIRT1, brain and muscle Arnt-like protein 1 (BMAL1), and acetylated BMAL1 using Western blotting. We found that 6-OHDA treatment altered the expression patterns of clock and antioxidative molecules in vivo and in vitro. We also detected an increased ratio of acetylated BMAL1:BMAL1 and a decreased level of SIRT1. Furthermore, resveratrol, an activator of SIRT1, decreased the acetylation of BMAL1 and inhibited its binding with CRY1, thereby reversing the impaired antioxidative activity induced by 6-OHDA. These results suggest that a dysfunctional circadian clock contributes to an abnormal antioxidative response in PD via a SIRT1-dependent BMAL1 pathway.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Antioxidantes/metabolismo , Relógios Circadianos/fisiologia , Doença de Parkinson Secundária/metabolismo , Sirtuína 1/metabolismo , Animais , Relógios Circadianos/efeitos dos fármacos , Masculino , Oxidopamina , Ratos , Ratos Sprague-Dawley
8.
Brain Behav Immun ; 67: 77-90, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28774789

RESUMO

Hydrogen sulfide (H2S), a novel neuromodulator, is linked to the pathogenesis of several neurodegenerative disorders. Exogenous application of H2S exerts neuroprotection via anti-inflammation and anti-oxidative stress in animal and cellular models of Parkinson's disease (PD). However, the role of endogenous H2S and the contribution of its various synthases in PD remain unclear. In the present study, we found a decline of plasma and striatal sulfide level in 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD mouse model. Interestingly, among the three H2S generating enzymes, only cystathionine ß-synthase (CBS) expression was largely reduced in the striatum of MPTP-treated mice. The in vitro study confirmed a significant decrease of CBS expression in 1-methyl-4-phenylpyridinium (MPP+)-stimulated astrocytes and microglia, but not in neurons or SH-SY5Y dopaminergic cells. Striatal CBS overexpression, elicited by stereotaxic delivery with Cbs gene using recombinant adeno-associated-virus (rAAV-Cbs), successfully enhanced the sulfide level in the striatum and partially rescued the MPTP-induced dopaminergic neurotoxicity in the midbrain. Specifically, striatal CBS overexpression alleviated the motor deficits and dopaminergic neuron losses in the nigro-striatal pathway, with a concomitant inhibition of glial activation in MPTP-treated mice. Furthermore, compared to rAAV-Vector, rAAV-Cbs injection reduced the aberrant accumulation of nitric oxide and 3-nitrotyrosine (an indicator of protein nitration) in the striatum of MPTP-treated mice. Notably, it also attenuated the increase of nitrated α-synuclein level in MPTP mice. The in vitro study demonstrated that lentivirus-mediated CBS overexpression elevated the sulfide generation in glial cells. Moreover, glial CBS overexpression offered protection to midbrain dopaminergic neurons through repressing nitric oxide overproduction in both glial and neuronal cells induced by MPP+. Taken together, our data suggest that impaired CBS-H2S axis may contribute to the pathogenesis of PD, and that modulation of this axis may become a novel therapeutic approach for PD.


Assuntos
Corpo Estriado/enzimologia , Cistationina beta-Sintase/metabolismo , Sulfeto de Hidrogênio/metabolismo , Doença de Parkinson/enzimologia , Animais , Astrócitos/enzimologia , Linhagem Celular Tumoral , Células Cultivadas , Modelos Animais de Doenças , Neurônios Dopaminérgicos/enzimologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Microglia/enzimologia , Transtornos Parkinsonianos/enzimologia , Transdução de Sinais
9.
Front Pharmacol ; 8: 741, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29163149

