RESUMEN
Aggregation of α-synuclein, a component of Lewy bodies (LBs) or Lewy neurites in Parkinson's disease (PD), is strongly linked with disease development, making it an attractive therapeutic target. Inhibiting aggregation can slow or prevent the neurodegenerative process. However, the bottleneck towards achieving this goal is the lack of such inhibitors. In the current study, we established a high-throughput screening platform to identify candidate compounds for preventing the aggregation of α-synuclein among the natural products in our in-house compound library. We found that a small molecule, 03A10, i.e., (+)-desdimethylpinoresinol, which is present in the fruits of Vernicia fordii (Euphorbiaceae), modulated aggregated α-synuclein, but not monomeric α-synuclein, to prevent further elongation of α-synuclein fibrils. In α-synuclein-overexpressing cell lines, 03A10 (10 µM) efficiently prevented α-synuclein aggregation and markedly ameliorated the cellular toxicity of α-synuclein fibril seeds. In the MPTP/probenecid (MPTP/p) mouse model, oral administration of 03A10 (0.3 mg· kg-1 ·d-1, 1 mg ·kg-1 ·d-1, for 35 days) significantly alleviated behavioral deficits, tyrosine hydroxylase (TH) neuron degeneration and p-α-synuclein aggregation in the substantia nigra (SN). As the Braak hypothesis postulates that the prevailing site of early PD pathology is the gastrointestinal tract, we inoculated α-synuclein preformed fibrils (PFFs) into the mouse colon. We demonstrated that α-synuclein PFF inoculation promoted α-synuclein pathology and neuroinflammation in the gut and brain; oral administration of 03A10 (5 mg· kg-1 ·d-1, for 4 months) significantly attenuated olfactory deficits, α-synuclein accumulation and neuroinflammation in the olfactory bulb and SN. We conclude that 03A10 might be a promising drug candidate for the treatment of PD. 03A10 might be a novel drug candidate for PD treatment, as it inhibits α-synuclein aggregation by modulating aggregated α-synuclein rather than monomeric α-synuclein to prevent further elongation of α-synuclein fibrils and prevent α-synuclein toxicity in vitro, in an MPTP/p mouse model, and PFF-inoculated mice.
Asunto(s)
Enfermedad de Parkinson , Ratones , Animales , Enfermedad de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Enfermedades Neuroinflamatorias , Sustancia Negra/metabolismo , Sustancia Negra/patología , Encéfalo/metabolismoRESUMEN
Parkinson's disease (PD) is pathologically characterized by intracellular α-synuclein-rich protein aggregates, named Lewy bodies (LB), and by the progressive loss of dopaminergic neurons in the substantia nigra. Several heavy metals, including zinc (Zn), have been suggested to play a role in PD progression, although the exact role of Zn in neurodegeneration remains to be fully elucidated. To address this gap, we investigated the effects of Zn modulation on the progression of degeneration in mice injected with PD patient-derived LB-extracts carrying toxic α-synuclein aggregates. Zn modulation was achieved using either a clioquinol-enriched diet, a Zn ionophore that redistributes cellular Zn, or a Zn-enriched diet that increases Zn levels. Clioquinol treatment significantly prevented dopaminergic neurodegeneration and reduced α-synuclein-associated pathology in LB-injected mice, while no differences were observed with Zn supplementation. Biochemical analyses further demonstrate that the expression levels of vesicle-specific Zn transporter ZnT3 in the striatum of LB-injected mice treated with clioquinol were decreased, suggesting an intracellular redistribution of Zn. Additionally, we found that clioquinol modulates the autophagy-lysosomal pathway by enhancing lysosomal redistribution within the neuronal compartments. Collectively, we found that in vivo pharmacological chelation of Zn, by dampening Zn-mediated cytotoxicity, can result in an overall attenuation of PD-linked lysosomal alterations and dopaminergic neurodegeneration. The results support zinc chelation as a disease-modifying strategy for treating PD.
Asunto(s)
Clioquinol , Enfermedad de Parkinson , Animales , Encéfalo/metabolismo , Clioquinol/farmacología , Clioquinol/uso terapéutico , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Humanos , Ionóforos/farmacología , Ionóforos/uso terapéutico , Ratones , Enfermedad de Parkinson/patología , Sustancia Negra/patología , Extractos de Tejidos , Zinc/metabolismo , alfa-Sinucleína/metabolismoRESUMEN
BACKGROUND: Degeneration of dopaminergic neurons within the brainstem substantia nigra (SN) is both a pathological hallmark of Parkinson's disease (PD) and a major contributor to symptom expression. Therefore, non-invasive evaluation of the SN is critical for diagnosis and evaluation of disease progression. Hyperechogenicity (HE+) on midbrain transcranial sonography (TCS) supports the clinically established diagnosis of PD. Further, postmortem studies suggest involvement of neuromelanin (NM) loss and iron deposition in nigral neurodegeneration and HE+ emergence. However, the associations between HE+ and signs of nigral NM loss and iron deposition revealed by magnetic resonance imaging (MRI) have not been examined. OBJECTIVE: To elucidate the magnetic resonance- (MR-) morphological representation of the HE+ by NM-weighted (NMI) and susceptibility-weighted MRI (SWI). METHODS: Thirty-four PD patients and 29 healthy controls (HCs) received TCS followed by NMI and SWI. From MR images, two independent raters manually identified the SN, placed seeds in non-SN midbrain areas, and performed semi-automated SN segmentation with different thresholds based on seed mean values and standard deviations. Masks of the SN were then used to extract mean area, mean signal intensity, maximal signal area, maximum signal (for NMI), and minimum signal (for SWI). RESULTS: There were no significant differences in NMI- and SWI-based parameters between patients and HCs, and no significant associations between HE+ extent and NMI- or SWI-based parameters. CONCLUSION: HE+ on TCS appears unrelated to PD pathology revealed by NMI and SWI. Thus, TCS and MRI parameters should be considered complementary, and the pathophysiological correlates of the HE+ require further study.
