RESUMEN

BACKGROUND: High-frequency repeated transcranial magnetic stimulation (rTMS) stimulating the primary motor cortex (M1) is an alternative, adjunctive therapy for improving the motor symptoms of Parkinson's disease (PD). However, whether the high frequency of rTMS positively correlates to the improvement of motor symptoms of PD is still undecided. By controlling for other parameters, a disease animal model may be useful to compare the neuroprotective effects of different high frequencies of rTMS. OBJECTIVE: The current exploratory study was designed to compare the protective effects of four common high frequencies of rTMS (5, 10, 15, and 20 Hz) and iTBS (a special form of high-frequency rTMS) and explore the optimal high-frequency rTMS on an animal PD model. METHODS: Following high frequencies of rTMS application (twice a week for 5 weeks) in a MPTP/probenecid-induced chronic PD model, the effects of the five protocols on motor behavior as well as dopaminergic neuron degeneration levels were identified. The underlying molecular mechanisms were further explored. RESULTS: We found that all the high frequencies of rTMS had protective effects on the motor functions of PD models to varying degrees. Among them, the 10, 15, and 20 Hz rTMS interventions induced comparable preservation of motor function through the protection of nigrostriatal dopamine neurons. The enhancement of brain-derived neurotrophic factor (BDNF), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT-2) and the suppression of TNF-α and IL-1ß in the nigrostriatum were involved in the process. The efficacy of iTBS was inferior to that of the above three protocols. The effect of 5 Hz rTMS protocol was weakest. CONCLUSIONS: Combined with the results of the present study and the possible side effects induced by rTMS, we concluded that 10 Hz might be the optimal stimulation frequency for preserving the motor functions of PD models using rTMS treatment.

Asunto(s)

Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Trastornos Parkinsonianos , Probenecid , Estimulación Magnética Transcraneal , Animales , Estimulación Magnética Transcraneal/métodos , Ratones , Masculino , Probenecid/farmacología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/terapia , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/fisiopatología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corteza Motora/metabolismo , Corteza Motora/fisiopatología , Neuronas Dopaminérgicas/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Interleucina-1beta/metabolismo , Sustancia Negra/metabolismo , Cuerpo Estriado/metabolismo , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Intoxicación por MPTP/terapia , Intoxicación por MPTP/prevención & control , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/fisiopatología , Actividad Motora/fisiología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología

RESUMEN

The gut microbiota plays a crucial role in neural development and progression of neural disorders like Parkinson's disease (PD). Probiotics have been suggested to impact neurodegenerative diseases via gut-brain axis. This study aims to investigate the therapeutic potential of Lacticaseibacillus rhamnosus E9, a high exopolysaccharide producer, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced mouse model of PD. C57BL/6 mice subjected to MPTP were fed L. rhamnosus E9 for fifteen days and sacrificed after the last administration. Motor functions were determined by open-field, catalepsy, and wire-hanging tests. The ileum and the brain tissues were collected for ELISA, qPCR, and immunohistochemistry analyses. The cecum content was obtained for microbiota analysis. E9 supplementation alleviated MPTP-induced motor dysfunctions accompanied by decreased levels of striatal TH and dopamine. E9 also reduced the level of ROS in the striatum and decreased the DAT expression while increasing the DR1. Furthermore, E9 improved intestinal integrity by enhancing ZO-1 and Occludin levels and reversed the dysbiosis of the gut microbiota induced by MPTP. In conclusion, E9 supplementation improved the MPTP-induced motor deficits and neural damage as well as intestinal barrier by modulating the gut microbiota in PD mice. These findings suggest that E9 supplementation holds therapeutic potential in managing PD through the gut-brain axis.

Asunto(s)

1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Lacticaseibacillus rhamnosus , Ratones Endogámicos C57BL , Probióticos , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Lacticaseibacillus rhamnosus/fisiología , Masculino , Probióticos/farmacología , Probióticos/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/microbiología , Cuerpo Estriado/metabolismo , Intoxicación por MPTP/microbiología , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/tratamiento farmacológico , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/efectos de los fármacos , Dopamina/metabolismo