RESUMO

The neuromodulator hydrogen sulfide (H2S) was shown to exert neuroprotection in different models of Parkinson's disease (PD) via its anti-inflammatory and anti-apoptotic properties. In this study, we evaluated the effect of an H2S slow-releasing compound GYY4137 (GYY) on a mouse PD model induced by acute injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). GYY was intraperitoneally (i.p.) injected once daily into male C57BL/6J mice 3 days before and 2 weeks after MPTP (14 mg/kg, four times at 2-h intervals, i.p.) administration. Saline was given as a control. Behavioral tests (rotarod, balance beam, and grid walking) showed that 50 mg/kg GYY significantly ameliorated MPTP-caused motor impairments. At lower doses (12.5 and 25 mg/kg) GYY exhibited a less obvious effect. Consistent with this, immunohistochemistry and western blot analysis demonstrated that 50 mg/kg GYY attenuated the loss of tyrosine hydroxylase (TH) positive neurons in the substantia nigra and the decrease of TH expression in the striatum of MPTP-treated mice. Moreover, at this regimen GYY relieved the nitrative stress, as indicated by the decreases in nitric oxide (NO) generation and neuronal NO synthase (nNOS) upregulation elicited by MPTP in the striatum. The suppression of GYY on nNOS expression was verified in vitro, and the results further revealed that Akt activation may participate in the inhibition by GYY on nNOS upregulation. More important, GYY reduced the nitrated modification of α-synuclein, a PD-related protein, in MPTP-induced mice. Overall, our findings suggest that GYY attenuated dopaminergic neuron degeneration and reduced α-synuclein nitration in the midbrain, thus exerting neuroprotection in MPTP-induced mouse model of PD.

10.
Neurobiol Aging ; 60: 104-115, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28941726

RESUMO

Many studies reveal that BAG3 plays a critical role in the regulation of protein degradation via macroautophagy. However, it remains unknown whether BAG3 affects the quality control of α-synuclein (SNCA), a Parkinson's disease-related protein. In this study, we demonstrated the increases of BAG3 expression in the ventral midbrain of SNCAA53T transgenic mice and also in MG132-treated PC12 cells overexpressing wild-type SNCA (SNCAWT-PC12). Moreover, we showed that BAG3 overexpression was sufficient to enhance the autophagy activity while knockdown of Bag3 reduced it in SNCAWT-PC12 cells. Immunoprecipitation revealed that BAG3 interacted with heat shock protein 70 and sequestosome 1. The immunostaining also showed the perinuclear accumulation and colocalization of BAG3 with these 2 proteins, as well as with LC3 dots in tyrosine hydroxylase-positive neurons in the midbrain of SNCAA53T mice. BAG3 overexpression was able to modulate SNCA degradation via macroautophagy which was prevented by Atg5 knockdown. Taken together, these results indicate that BAG3 plays a relevant role in regulating SNCA clearance via macroautophagy, and the heat shock protein 70-BAG3-sequestosome 1 complex may be involved in this process.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas Reguladoras de Apoptose/fisiologia , Autofagia/genética , Autofagia/fisiologia , alfa-Sinucleína/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Expressão Gênica , Proteínas de Choque Térmico HSP70/fisiologia , Masculino , Mesencéfalo/metabolismo , Camundongos Transgênicos , Células PC12 , Ratos , Proteína Sequestossoma-1/fisiologia
11.
Exp Neurol ; 297: 138-147, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28821398

RESUMO

Serum urate levels are reported to be significantly lowered in patients with Parkinson's disease (PD) and inversely correlated to the risk and progression of PD. However, the mechanism by which urate affects PD is poorly understood. Here we showed that treatment with uric acid (UA) resulted in an autophagy activity enhancement in PC12 cells in dose- and time-dependent manners, as indicated by LC3-II increase and P62 decrease. Moreover, UA was still able to increase the LC3-II level and the number of LC3 puncta in the presence of Bafilomycin A1, a lysosomal inhibitor. These changes of autophagic markers were preceded by mTOR inhibition and ULK1 activation. Co-treatment with 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO), an mTOR activator, abolished the UA-induced LC3-II increase. More importantly, UA reduced SNCA/α-synuclein accumulation in PC12 cells that overexpress wildtype or A53T mutant SNCA, and this was blocked by Bafilomycin A1 co-treatment. The in vivo study showed that UA administration was able to modulate the levels of autophagy markers, increase the autophagosome/autolysosome formation, and reduce SNCA accumulation in the midbrain of SNCAA53T transgenic mice. Taken together, our findings suggest that UA could induce autophagy activation via an mTOR-dependent signaling and ameliorate SNCA accumulation. This implicates that urate-elevating agent may become a potential strategy for PD therapy.