Asunto(s)
Enfermedad de Parkinson , Humanos , Hierro/metabolismo , Imagen por Resonancia Magnética/métodos , Neuroimagen , Enfermedad de Parkinson/metabolismo , Sustancia Negra/patologíaRESUMEN
Mild to moderate dopaminergic (DA) neuronal death in substantia nigra pars compacta (SNc) as the main pathological hallmark of Parkinson's disease (PD) is usually silent and does not produce marked clinical symptoms. In this study, we investigated the association between SNc DA neuronal loss and serum levels of total bilirubin (TB), selenium (Se), and zinc (Zn) in 6-hydroxydopamine (6-OHDA) animal model of PD. The neurotoxin of 6-OHDA was injected into the medial forebrain bundle of right hemisphere by stereotaxic surgery. Two conventional behavioral tests were carried out in several steps after the toxin to confirm the model reproduction and quantify severity and progress of 6-OHDA-induced PD. Blood samples were collected within 1 week before the toxin and in the second, fifth, and eighth weeks thereafter. Immunohistochemistry (IHC) assessments were performed on the rat's brain to determine the severity of DA neuronal loss in SNc. The severity of behavioral symptoms and TB levels were progressively increased in 6-OHDA-treated rats. On the other hand, Se and Zn levels in them were lower than control. These changes were observed in rats with severe or mild behavioral symptoms. Also, IHC revealed that changes in TB, Se, and Zn associate with SNc DA neuronal loss but do not correlate with its severity. Significant changes in serum levels of TB, Se, and Zn in the mild SNc DA neuronal loss suggest them as valuable parameters for establishment of a serum profile for early detection of PD.
Asunto(s)
Enfermedad de Parkinson , Selenio , Animales , Bilirrubina , Modelos Animales de Enfermedad , Dopamina , Neuronas Dopaminérgicas , Oxidopamina , Ratas , Sustancia Negra/patología , ZincRESUMEN
Parkinson's disease (PD) is a disease that involves brain damage and is associated with neuroinflammation, mitochondrial damage, and cell aging. However, the pathogenic mechanism of PD is still unknown. Sequencing data and proteomic data can describe the fluctuation of molecular abundance in diseases at the mRNA level and protein level, respectively. In order to explore new targets in the pathogenesis of PD, the study analyzed molecular changes from the database by combining transcriptomic and proteomic analysis. Differentially expressed genes and differentially abundant proteins were summarized and analyzed. Enrichment and cluster analysis emphasized the importance of neurotransmitter release, mitochondrial damage, and vesicle transport. The molecular network revealed a subnetwork of 9 molecules related to SCNA and TH and revealed hub gene with differential expression at both mRNA and protein levels. It found that ACHE and CADPS could be used as new targets in PD, emphasizing that impaired nerve signal transmission and vesicle transport affect the pathogenesis of PD. Our research emphasized that the joint analysis and verification of transcriptomics and proteomics were devoted to understanding the comprehensive views and mechanism of pathogenesis in PD.
Asunto(s)
Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Proteínas/genética , Proteínas/metabolismo , Sustancia Negra/metabolismo , Acetilcolinesterasa/genética , Acetilcolinesterasa/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Análisis por Conglomerados , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Humanos , Enfermedad de Parkinson/patología , ARN Mensajero/genética , Sustancia Negra/patología , Transcriptoma , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMEN
Parkinson's disease (PD) is a neurodegenerative disease caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc), characterized by motor dysfunction. While PD symptoms are well treated with L-DOPA, continuous use can cause L-DOPA-induced dyskinesia (LID). We have previously demonstrated that sub-anesthetic ketamine attenuated LID development in rodents, measured by abnormal involuntary movements (AIMs), and reduced the density of maladaptive striatal dendritic mushroom spines. Microglia may play a role by phagocytosing maladaptive neuronal spines. In this exploratory study, we hypothesized that ketamine would prevent AIMs and change microglia ramified morphology - an indicator of a microglia response. Unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats were primed with daily injections of L-DOPA for 14 days, treated on days 0 and 7 for 10-hours with sub-anesthetic ketamine (i.p.), and we replicated that this attenuated LID development. We further extended our prior work by showing that while ketamine treatment did lead to an increase of striatal interleukin-6 in dyskinetic rats, indicating a modulation of an inflammatory response, it did not change microglia number or morphology in the dyskinetic striatum. Yet an increase of CD68 in the SNpc of 6-OHDA-lesioned hemispheres post-ketamine indicates increased microglia phagocytosis suggestive of a lingering microglial response to 6-OHDA injury in the SNpc pointing to possible anti-inflammatory action in the PD model in addition to anti-dyskinetic action. In conclusion, we provide further support for sub-anesthetic ketamine treatment of LID. The mechanisms of action for ketamine, specifically related to inflammation and microglia phagocytic functions, are emerging, and require further examination.