RESUMEN

Parkinson's disease (PD) is characterized by a long prodromal period, during which patients often have sleep disturbances. The histaminergic system and circadian rhythms play an important role in the regulation of the sleep-wake cycle. Changes in the functioning of these systems may be involved in the pathogenesis of early stages of PD and may be age-dependent. Here, we have analyzed changes in the expression of genes associated with the regulation of the sleep-wake cycle (Hnmt, Hrh1, Hrh3, Per1, Per2, and Chrm3) in the substantia nigra (SN) and striatum of normal male mice of different ages, as well as in young and adult male mice with an MPTP-induced model of the early symptomatic stage (ESS) of PD. Age-dependent expression analysis in normal mouse brain tissue revealed changes in Hrh3, Per1, Per2, and Chrm3 genes in adult mice relative to young mice. When gene expression was examined in mice with the MPTP-induced model of the ESS of PD, changes in the expression of all studied genes were found only in the SN of adult mice with the ESS model of PD. These data suggest that age is a significant factor influencing changes in the expression of genes associated with sleep-wake cycle regulation in the development of PD.

Asunto(s)

Ritmo Circadiano , Animales , Ratones , Masculino , Ritmo Circadiano/genética , Regulación de la Expresión Génica , Ratones Endogámicos C57BL , Sueño/genética , Envejecimiento/genética , Modelos Animales de Enfermedad , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Sustancia Negra/metabolismo , Cuerpo Estriado/metabolismo , Intoxicación por MPTP/genética , Intoxicación por MPTP/metabolismo , Factores de Edad , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Vigilia

RESUMEN

Pterostilbene (PTE), a naturally occurring phenolic compound primarily found in blueberries, demonstrates neuroprotective properties. However, the role of PTE in Parkinson's disease (PD) remains unclear. This study aimed to investigate the neuroprotective role of PTE in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD animal model. Our findings demonstrate that administering PTE effectively reversed the diminished levels of dopamine in the striatum, thereby ameliorating motor impairments in the MPTP model. Moreover, PTE administration mitigated the loss of dopaminergic (DA) neurons and reduced the upregulation of α-synuclein (α-syn) induced by MPTP. Mechanistic analysis revealed that PTE administration inhibited the activation of microglia and astrocytes, as well as pro-inflammatory factors such as TNF-α and IL-1ß in the MPTP model. Additionally, PTE administration decreased MPTP-induced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), while increasing total antioxidant capacity (TAOC) and superoxide dismutase (SOD) activity, thereby attenuating oxidative stress. Collectively, these findings demonstrate that PTE exerts neuroprotective effects in the MPTP mouse model of PD by suppressing neuroinflammation and oxidative stress. Thus, PTE holds promise as a therapeutic agent for PD.

Asunto(s)

Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias , Fármacos Neuroprotectores , Estrés Oxidativo , Estilbenos , Animales , Estrés Oxidativo/efectos de los fármacos , Estilbenos/farmacología , Estilbenos/uso terapéutico , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Ratones , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Especies Reactivas de Oxígeno/metabolismo , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/patología , alfa-Sinucleína/metabolismo

RESUMEN

Cerebral dopamine neurotrophic factor (CDNF) and its close structural relative, mesencephalic astrocyte-derived neurotrophic factor (MANF), are proteins with neurotrophic properties. CDNF protects and restores the function of dopamine (DA) neurons in rodent and non-human primate (NHP) toxin models of Parkinson's disease (PD) and therefore shows promise as a drug candidate for disease-modifying treatment of PD. Moreover, CDNF was found to be safe and to have some therapeutic effects on PD patients in phase 1/2 clinical trials. However, the mechanism underlying the neurotrophic activity of CDNF is unknown. In this study, we delivered human CDNF (hCDNF) to the brain using an adeno-associated viral (AAV) vector and demonstrated the neurotrophic effect of AAV-hCDNF in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. AAV-hCDNF resulted in the expression of hCDNF in the striatum (STR) and substantia nigra (SN), and no toxic effects on the nigrostriatal pathway were observed. Intrastriatal injection of AAV-hCDNF reduced motor impairment and partially alleviated gait dysfunction in the acute MPTP mouse model. In addition, gene therapy with AAV-hCDNF had significant neuroprotective effects on the nigrostriatal pathway and decreased the levels of interleukin 1beta (IL-1ß) and complement 3 (C3) in glial cells in the acute MPTP mouse model. Moreover, AAV-hCDNF reduced C/EBP homologous protein (CHOP) and glucose regulatory protein 78 (GRP78) expression in astroglia. These results suggest that the neuroprotective effects of CDNF may be mediated at least in part through the regulation of neuroinflammation and the UPR pathway in a mouse MPTP model of PD in vivo.