Assuntos
Autofagia/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Ácido Úrico/farmacologia , alfa-Sinucleína/metabolismo , Animais , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Humanos , Masculino , Taxa de Depuração Metabólica/efeitos dos fármacos , Taxa de Depuração Metabólica/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células PC12 , Projetos Piloto , Ratos
12.
Chin Med J (Engl) ; 130(9): 1085-1092, 2017 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-28469105

RESUMO

BACKGROUND: Parkinson's disease (PD) patients with long-term levodopa (L-DOPA) treatment are suffering from severe circadian dysfunction. However, it is hard to distinguish that the circadian disturbance in patients is due to the disease progression itself, or is affected by L-DOPA replacement therapy. This study was to investigate the role of L-DOPA on the circadian dysfunction in a rat model of PD. METHODS: The rat model of PD was constructed by a bilateral striatal injection with 6-hydroxydopamine (6-OHDA), followed by administration of saline or 25 mg/kg L-DOPA for 21 consecutive days. Rotarod test, footprint test, and open-field test were carried out to evaluate the motor function. Striatum, suprachiasmatic nucleus (SCN), liver, and plasma were collected at 6:00, 12:00, 18:00, and 24:00. Quantitative real-time polymerase chain reaction was used to examine the expression of clock genes. Enzyme-linked immunosorbent assay was used to determine the secretion level of cortisol and melatonin. High-performance liquid chromatography was used to measure the neurotransmitters. Analysis of variance was used for data analysis. RESULTS: L-DOPA alleviated the motor deficits induced by 6-OHDA lesions in the footprint and open-field test ( P < 0.01, P < 0.001, respectively). After L-DOPA treatment, Bmal1 decreased in the SCN compared with 6-OHDA group at 12:00 ( P < 0.01) and 24:00 ( P < 0.001). In the striatum, the expression of Bmal1, Rorα was lower than that in the 6-OHDA group at 18:00 (P < 0.05) and L-DOPA seemed to delay the peak of Per2 to 24:00. In liver, L-DOPA did not affect the rhythmicity and expression of these clock genes (P > 0.05). In addition, the cortisol secretion was increased (P > 0.05), but melatonin was further inhibited after L-DOPA treatment at 6:00 (P < 0.01). CONCLUSIONS: In the circadian system of advanced PD rat models, circadian dysfunction is not only contributed by the degeneration of the disease itself but also long-term L-DOPA therapy may further aggravate it.


Assuntos
Ritmo Circadiano/efeitos dos fármacos , Levodopa/uso terapêutico , Oxidopamina/toxicidade , Animais , Western Blotting , Peso Corporal/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Imunofluorescência , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real
13.
Mol Pain ; 13: 1744806917691525, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28326933

RESUMO

Background Although pain is one of the most distressing non-motor symptoms among patients with Parkinson's disease, the underlying mechanisms of pain in Parkinson's disease remain elusive. The aim of the present study was to investigate the role of serotonin (5-hydroxytryptamine) in the rostral ventromedial medulla (RVM) and spinal cord in pain sensory abnormalities in a 6-hydroxydopamine-treated rat model of Parkinson's disease. Methods The rotarod test was used to evaluate motor function. The radiant heat test and von Frey test were conducted to evaluate thermal and mechanical pain thresholds, respectively. Immunofluorescence was used to examine 5-hydroxytryptamine neurons and fibers in the rostral ventromedial medulla and spinal cord. High-performance liquid chromatography was used to determine 5-hydroxytryptamine and 5-hydroxyindoleacetic acid levels. Results The duration of running time on the rotarod test was significantly reduced in 6-hydroxydopamine-treated rats. Nociceptive thresholds of both mechanical and heat pain were reduced compared to sham-treated rats. In addition to the degeneration of cell bodies and fibers in the substantia nigra pars compacta, the number of rostral ventromedial medulla 5-hydroxytryptamine neurons and 5-hydroxytryptamine fibers in the spinal dorsal horn was dramatically decreased. 5-Hydroxytryptamine concentrations in both the rostral ventromedial medulla and spinal cord were reduced. Furthermore, the administration of citalopram significantly attenuated pain hypersensitivity. Interestingly, Intra-rostral ventromedial medulla (intra-RVM) microinjection of 5,7-dihydroxytryptamine partially reversed pain hypersensitivity of 6-hydroxydopamine-treated rats. Conclusions These results suggest that the decreased 5-hydroxytryptamine contents in the rostral ventromedial medulla and spinal dorsal horn may be involved in hyperalgesia in the 6-hydroxydopamine-induced rat model of Parkinson's disease.