Asunto(s)
Discinesia Inducida por Medicamentos/prevención & control , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Ketamina/administración & dosificación , Levodopa/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Discinesia Inducida por Medicamentos/etiología , Discinesia Inducida por Medicamentos/patología , Humanos , Levodopa/efectos adversos , Masculino , Microglía/efectos de los fármacos , Microglía/patología , Fagocitosis/efectos de los fármacos , Ratas , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patologíaRESUMEN
Parkinson's disease (PD), the typical neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). However, no therapeutic agent used currently could slow down neuronal cell loss so as to decelerate or halt the progression of PD. Traditional Chinese medicine (TCM) has been utilized to treat the dysfunction of the autonomic nervous system. Wen-Shen-Yang-Gan decoction (WSYGD) has a good effect on the clinical treatment of PD with constipation. However, it is not clear which ingredients and what mechanism are responsible for the therapeutic effect. In this study, the pharmacodynamic study of WSYGD in PD mice was applied. Concurrently, a novel method for the identification of metabolic profiles of WSYGD has been developed. Finally, we found that WSYGD could protect the PD mice induced by rotenone. The underlying mechanism of the protective effect may be related to the reduction of the DA neurons apoptosis via reducing inflammatory reaction. By virtue of UPLC-MS and chemoinformatics method, 35 prototype compounds and 27 metabolites were filtered out and tentatively characterized. In conclusion, this study provides an insight into the metabolism of WSYGD in vivo to enable understanding of the metabolic process and therapeutic mechanism of PD.
Asunto(s)
Antiparkinsonianos/farmacología , Metabolómica , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Extractos Vegetales/farmacología , Administración Oral , Animales , Antiparkinsonianos/aislamiento & purificación , Quimioinformática/métodos , Cromatografía Líquida de Alta Presión , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Análisis Multivariante , Fármacos Neuroprotectores/aislamiento & purificación , Enfermedad de Parkinson/patología , Extractos Vegetales/aislamiento & purificación , Rotenona , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Espectrometría de Masas en TándemRESUMEN
Recent studies show that neuron-glial communication plays an important role in neurological diseases. Particularly, dysfunction of astroglial glutamate transporter GLT-1 has been involved in various neuropsychiatric disorders, including Parkinson's disease (PD) and depression. Our previous studies indicated hyperactivity of neurons in the lateral habenula (LHb) of hemiparkinsonian rats with depressive-like behaviors. Thus, we hypothesized that impaired expression or function of GLT-1 in the LHb might be a potential contributor to LHb hyperactivity, which consequently induces PD-related depression. In the study, unilateral lesions of the substantia nigra pars compacta (SNc) by 6-hydroxydopamine in rats induced depressive-like behaviors and resulted in neuronal hyperactivity as well as increased glutamate levels in the LHb compared to sham-lesioned rats. Intra-LHb injection of GLT-1 inhibitor WAY-213613 induced the depressive-like behaviors in both groups, but the dose producing behavioral effects in the lesioned rats was lower than that of sham-lesioned rats. In the two groups of rats, WAY-213613 increased the firing rate of LHb neurons and extracellular levels of glutamate, and these excitatory effects in the lesioned rats lasted longer than those in sham-lesioned rats. The functional changes of the GLT-1 which primarily expresses in astrocytes in the LHb may attribute to its downregulation after degeneration of the nigrostriatal pathway. Bioinformatics analysis showed that GLT-1 is correlated with various biomarkers of PD and depression risks. Collectively, our study suggests that astroglial GLT-1 in the LHb regulates the firing activity of the neurons, whereupon its downregulation and dysfunction are closely associated with PD-related depression.