Asunto(s)

Dependovirus , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas , Chaperón BiP del Retículo Endoplásmico , Estrés del Retículo Endoplásmico , Vectores Genéticos , Factores de Crecimiento Nervioso , Animales , Neuronas Dopaminérgicas/metabolismo , Dependovirus/genética , Ratones , Humanos , Factores de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/genética , Vectores Genéticos/administración & dosificación , Vectores Genéticos/genética , Técnicas de Transferencia de Gen , Masculino , Enfermedad de Parkinson/terapia , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/genética , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Inflamación/metabolismo , Terapia Genética/métodos , Ratones Endogámicos C57BL , Cuerpo Estriado/metabolismo , Intoxicación por MPTP/terapia , Intoxicación por MPTP/metabolismo , Sustancia Negra/metabolismo

RESUMEN

Parkinson's disease (PD) is a chronic neurodegenerative disease with unclear pathogenesis that involves neuroinflammation and intestinal microbial dysbiosis. Intercellular adhesion molecule-1 (ICAM-1), an inflammatory marker, participates in neuroinflammation during dopaminergic neuronal damage. However, the explicit mechanisms of action of ICAM-1 in PD have not been elucidated. We established a subacute PD mouse model by the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and observed motor symptoms and gastrointestinal dysfunction in mice. Immunofluorescence was used to examine the survival of dopaminergic neurons, expression of microglial and astrocyte markers, and intestinal tight junction-associated proteins. Then, we use 16 S rRNA sequencing to identify alterations in the microbiota. Our findings revealed that ICAM-1-specific antibody (Ab) treatment relieved behavioural defects, gastrointestinal dysfunction, and dopaminergic neuronal death in MPTP-induced PD mice. Further mechanistic investigations indicated that ICAM-1Ab might suppress neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra and relieving colon barrier impairment and intestinal inflammation. Furthermore, 16 S rRNA sequencing revealed that the relative abundances of bacterial Firmicutes, Clostridia, and Lachnospiraceae were elevated in the PD mice. However, ICAM-1Ab treatment ameliorated the MPTP-induced disorders in the intestinal microbiota. Collectively, we concluded that the suppressing ICAM-1 might lead to the a significant decrease of inflammation and restore the gut microbial community, thus ameliorating the damage of DA neurons.

Asunto(s)

Neuronas Dopaminérgicas , Molécula 1 de Adhesión Intercelular , Ratones Endogámicos C57BL , Animales , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Neuronas Dopaminérgicas/efectos de los fármacos , Molécula 1 de Adhesión Intercelular/metabolismo , Ratones , Masculino , Modelos Animales de Enfermedad , Enfermedades Neuroinflamatorias/metabolismo , Microbioma Gastrointestinal/fisiología , Microbioma Gastrointestinal/efectos de los fármacos , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Inflamación/metabolismo , Sustancia Negra/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Microglía/metabolismo , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Trastornos Parkinsonianos/metabolismo , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/patología

RESUMEN

Neurodegenerative diseases have common underlying pathological mechanisms including progressive neuronal dysfunction, axonal and dendritic retraction, and mitochondrial dysfunction resulting in neuronal death. The retina is often affected in common neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Studies have demonstrated that the retina in patients with Parkinson's disease undergoes changes that parallel the dysfunction in the brain. These changes classically include decreased levels of dopamine, accumulation of alpha-synuclein in the brain and retina, and death of dopaminergic nigral neurons and retinal amacrine cells leading to gross neuronal loss. Exploring this disease's retinal phenotype and vision-related symptoms is an important window for elucidating its pathophysiology and progression, and identifying novel ways to diagnose and treat Parkinson's disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson's disease in animal models. MPTP is a neurotoxin converted to its toxic form by astrocytes, transported to neurons through the dopamine transporter, where it causes mitochondrial Complex I inhibition and neuron degeneration. Systemic administration of MPTP induces retinal changes in different animal models. In this study, we assessed the effects of MPTP on the retina directly via intravitreal injection in mice (5 mg/mL and 50 mg/mL to 7, 14 and 21 days post-injection). MPTP treatment induced the reduction of retinal ganglion cells-a sensitive neuron in the retina-at all time points investigated. This occurred without a concomitant loss of dopaminergic amacrine cells or neuroinflammation at any of the time points or concentrations tested. The observed neurodegeneration which initially affected retinal ganglion cells indicated that this method of MPTP administration could yield a fast and straightforward model of retinal ganglion cell neurodegeneration. To assess whether this model could be amenable to neuroprotection, mice were treated orally with nicotinamide (a nicotinamide adenine dinucleotide precursor) which has been demonstrated to be neuroprotective in several retinal ganglion cell injury models. Nicotinamide was strongly protective following intravitreal MPTP administration, further supporting intravitreal MPTP use as a model of retinal ganglion cell injury. As such, this model could be utilized for testing neuroprotective treatments in the context of Parkinson's disease and retinal ganglion cell injury.