Assuntos
Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Bulbo/metabolismo , Doença de Parkinson/complicações , Serotonina/metabolismo , Transdução de Sinais/fisiologia , Medula Espinal/metabolismo , 5,7-Di-Hidroxitriptamina/uso terapêutico , Animais , Modelos Animais de Doenças , Indóis/metabolismo , Masculino , Bulbo/efeitos dos fármacos , Oxidopamina/toxicidade , Doença de Parkinson/etiologia , Doença de Parkinson/patologia , Ratos , Ratos Sprague-Dawley , Receptores Opioides mu/metabolismo , Serotoninérgicos/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Medula Espinal/efeitos dos fármacos , Simpatolíticos/toxicidade , Tirosina 3-Mono-Oxigenase/metabolismo , Ácido gama-Aminobutírico/metabolismo
14.
Neurotoxicology ; 58: 103-109, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27866991

RESUMO

The pesticide rotenone is widely used to produce Parkinson's disease (PD)-like symptoms in rodents, but few studies have examined whether rotenone-treated zebrafish can serve as an animal model of PD. Here, we report that 4 weeks of rotenone treatment induced motor and non-motor PD-like symptoms in adult zebrafish. Compared with control fish, rotenone-treated fish spent less time swimming at a fast speed, indicating a deficit in motor function. In the light-dark box test, rotenone-treated fish exhibited longer latencies to enter the dark compartment and spent more time in the light compartment, reflecting anxiety- and depression-like behavior. Furthermore, rotenone-treated fish showed less of an olfactory preference for amino acid, indicating olfactory dysfunction. These behavioral symptoms were associated with decreased levels of dopamine in the brains of rotenone-treated fish. Taken together, these results suggest that rotenone-treated zebrafish are a suitable model of PD.


Assuntos
Ansiedade/etiologia , Inseticidas/toxicidade , Transtornos do Olfato/etiologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/complicações , Rotenona/toxicidade , Animais , Adaptação à Escuridão/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Neurotransmissores/metabolismo , RNA Mensageiro/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
15.
Neurosci Bull ; 33(1): 62-72, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27995565

RESUMO

Circadian rhythm is manifested by the behavioral and physiological changes from day to night, which is controlled by the pacemaker and its regulator. The former is located at the suprachiasmatic nuclei (SCN) in the anterior hypothalamus, while the latter is composed of clock genes present in all tissues. Circadian desynchronization influences normal patterns of day-night rhythms such as sleep and alertness cycles, rest and activity cycles. Parkinson's disease (PD) exhibits diurnal fluctuations. Circadian dysfunction has been observed in PD patients and animal models, which may result in negative consequences to the homeostasis and even exacerbate the disease progression. Therefore, circadian therapies, including light stimulation, physical activity, dietary and social schedules, may be helpful for PD patients. However, the cellular and molecular mechanisms that underlie the circadian dysfunction in PD remain elusive. Further research on circadian patterns is needed. This article summarizes the existing research on the circadian rhythms in PD, focusing on the clinical symptom variations, molecular changes, as well as the available treatment options.