Asunto(s)
Astrocitos/metabolismo , Depresión/metabolismo , Transportador 2 de Aminoácidos Excitadores/metabolismo , Ácido Glutámico/metabolismo , Habénula/metabolismo , Trastornos Parkinsonianos/metabolismo , Porción Compacta de la Sustancia Negra/metabolismo , Animales , Modelos Animales de Enfermedad , Regulación hacia Abajo , Transportador 2 de Aminoácidos Excitadores/antagonistas & inhibidores , Oxidopamina/toxicidad , Trastornos Parkinsonianos/patología , Porción Compacta de la Sustancia Negra/patología , Ratas , Sustancia Negra/metabolismo , Sustancia Negra/patología , Tálamo/metabolismo , Tálamo/patología , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/patologíaRESUMEN
Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects more than 10 million people worldwide. Oxidative stress and mitochondrial dysfunction play a significant role in altering the homeostasis of energy production and free radical generation. Current PD therapies are focused on reducing the cardinal symptoms rather than preventing disease progression in the patients. Adenosine A2A receptor (A2A R) antagonist (Istradephylline) combined with levodopa shows a promising therapy for PD. In animal studies, caffeine administration showed to improve motor functions and neuroprotective effect in the neurons. Caffeine is probably the most extensively used psychoactive substance. In this current study, we investigated the neuroprotective effect of caffeine against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration. Here, we demonstrate that caffeine improves behavioral and neurotransmitter recovery against MPTP-induced toxicity. Caffeine restores endogenous antioxidant levels and suppresses neuroinflammation. Our finding suggests that the blockage of A2AR is a promising disease-modifying therapy for PD. Target engagement strategies could be more beneficial in preventing disease progression rather than symptomatic reliefs in PD patients.
Asunto(s)
Cafeína/farmacología , Suplementos Dietéticos , Neuronas Dopaminérgicas/efectos de los fármacos , Intoxicación por MPTP/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Animales , Antioxidantes/farmacología , Conducta Animal/efectos de los fármacos , Intoxicación por MPTP/patología , Intoxicación por MPTP/psicología , Ratones , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Mercury sulfides (HgS) are frequently included in Ayurveda, Tibetan and Chinese medicines to assist the presumed therapeutic effects, but the ethnopharmacology remains elusive. The present study examined the protective effects of α-HgS-containing Hua-Feng-Dan and ß-HgS-containing 70 Wei-Zhen-Zhu-Wan (70W, Rannasangpei) against Parkinson's disease mice induced by lipopolysaccharide (LPS) plus 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). METHOD: A single injection of LPS (5 mg/kg ip) was given to adult male C57BL/6 mice, and 150 days later, the low dose of MPTP (15 mg/kg, ip, for 4 days) was given to produce the "two-hit" Parkinson's disease model. Together with MPTP treatment, mice were fed with clinically-relevant doses of Hua-Feng-Dan (0.6 g/kg) and 70W (0.2 g/kg) for 35 days. Rotarod test was performed to examine muscle coordination capability. At the end of the experiment, brain was transcardially perfused with paraformaldehyde, the substantia nigra was sectioned for microglia (Iba1 staining) and dopaminergic neuron (THir staining) determination. Colon bacterial DNA was extracted and subjected to qPCR analysis with 16S rRNA probes. RESULTS: The low-grade, chronic neuroinflammation produced by LPS aggravated MPTP neurotoxicity, as evidenced by decreased motor activity, intensified microglia activation and loss of dopaminergic neurons. Both Hua-Feng-Dan and 70W increased rotarod activity and ameliorated the pathological lesions in the brain. In gut microbiomes examined, LPS plus MPTP increased Verrucomicrobiaceae, Methanobacteriaceae, Pronicromonosporaceae, and Clostridaceae species were attenuated by Hua-Feng-Dan and 70W. CONCLUSIONS: α-HgS-containing Hua-Feng-Dan and ß-HgS-containing 70W at clinical doses protected against chronic LPS plus MPTP-induced toxicity to the brain and gut, suggesting HgS-containing traditional medicines could target gut microbiota as a mechanism of their therapeutic effects.
Asunto(s)
Colon/microbiología , Compuestos de Mercurio/farmacología , Enfermedad de Parkinson Secundaria/prevención & control , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Colon/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Lipopolisacáridos , Masculino , Ratones , Microglía/patología , Enfermedad de Parkinson Secundaria/inducido químicamente , Prueba de Desempeño de Rotación con Aceleración Constante , Sustancia Negra/patologíaRESUMEN
Parthenolide (PTL) is a natural compound with anti-inflammatory and antioxidant properties and is an active ingredient extracted from the medicinal plant Tanacetum parthenium. ACT001 is derived from parthenolide and is a fumarate form of dimethylaminomylide (DMAMCL). Its effect is equivalent to that of PTL, but it is more stable in plasma and has lower acquisition costs. Related reports indicate that NLRP3-mediated neuroinflammation is involved in the progression of Parkinson's disease (PD). In our research, we explored whether ACT001 alleviates NLRP3-mediated neuroinï¬ammation in PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our results revealed that ACT001 reduces movement impairment and cognitive deï¬cit in PD mice. In addition, it alleviates dopaminergic neurodegeneration in the nigrostriatal pathway and inhibits oxidative stress, the inflammatory response and activation of the NLRP3 inflammasome in the midbrain of MPTP-induced PD mice. Moreover, it attenuates microglial activation in the nigrostriatal pathway. Overall, our study showed that ACT001 alleviates NLRP3-mediated neuroinï¬ammation in PD mice induced by MPTP.