Asunto(s)

Ratones Endogámicos C57BL , Fármacos Neuroprotectores , Niacinamida , Células Ganglionares de la Retina , Animales , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/metabolismo , Niacinamida/farmacología , Niacinamida/administración & dosificación , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/administración & dosificación , Masculino , Ratones , Administración Oral , Inyecciones Intravítreas , Modelos Animales de Enfermedad , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/tratamiento farmacológico , Intoxicación por MPTP/patología , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/tratamiento farmacológico

RESUMEN

Mitochondrial dysfunction, a common cellular hallmark in both familial and sporadic forms of Parkinson's disease (PD), is assumed to play a significant role in pathologic development and progression of the disease. Teaghrelin, a unique bioactive compound in some oolong tea varieties, has been demonstrated to protect SH-SY5Y cells against 1-methyl-4-phenylpyridinium induced neurotoxicity by binding to the ghrelin receptor to activate the AMPK/SIRT1/PGC-1α pathway. In this study, an animal model was established using a neurotoxin, 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP), a byproduct of a prohibited drug, to evaluate the oral efficacy of teaghrelin on PD by monitoring motor dysfunction of mice in open field, pole, and bean walking tests. The results showed that MPTP-induced motor dysfunction of mice was significantly attenuated by teaghrelin supplementation. Tyrosine hydroxylase and dopamine transporter protein were found reduced in the striatum and midbrain of MPTP-treated mice, and significantly mitigated by teaghrelin supplementation. Furthermore, teaghrelin administration enhanced mitophagy and mitochondria biogenesis, which maintained cell homeostasis and prevented the accumulation of αSyn and apoptosis-related proteins. It seemed that teaghrelin protected dopaminergic neurons in MPTP-treated mice by increasing PINK1/Parkin-mediated mitophagy and AMPK/SIRT1/PGC-1α-mediated mitochondria biogenesis, highlighting its potential therapeutic role in maintaining dopaminergic neurons function in PD. Mitochondrial dysfunction, a common cellular hallmark in both familial and sporadic forms of Parkinson's disease (PD), is assumed to play a significant role in pathologic development and progression of the disease. Teaghrelin, a unique bioactive compound in some oolong tea varieties, has been demonstrated to protect SH-SY5Y cells against 1-methyl-4-phenylpyridinium induced neurotoxicity by binding to the ghrelin receptor to activate the AMPK/SIRT1/PGC-1α pathway. In this study, an animal model was established using a neurotoxin, 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP), a byproduct of a prohibited drug, to evaluate the oral efficacy of teaghrelin on PD by monitoring motor dysfunction of mice in open field, pole, and bean walking tests. The results showed that MPTP-induced motor dysfunction of mice was significantly attenuated by teaghrelin supplementation. Tyrosine hydroxylase and dopamine transporter protein were found reduced in the striatum and midbrain of MPTP-treated mice, and significantly mitigated by teaghrelin supplementation. Furthermore, teaghrelin administration enhanced mitophagy and mitochondria biogenesis, which maintained cell homeostasis and prevented the accumulation of αSyn and apoptosis-related proteins. It seemed that teaghrelin protected dopaminergic neurons in MPTP-treated mice by increasing PINK1/Parkin-mediated mitophagy and AMPK/SIRT1/PGC-1α-mediated mitochondria biogenesis, highlighting its potential therapeutic role in maintaining dopaminergic neurons function in PD.