Assuntos
Ritmo Circadiano/fisiologia , Doença de Parkinson/fisiopatologia , Animais , Humanos
16.
Neurochem Res ; 41(11): 2923-2936, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27447883

RESUMO

Paeoniflorin (PF) is the main active component extracted from the roots of Paeonialactiflora, a traditional Chinese medicine used for the treatment of neurodegenerative disorders, especially Parkinson's disease (PD). The degeneration of dopaminergic (DA-) neurons in PD may be caused by pathological activation of acid-sensing ion channels (ASICs). Thus, we designed a series of experiments to evaluate the therapeutic effects of PF and to test whether its effects are related to its inhibitory effect on ASIC1a. We found that systemic administration of PF or ASICs blockers (psalmotoxin-1 and amiloride) improved behavioral symptoms, delayed DA-neuronal loss and attenuated the reduction of dopamine (DA) and its metabolites in a rat model of 6-hydroxydopamine (6-OHDA)-induced PD. In addition, our data showed that PF, like ASICs blockers, regulated the expression of ASIC1a, decreased the level of α-synuclein (α-SYN), and improved autophagic dysfunction. Further experiments showed that ASIC1a knockdown down-regulated the α-SYN level and alleviated the autophagic injury in the 6-OHDA-treated ASIC1a-silenced PC12 cells. In summary, these findings indicate that PF enhanced the autophagic degradation of α-SYN and, thus, protected DA-neurons against the neurotoxicity caused by 6-OHDA. These findings also provide experimental evidence that PF may be a neuroprotectant for PD by acting on ASIC1a and that ASIC1a may be involved in the pathogenesis of PD.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Glucosídeos/farmacologia , Monoterpenos/farmacologia , Fármacos Neuroprotetores/farmacologia , Oxidopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Autofagia/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Dopamina/metabolismo , Masculino , Células PC12 , Doença de Parkinson/metabolismo , Ratos , Ratos Sprague-Dawley
17.
Free Radic Res ; 50(6): 654-65, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26982248

RESUMO

Hydrogen sulfide (H2S) is a novel gaseous transmitter, regulating a multitude of biological processes in the cardiovascular and other systems. However, it remains unclear whether it exerts any effect on arterial thrombosis. In this study, we examined the effect of H2S on ferric chloride (FeCl3)-induced thrombosis in the rat common carotid artery (CCA). The results revealed a decrease of the H2S-producing enzyme cystathionine γ-lyase (CSE) expression and H2S production that persisted until 48 h after FeCl3 application. Intriguingly, administration with NaHS at appropriate regimen reduced the thrombus formation and enhanced the blood flow, accompanied with the alleviation of CSE and CD31 downregulation, and endothelial cell apoptosis in the rat CCA following FeCl3 application. Moreover, the antithrombotic effect of H2S was also observed in Rose Bengal photochemical model in which the development of thrombosis is contributed by oxidative injury to the endothelium. The in vitro study demonstrated that the mRNA and protein expression of CSE, as well as H2S production, was decreased in hydrogen peroxide (H2O2)-treated endothelial cells. Exogenous supplement of NaHS and CSE overexpression consistently alleviated the increase of cleaved caspase-3 and endothelial cell damage caused by H2O2. Taken together, our findings suggest that endogenous H2S generation in the endothelium may be impaired during arterial thrombosis and that modulation of H2S, either exogenous supplement or boost of endogenous production, may become a potential venue for arterial thrombosis therapy.


Assuntos
Cloretos/química , Compostos Férricos/química , Sulfeto de Hidrogênio/química , Trombose/etiologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Transdução de Sinais
18.
Biochem Biophys Res Commun ; 470(4): 792-7, 2016 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-26801555

RESUMO

Vesicular monoamine transporter 2 (Vmat2) is widely distributed in the central nervous system, and responsible for uptaking transmitters into the vesicles. However, whether Vmat2-deficiency is related to the anxiety is rarely investigated, especially in zebrafish. Here, we reported Vmat2 heterzygous mutant zebrafish displayed anxiety-like behavior. The mutants spent less time in the top area and took longer latency to the top in the novel tank test. Consistently, they showed dark avoidance in the light/dark box test, with longer duration in the light zone and increased number of crossing between the two zones. Monoamine concentration analysis showed that the levels of monoamine neurotransmitters including dopamine (DA), 5-hydroxy tryptamine (5-HT) and norepinephrine (NE), as well as their metabolites were decreased in VMAT mutants. Taken together, these findings suggest that Vmat2 heterzygous mutant zebrafish may serve as a new model of anxiety, which may be related with the low level of DA, 5-HT and NE.