Asunto(s)
Conducta Animal/efectos de los fármacos , Citocinas/efectos de los fármacos , Inflamasomas/efectos de los fármacos , Inflamación/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/efectos de los fármacos , Trastornos Parkinsonianos/metabolismo , Sesquiterpenos de Guayano/farmacología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Catalasa/efectos de los fármacos , Catalasa/metabolismo , Ritmo Circadiano/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Citocinas/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Inflamasomas/metabolismo , Inflamación/fisiopatología , Malondialdehído/metabolismo , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Estrés Oxidativo/efectos de los fármacos , Trastornos Parkinsonianos/fisiopatología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patología , Superóxido Dismutasa/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Oxidative stress is a major pathogenic mechanism in Parkinson's disease (PD). As an important cellular antioxidant, glutathione (GSH) balances the production and incorporation of free radicals to protect neurons from oxidative damage. GSH level is decreased in the brains of PD patients. Hence, clarifying the molecular mechanism of GSH deficiency may help deepen our knowledge of PD pathogenesis. Here we report that the astrocytic dopamine D2 receptor (DRD2) regulates GSH synthesis via PKM2-mediated Nrf2 transactivation. In addition we find that pyridoxine can dimerize PKM2 to promote GSH biosynthesis. Further experiments show that pyridoxine supplementation increases the resistance of nigral dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in wild-type mice as well as in astrocytic Drd2 conditional knockout mice. We conclude that dimerizing PKM2 may be a potential target for PD treatment.
Asunto(s)
Glutatión/biosíntesis , Intoxicación por MPTP/patología , Factor 2 Relacionado con NF-E2/genética , Fármacos Neuroprotectores/administración & dosificación , Piruvato Quinasa/metabolismo , Receptores de Dopamina D2/metabolismo , Animales , Astrocitos , Técnicas de Observación Conductual , Conducta Animal/efectos de los fármacos , Células Cultivadas , Dopamina/metabolismo , Neuronas Dopaminérgicas , Intoxicación por MPTP/diagnóstico , Intoxicación por MPTP/tratamiento farmacológico , Ratones Noqueados , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Cultivo Primario de Células , Multimerización de Proteína/efectos de los fármacos , Piridoxina/administración & dosificación , Especies Reactivas de Oxígeno/metabolismo , Receptores de Dopamina D2/genética , Sustancia Negra/citología , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Activación TranscripcionalRESUMEN
Parkinson's disease (PD) is the second common age-related neurodegenerative disease. It is characterized by control loss of voluntary movements control, resting tremor, postural instability, bradykinesia, and rigidity. The aim of the present work is to evaluate curcumin, niacin, dopaminergic and non-dopaminergic drugs in mice model of Parkinson's disease through behavioral, biochemical, genetic and histopathological observations. Mice treated with rotenone rerecorded significant increase in adenosine A2A receptor (A2AR) gene expression, α synuclein, acetylcholinesterase (AchE), malondialdehyde (MDA), angiotensin-II (Ang-II), c-reactive protein (CRP), interleukin-6 (IL-6), caspase-3 (Cas-3) and DNA fragmentation levels as compared with the control group. While, significant decrease in dopamine (DA), norepinephrine (NE), serotonin (5-HT), superoxide dismutase (SOD), reduced glutathione (GSH), ATP, succinate and lactate dehydrogenases (SDH &LDH) levels were detected. Treatment with curcumin, niacin, adenosine A2AR antagonist; ZM241385 and their combination enhanced the animals' behavior and restored all the selected parameters with variable degrees of improvement. The brain histopathological features of hippocampal and substantia nigra regions confirmed our results. In conclusion, the combination of curcumin, niacin and ZM241385 recorded the most potent treatment effect in Parkinsonism mice followed by ZM241385, as a single treatment. ZM241385 succeeded to antagonize adenosine A2A receptor by diminishing its gene expression and ameliorating all biochemical parameters under investigation. The newly investigated agent; ZM241385 has almost the same pattern of improvement as the classical drug; Sinemet®. This could shed the light to the need of detailed studies on ZM241385 for its possible role as a promising treatment against PD. Additionally, food supplements such as curcumin and niacin were effective in Parkinson's disease eradication.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/farmacología , Curcumina/farmacología , Niacina/farmacología , Enfermedad de Parkinson Secundaria , Receptor de Adenosina A2A/metabolismo , Rotenona/administración & dosificación , Animales , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Masculino , Ratones , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/metabolismo , Enfermedad de Parkinson Secundaria/patología , Rotenona/farmacología , Sustancia Negra/metabolismo , Sustancia Negra/patologíaRESUMEN