Asunto(s)

Proteínas Quinasas Activadas por AMP , Neuronas Dopaminérgicas , Ghrelina , Ratones Endogámicos C57BL , Mitofagia , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Proteínas Quinasas , Sirtuina 1 , Ubiquitina-Proteína Ligasas , Animales , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Sirtuina 1/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Proteínas Quinasas/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/patología , Ghrelina/farmacología , Masculino , Mitofagia/efectos de los fármacos , Ratones , Proteínas Quinasas Activadas por AMP/metabolismo , Modelos Animales de Enfermedad , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Fármacos Neuroprotectores/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Biogénesis de Organelos , Enfermedad de Parkinson/tratamiento farmacológico , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/patología

RESUMEN

BACKGROUND: Parkinson's disease (PD), a neurodegenerative disorder, is characterized by motor symptoms due to the progressive loss of dopaminergic neurons in the substantia nigra (SN) and striatum (STR), alongside neuroinflammation. Asiaticoside (AS), a primary active component with anti-inflammatory and neuroprotective properties, is derived from Centella asiatica. However, the precise mechanisms through which AS influences PD associated with inflammation are not yet fully understood. PURPOSE: This study aimed to explore the protective mechanism of AS in PD. METHODS: Targets associated with AS and PD were identified from the Swiss Target Prediction, Similarity Ensemble Approach, PharmMapper, and GeneCards database. A protein-protein interaction (PPI) network was constructed to identify potential therapeutic targets. Concurrently, GO and KEGG analyses were performed to predict potential signaling pathways. To validate these mechanisms, the effects of AS on 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice were investigated. Furthermore, neuroinflammation and the activation of the NLRP3 inflammasome were assessed to confirm the anti-inflammatory properties of AS. In vitro experiments in BV2 cells were then performed to investigate the mechanisms of AS in PD. Moreover, CETSA, molecular docking, and molecular dynamics simulations (MDs) were performed for further validation. RESULTS: Network pharmacology analysis identified 17 potential targets affected by AS in PD. GO and KEGG analyses suggested the biological roles of these targets, demonstrating that AS interacts with 149 pathways in PD. Notably, the NOD-like receptor signaling pathway was identified as a key pathway mediating AS's effect on PD. In vivo studies demonstrated that AS alleviated motor dysfunction and reduced the loss of dopaminergic neurons in MPTP-induced PD mice. In vitro experiments demonstrated that AS substantially decreased IL-1ß release in BV2 cells, attributing this to the modulation of the NLRP3 signaling pathway. CETSA and molecular docking studies indicated that AS forms a stable complex with NLRP3. MDs suggested that ARG578 played an important role in the formation of the complex. CONCLUSION: In this study, we first predicted that the potential target and pathway of AS's effect on PD could be NLRP3 protein and NOD-like receptor signaling pathway by network pharmacology analysis. Further, we demonstrated that AS could alleviate symptoms of PD induced by MPTP through its interaction with the NLRP3 protein for the first time by in vivo and in vitro experiments. By binding to NLRP3, AS effectively inhibits the assembly and activation of the inflammasome. These findings suggest that AS is a promising inhibitor for PD driven by NLRP3 overactivation.

Asunto(s)

Intoxicación por MPTP , Fármacos Neuroprotectores , Enfermedad de Parkinson , Triterpenos , Ratones , Animales , Inflamasomas , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/metabolismo , Neuroprotección , Enfermedades Neuroinflamatorias , Simulación del Acoplamiento Molecular , Microglía , Enfermedad de Parkinson/metabolismo , Neuronas Dopaminérgicas , Antiinflamatorios/uso terapéutico , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico

RESUMEN

Parkinson's disease (PD) is marked by the degeneration of dopaminergic neurons of the substantia nigra (SN), with neuroinflammation and mitochondrial dysfunction being key contributors. The neuroprotective potential of folic acid (FA) in the dopaminergic system of PD was assessed in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model. MPTP (20 mg/kg of body weight) was administered to C57BL/6J mice to simulate PD symptoms followed by FA treatment (5 mg/kg of body weight). Behavioral tests, pole, rotarod, and open-field tests, evaluated motor function, while immunohistochemistry, ELISA, RT-qPCR, and Western blotting quantified neuroinflammation, oxidative stress markers, and mitochondrial function. FA supplementation considerably improved motor performance, reduced homocysteine levels and mitigated oxidative damage in the SN. The FA-attenuated activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome lessened glial cell activity and reduced neuroinflammation. At the molecular level, FA reduced DNA damage, downregulated phosphorylated p53, and induced the expression of peroxisome proliferator-activated receptor α coactivator 1α (PGC-1α), enhancing mitochondrial function. Therefore, FA exerts neuroprotection in MPTP-induced PD by inhibiting neuroinflammation via NLRP3 inflammasome suppression and promoting mitochondrial integrity through the p53-PGC-1α pathway. Notable limitations of our study include its reliance on a single animal model and the incompletely elucidated mechanisms underlying the impact of FA on mitochondrial dynamics. Future investigations will explore the clinical utility of FA and its molecular mechanisms, further advancing it as a potential therapeutic for managing and delaying the progression of PD.

Asunto(s)

Intoxicación por MPTP , Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratones , Animales , Inflamasomas/genética , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Neuronas Dopaminérgicas , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/metabolismo , Enfermedades Neuroinflamatorias , Proteína p53 Supresora de Tumor/metabolismo , Ratones Endogámicos C57BL , Enfermedad de Parkinson/genética , Mitocondrias/metabolismo , Peso Corporal , Modelos Animales de Enfermedad , Fármacos Neuroprotectores/farmacología

RESUMEN

Increasing evidence has shown that mitochondrial dysfunction and iron accumulation contribute to the pathogenesis of Parkinson's disease (PD). Nedd4 family interacting protein 1 (Ndfip1) is an adaptor protein of the Nedd4 E3 ubiquitin ligases. We have previously reported that Ndfip1 showed a neuroprotective effect in cell models of PD. However, whether Ndfip1 could protect dopaminergic neurons in PD animal models in vivo and the possible mechanisms are not known. Here, our results showed that the expression of Ndfip1 decreased in the substantia nigra (SN) of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mouse model. Overexpression of Ndfip1 could improve MPTP-induced motor dysfunction significantly and antagonize the loss of dopaminergic neurons in the SN of MPTP-induced mice. Further study showed that overexpression of Ndfip1 might protect against MPTP-induced neurotoxicity through regulation of voltage-dependent anion-selective channel (VDAC). In addition, we observed the downregulation of Ndfip1 and upregulation of VDAC1/2 in 1-methyl-4-phenylpyridinium ion (MPP+)-induced SH-SY5Y cells. Furthermore, high expression of Ndfip1 in SH-SY5Y cells inhibited MPP+-induced increase of VDAC1/2 and restored MPP+-induced mitochondrial dysfunction. Furthermore, Ndfip1 prevented MPP+-induced increase in the expression of long-chain acyl-CoA synthetase 4 (ACSL4), suggesting the possible role of Ndfip1 in regulating ferroptosis. Our results provide new evidence for the neuroprotective effect of Ndfip1 on dopaminergic neurons in PD animal models and provide promising targets for the treatment of iron-related diseases, including PD.

Asunto(s)

Ferroptosis , Intoxicación por MPTP , Enfermedades Mitocondriales , Neuroblastoma , Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Humanos , Ratones , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/patología , Hierro/metabolismo , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Neuroblastoma/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/metabolismo , Enfermedad de Parkinson/patología

RESUMEN

Currently, there is no effective treatment for Parkinson's disease (PD), and the regenerative treatment of neural stem cells (NSCs) is considered the most promising method. This study aimed to investigate the protective effect and mechanism of NSCs on neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced cynomolgus monkey (Macaca fascicularis) model of PD. We first found that injecting NSCs into the subarachnoid space relieved motor dysfunction in PD cynomolgus monkeys, as well as reduced dopaminergic neuron loss and neuronal damage in the substantia nigra (SN) and striatum. Besides, NSCs decreased 17-estradiol (E2) level, an estrogen, in the cerebrospinal fluid (CSF) of PD cynomolgus monkeys, which shows NSCs may provide neuro-protection by controlling estrogen levels in the CSF. Furthermore, NSCs elevated proliferator-activated receptor gamma coactivator-1 alpha (PGC-1a), mitofusin 2 (MFN2), and optic atrophy 1 (OPA1) expression, three genes mediating mitochondrial biogenesis, in the SN and striatum of PD monkeys. In addition, NSCs suppress reactive oxygen species (ROS) production caused by MPTP, as well as mitochondrial autophagy, therefore preserving dopaminergic neurons. In summary, our findings show that NSCs may preserve dopaminergic and neuronal cells in an MPTP-induced PD cynomolgus monkey model. These protective benefits might be attributed to NSCs' ability of modulating estrogen balance, increasing mitochondrial biogenesis, and limiting oxidative stress and mitochondrial autophagy. These findings add to our understanding of the mechanism of NSC treatment and shed light on further clinical treatment options.