Assuntos
Ansiedade/fisiopatologia , Aprendizagem da Esquiva , Comportamento Animal , Modelos Animais de Doenças , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Peixe-Zebra , Animais , Técnicas de Silenciamento de Genes , Proteínas Vesiculares de Transporte de Monoamina/genética
19.
Biochem Biophys Res Commun ; 469(3): 776-82, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26692478

RESUMO

Recent studies suggest that epigenetic alterations such as DNA methylation control many aspects of monocytes/macrophages and participate in the pathogenesis of atherosclerosis, a lipid-driven inflammatory disorder. Our and other groups demonstrated that dysregulation of cystathionine γ-lyase (CSE) -hydrogen sulfide (H2S) pathway was involved in monocyte/macrophages-mediated inflammation and atherosclerosis. However, it remains unknown whether altered cse methylation in macrophages may play a role in linking CSE-H2S dysregulation and atherosclerosis. In the present study, we showed that plasma H2S and H2S production in the peritoneal macrophages of apolipoprotein knockout (apoE(-/-)) mice gradually decreased with ages, and were also lower than that in control mice at 12 weeks older. Moreover, CSE mRNA expressions decreased while DNA methyltransferase (DNMT) expressions increased in the peritoneal macrophages isolated from apoE(-/-) mice, compared to age-matched wildtype mice. Similar observations were obtained in an in vitro study. In oxidized low-density lipoprotein (ox-LDL)-treated raw264.7 macrophages, cse transcription was down-regulated while the expression and activity of DNMT was up-regulated, associated with enhanced DNA methylation in cse promoter. Suppression of DNMT with its inhibitor or siRNA reversed the decrease of CSE mRNA. Therefore, our data suggest that DNA hypermethylation of CpG rich region in cse promoter might contribute to the decrease of cse transcription and H2S production in macrophages, and thus contribute to atherosclerosis development.


Assuntos
Cistationina gama-Liase/genética , Metilação de DNA/genética , Sulfeto de Hidrogênio/sangue , Lipoproteínas LDL/farmacologia , Macrófagos/fisiologia , Regiões Promotoras Genéticas/genética , Animais , Células Cultivadas , Metilação de DNA/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células RAW 264.7
20.
Autophagy ; 11(11): 2057-2073, 2015 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-26649942

RESUMO

Autophagy dysfunction is implicated in the pathogenesis of Parkinson disease (PD). BECN1/Beclin 1 acts as a critical regulator of autophagy and other cellular processes; yet, little is known about the function and regulation of BECN1 in PD. In this study, we report that dopamine D2 and D3 receptor (DRD2 and DRD3) activation by pramipexole and quinpirole could enhance BECN1 transcription and promote autophagy activation in several cell lines, including PC12, MES23.5 and differentiated SH-SY5Y cells, and also in tyrosine hydroxylase positive primary midbrain neurons. Moreover, we identified a novel FOS (FBJ murine osteosarcoma viral oncogene homolog) binding sequence (5'-TGCCTCA-3') in the rat and human Becn1/BECN1 promoter and uncovered an essential role of FOS binding in the enhancement of Becn1 transcription in PC12 cells in response to the dopamine agonist(s). In addition, we demonstrated a critical role of intracellular Ca2+ elevation, followed by the enhanced phosphorylation of CAMK4 (calcium/calmodulin-dependent protein kinase IV) and CREB (cAMP responsive element binding protein) in the increases of FOS expression and autophagy activity. More importantly, pramipexole treatment ameliorated the SNCA/α-synuclein accumulation in rotenone-treated PC12 cells that overexpress wild-type or A53T mutant SNCA by promoting autophagy flux. This effect was also demonstrated in the substantia nigra and the striatum of SNCAA53T transgenic mice. The inhibition of SNCA accumulation by pramipexole was attenuated by cotreatment with the DRD2 and DRD3 antagonists and Becn1 siRNAs. Thus, our findings suggest that DRD2 and DRD3 agonist(s) may induce autophagy activation via a BECN1-dependent pathway and have the potential to reduce SNCA accumulation in PD.

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