Parkinson's disease (PD) is characterized by dopaminergic neuron loss in the substantia nigra. However, specific sensory stimulation via electroacupuncture (EA) therapy may attenuate this loss by promoting the expression of endogenous neurotrophic factors in a manner similar to physical therapy. We investigated the potential protective effects of EA on dopaminergic neurons in a mouse model of PD and whether these effects are associated with the promotion of endogenous brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Mouse models of PD were generated using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine. Motor performance was assessed using behavioral tests, and Western blot experiments, enzyme-linked immunosorbent assays (ELISAs), and immunohistochemical assays were performed. In both mouse models, EA treatment ameliorated motor impairments and dopaminergic neuron loss; these changes were accompanied by increases in BDNF and GDNF. In the MPTP group, EA treatment improved motor dysfunction by attenuating dopaminergic neuron loss in the substantia nigra, similar to the effects of levodopa. EA treatment significantly upregulated BDNF and GDNF expression in both the substantia nigra and striatum. Moreover, EA treatment induced the expression of cAMP response element binding protein (CREB) as well as Akt and Pitx3 in dopaminergic neurons in the substantia nigra. However, levodopa treatment did not induce BDNF/GDNF activation or related signaling factors. Thus, EA therapy may exert protective effects on dopaminergic neurons by upregulating the expression of BDNF, GDNF, and related signaling factors, thereby improving motor function. Hence, EA may represent an effective adjuvant therapy for motor deficits in patients with PD.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/fisiología , Electroacupuntura , Factor Neurotrófico Derivado de la Línea Celular Glial/fisiología , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/terapia , Animales , Cuerpo Estriado/patología , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/patología , Neuronas Dopaminérgicas/fisiología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Degeneración Nerviosa/patología , Degeneración Nerviosa/terapia , Oxidopamina/toxicidad , Enfermedad de Parkinson/patología , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/fisiopatología , Trastornos Parkinsonianos/terapia , Transducción de Señal , Sustancia Negra/patología , Sustancia Negra/fisiopatologíaRESUMEN
Exposure to lead is a threat factor for neurodegenerative disorders progress as it could trigger dopaminergic deficiency. We aimed herein to assess the effect of acute lead exposure (25mg/kg B.W i.p.) during three continuous days on the dopaminergic and noradrenergic systems together with locomotor performance in Meriones shawi (M. shawi), then the neuroprotective potential of curcumin-III (30mg/kg B.W) by oral gavage. Pb-exposed M. shawi exhibited increased tyrosine hydroxylase (TH) immunoreactivity in substantia nigra compacta (SNc), ventral tegmental area (VTA), locus coeruleus (LC), and dorsal striatum (DS), unlike the controls. This was correlated with decreased locomotor performance. A noticeable protective effect by co-treatment with curcumin-III was observed; in consequence, TH-immunoreactivity and locomotor disturbance were restored in Pb-treated Meriones. Our data results proved, on the one hand, an evident neurotoxic effect of acute Pb exposure and, on the other hand, a potent therapeutic effect of curcumin-III. Thereby, this compound may be recommended as a neuroprotective molecule for neurodegenerative disorders involving catecholaminergic impairment initiated by metallic elements.
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Cuerpo Estriado/patología , Curcumina/análogos & derivados , Neuronas Dopaminérgicas/efectos de los fármacos , Intoxicación del Sistema Nervioso por Plomo/tratamiento farmacológico , Intoxicación del Sistema Nervioso por Plomo/patología , Fármacos Neuroprotectores/uso terapéutico , Sistema Nervioso Parasimpático/patología , Sustancia Negra/patología , Administración Oral , Animales , Curcumina/uso terapéutico , Gerbillinae , Locus Coeruleus/patología , Masculino , Trastornos del Movimiento/psicología , Área Tegmental Ventral/patologíaRESUMEN
To meet the need for Parkinson's disease biomarkers and evidence for amount and distribution of pathological changes, MRI diffusion tensor imaging (DTI) has been explored in a number of previous studies. However, conflicting results warrant further investigations. As tissue microstructure, particularly of the grey matter, is heterogeneous, a more precise diffusion model may benefit tissue characterization. The purpose of this study was to analyze the diffusion-based imaging technique restriction spectrum imaging (RSI) and DTI, and their ability to detect microstructural changes within brain regions associated with motor function in Parkinson's disease. Diffusion weighted (DW) MR images of a total of 100 individuals, (46 Parkinson's disease patients and 54 healthy controls) were collected using b-values of 0-4000s/mm2. Output diffusion-based maps were estimated based on the RSI-model combining the full set of DW-images (Cellular Index (CI), Neurite Density (ND)) and DTI-model combining b = 0 and b = 1000 s/mm2 (fractional anisotropy (FA), Axial-, Mean- and Radial diffusivity (AD, MD, RD)). All parametric maps were analyzed in a voxel-wise group analysis, with focus on typical brain regions associated with Parkinson's disease pathology. CI, ND and DTI diffusivity metrics (AD, MD, RD) demonstrated the ability to differentiate between groups, with strongest performance within the thalamus, prone to pathology in Parkinson's disease. Our results indicate that RSI may improve the predictive power of diffusion-based MRI, and provide additional information when combined with the standard diffusivity measurements. In the absence of major atrophy, diffusion techniques may reveal microstructural pathology. Our results suggest that protocols for MRI diffusion imaging may be adapted to more sensitive detection of pathology at different sites of the central nervous system.
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Diagnóstico por Imagen , Imagen de Difusión Tensora , Degeneración Nerviosa/diagnóstico , Enfermedad de Parkinson/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Tronco Encefálico/diagnóstico por imagen , Tronco Encefálico/patología , Imagen de Difusión por Resonancia Magnética , Femenino , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Humanos , Masculino , Persona de Mediana Edad , Degeneración Nerviosa/diagnóstico por imagen , Degeneración Nerviosa/patología , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/patología , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/patología , Tálamo/diagnóstico por imagen , Tálamo/patologíaRESUMEN
Glial cell line-derived neurotrophic factor (GDNF) has potent neurotrophic effects and is known to promote the dopaminergic (DA) neuronal survival in cellular and animal models of Parkinson's disease (PD). However, long-term ectopic GDNF delivery is associated with long lasting adverse side effects in PD patients. Therefore, finding safer and effective ways to elevate endogenous GDNF levels is an active area of research. This study underlines the importance of sodium benzoate (NaB), a metabolite of commonly-used spice cinnamon, a food-additive and an FDA-approved drug against hyperammonemia, in stimulating GDNF in primary mouse and human astrocytes. Presence of cAMP response element (CRE) in the Gdnf gene promoter, recruitment of CREB to the Gdnf promoter by NaB and abrogation of NaB-mediated GDNF expression by siRNA knockdown of CREB suggest that NaB induces the transcription of Gdnf via CREB. Finally, oral administration of NaB and cinnamon itself increased the level of GDNF in vivo in the substantia nigra pars compacta (SNpc) of normal as well as MPTP-intoxicated mice. Accordingly, cinnamon and NaB treatment protected tyrosine hydroxylase positive neurons in the SNpc and fibers in the striatum, normalized striatal neurotransmitters, and improved locomotor activities in MPTP-intoxicated Gfapcre mice, but not GdnfΔastro mice lacking GDNF in astrocytes. These findings highlight the importance of astroglial GDNF in cinnamon- and NaB-mediated protection of the nigrostriatum in MPTP mouse model of PD and suggest possible therapeutic potential of cinnamon and NaB in PD patients. Graphical abstract Cinnamon metabolite sodium benzoate (NaB) activates cAMP-response element-binding (CREB) via protein kinase A (PKA) in astrocytes. Activated CREB then binds to cAMP-response element (CRE) present in GDNF gene promoter to stimulate the transcription of GDNF in astrocytes. This astrocytic GDNF leads to nigral trophism and protects dopaminergic neurons from MPTP insult.
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Antiparkinsonianos/uso terapéutico , Astrocitos/metabolismo , Cinnamomum zeylanicum/metabolismo , Cuerpo Estriado/efectos de los fármacos , Factor Neurotrófico Derivado de la Línea Celular Glial/fisiología , Trastornos Parkinsonianos/tratamiento farmacológico , Benzoato de Sodio/farmacología , Sustancia Negra/efectos de los fármacos , Animales , Antiparkinsonianos/farmacología , Biotransformación , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Evaluación Preclínica de Medicamentos , Conducta Exploratoria , Regulación de la Expresión Génica/efectos de los fármacos , Factor Neurotrófico Derivado de la Línea Celular Glial/biosíntesis , Factor Neurotrófico Derivado de la Línea Celular Glial/genética , Humanos , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/patología , Ratones , Ratones Endogámicos C57BL , Trastornos Parkinsonianos/patología , Porción Compacta de la Sustancia Negra/efectos de los fármacos , Porción Compacta de la Sustancia Negra/metabolismo , Porción Compacta de la Sustancia Negra/patología , Corteza de la Planta , Regiones Promotoras Genéticas/genética , Prueba de Desempeño de Rotación con Aceleración Constante , Sustancia Negra/metabolismo , Sustancia Negra/patología , Factores de Transcripción/metabolismo , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Parkinson's disease (PD), a multifactorial movement disorder that involves progressive degeneration of the nigrostriatal system affecting the movement ability of the patient. Oxidative stress and neuroinflammation both are shown to be involved in the etiopathogenesis of PD. The aim of this study was to evaluate the therapeutic potential of thymol, a dietary monoterpene phenol in rotenone (ROT)-induced neurodegeneration in rats that precisely mimics PD in humans. Male Wistar rats were injected ROT at a dose of 2.5 mg/kg body weight for 4 weeks, to induce PD. Thymol was co-administered for 4 weeks at a dose of 50 mg/kg body weight, 30 min prior to ROT injection. The markers of dopaminergic neurodegeneration, oxidative stress and inflammation were estimated using biochemical assays, enzyme-linked immunosorbent assay, western blotting and immunocytochemistry. ROT challenge increased the oxidative stress markers, inflammatory enzymes and cytokines as well as caused significant damage to nigrostriatal dopaminergic system of the brain. Thymol treatment in ROT challenged rats appears to significantly attenuate dopaminergic neuronal loss, oxidative stress and inflammation. The present study showed protective effects of thymol in ROT-induced neurotoxicity and neurodegeneration mediated by preservation of endogenous antioxidant defense networks and attenuation of inflammatory mediators including cytokines and enzymes.
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Dieta , Neuronas Dopaminérgicas/patología , Degeneración Nerviosa/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Timol/uso terapéutico , Animales , Catalasa/metabolismo , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Glutatión/metabolismo , Mediadores de Inflamación/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Malondialdehído/metabolismo , Neostriado/efectos de los fármacos , Neostriado/patología , Degeneración Nerviosa/patología , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Fármacos Neuroprotectores/farmacología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas Wistar , Rotenona , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Superóxido Dismutasa/metabolismo , Timol/química , Timol/farmacología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Background The substantia nigra (SN) is suspected to be affected after remote infarction, in view of its large array of connections with the supratentorial brain. Whether secondary involvement of SN worsens overall clinical outcome after a supratentorial stroke has not previously been studied. Purpose To assess longitudinal changes in SN R2* by using MRI in the setting of ipsilesional supratentorial infarct and the relationship of SN signal change to clinical outcome. Materials and Methods Participants prospectively included from 2012 to 2015 were evaluated at 24-72 hours (baseline visit) and at 1 year with MRI to quantify R2*. The SN was segmented bilaterally to calculate an R2* asymmetry index (SN-AI); greater SN-AI indicated greater relative R2* in the ipsilateral compared with contralateral SN. The 95th percentile of R2* (hereafter, SN-AI95) was compared according to infarct location with mixed linear regression models. We also conducted voxel-based comparisons of R2* and identified individual infarcted voxels associated with high SN-AI95 through voxel-based lesion-symptom mapping. Multivariable regression models tested the association between SN-AI95 and clinical scores. Results A total of 181 participants were evaluated (127 men, 54 women; mean age ± standard deviation, 64.2 years ± 13.1; 75 striatum infarcts, 106 other locations). Visual inspection, SN-AI95, and average maps consistently showed higher SN R2* at 1 year if ipsilateral striatum was infarcted than if it was not (SN-AI95, 4.25 vs -0.88; P < .001), but this was not observed at baseline. The striatal location of the infarct was associated with higher SN-AI95 at 1 year independently from infarct volume, SN-AI95 at baseline, microbleeds, age, and sex (ß = 4.99; P < .001). Voxel-based lesion-symptom mapping confirmed that striatum but also insula, internal capsule, and external capsule were associated with higher SN-AI95 at 1 year. SN-AI95 was an independent contributor of poor motor outcome (Box and Block Test, ß = -.62 points; P = .01). Conclusion In patients with stroke, greater substantia nigra R2*, likely reflective of greater iron content, can be observed at 1 year ipsilateral from remote infarcts of specific location, which is associated with worse motor function. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Vernooij in this issue.
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Infarto Encefálico/diagnóstico por imagen , Infarto Encefálico/patología , Imagen por Resonancia Magnética , Sustancia Negra/diagnóstico por imagen , Sustancia Negra/patología , Anciano , Infarto Encefálico/epidemiología , Infarto Encefálico/terapia , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Parkinson's disease (PD) is one of the widely reported neurodegenerative disorders affecting more than ten million people worldwide. Due to therapeutic limitations and several adverse effects associated with currently used drugs, it is crucial to search for safe and effective options for treatment of PD. Oxidative stress, mitochondrial dysfunction, α-synuclein oligomeric aggregates, and glucocerebrosidase (GCase) deficiency are involved in PD pathogenesis. Rebamipide, an anti-ulcer drug, is a proven free-radical scavenger and antioxidant. The drug has shown neuroprotective effects in cultured SH-SY5Y cells. Therefore, we investigated the pharmacological effect of rebamipide in 6-hydroxydopamine (6-OHDA)-induced experimental PD model. Rebamipide was given to adult male albino rats of Charles-Foster strain in 20, 40, and 80 mg/kg (R-20, R-40, and R-80) oral dose twice daily for 24 days (day 4 to day 27) after 6-OHDA intrastriatal injection. The drug inhibited 6-OHDA-induced motor deficits and nigral α-synuclein aggregates in dose-dependent manner. R-40 and R-80 dose dependently increased striatal mitochondrial complex I, II, IV, and V activities; mitochondrial bioenergetics; and nigral GCase activity. 6-OHDA-induced lipid peroxidation was decreased. Highest dose (R-80) also decreased apoptotic proteins and upregulated striatal dopamine concentration in 6-OHDA-induced hemiparkinson's rat model. Therefore, the anti-PD effect of rebamipide may involve stabilization of mitochondrial bioenergetics, enhancement of GCase enzymatic activity as well as decreased oxidative stress with α-synuclein pathology, and apoptosis in 6-OHDA-induced hemiparkinson's rat model. Hence, preclinical evidence indicates rebamipide to be a potential drug for management of PD.