Asunto(s)

Intoxicación por MPTP , Células-Madre Neurales , Enfermedad de Parkinson , Animales , Humanos , Macaca fascicularis/metabolismo , Intoxicación por MPTP/terapia , Intoxicación por MPTP/metabolismo , Células-Madre Neurales/metabolismo , Enfermedad de Parkinson/metabolismo , Neuronas Dopaminérgicas , Dopamina/metabolismo , Estrógenos/farmacología

RESUMEN

Over the years, evidence has accumulated on a possible contributive role of the cytosolic quinone reductase NQO2 in models of dopamine neuron degeneration induced by parkinsonian toxin, but most of the data have been obtained in vitro. For this reason, we asked the question whether NQO2 is involved in the in vivo toxicity of MPTP, a neurotoxin classically used to model Parkinson disease-induced neurodegeneration. First, we show that NQO2 is expressed in mouse substantia nigra dopaminergic cell bodies and in human dopaminergic SH-SY5Y cells as well. A highly specific NQO2 inhibitor, S29434, was able to reduce MPTP-induced cell death in a co-culture system of SH-SY5Y cells with astrocytoma U373 cells but was inactive in SH-SY5Y monocultures. We found that S29434 only marginally prevents substantia nigra tyrosine hydroxylase+ cell loss after MPTP intoxication in vivo. The compound produced a slight increase of dopaminergic cell survival at day 7 and 21 following MPTP treatment, especially with 1.5 and 3 mg/kg dosage regimen. The rescue effect did not reach statistical significance (except for one experiment at day 7) and tended to decrease with the 4.5 mg/kg dose, at the latest time point. Despite the lack of robust protective activity of the inhibitor of NQO2 in the mouse MPTP model, we cannot rule out a possible role of the enzyme in parkinsonian degeneration, particularly because it is substantially expressed in dopaminergic neurons.

Asunto(s)

Intoxicación por MPTP , Neuroblastoma , Ratones , Humanos , Animales , Neuronas Dopaminérgicas/metabolismo , Sustancia Negra/metabolismo , Dopamina/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad

RESUMEN

Baicalin, a potent anti-oxidative and anti-inflammatory flavonoid compound derived from Scutellaria baicalensis, has emerged as a neuroprotective agent. However, the mechanisms by which baicalin is neuroprotective in Parkinson's disease (PD) remain unclear. In this research, α-syn/MPP+ and MPTP were used to establish PD models in BV2 cells and C57BL/6 mice, respectively. The effect and mechanism of action of baicalin in PD were investigated by Western blotting, RT-qPCR, ELISA, Immunohistochemistry (IHC) staining, Immunofluorescence (IF) staining, HPLC and methods. Results demonstrate that baicalin mitigates oxidative stress, microglia activation and inflammatory response caused by α-syn/MPP+ and MPTP. It protects against dopaminergic neuron loss and relieves motor deficits. Meanwhile, baicalin not only significantly up-regulates the expression of Nrf2 and its downstream antioxidant enzyme, but also suppresses the activation of NLRP3 inflammasome simultaneously. Notably, the beneficial effects of baicalin in PD treatment are blocked by Nrf2 knockdown. This research reveals that baicalin may exert neuroprotective effects in PD treatment by suppressing the activation of NLRP3 inflammasome and it is dependent on the Nrf2-mediated antioxidative response.

Asunto(s)

Flavonoides , Intoxicación por MPTP , Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Ratones , Antioxidantes/metabolismo , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas , Flavonoides/farmacología , Flavonoides/uso terapéutico , Flavonoides/metabolismo , Inflamasomas/metabolismo , Ratones Endogámicos C57BL , Microglía , Intoxicación por MPTP/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo

RESUMEN

The study was performed to evaluate the neuroprotective effects of Benfotiamine (BFT) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) in rats. The rats were given daily doses of BFT (100 mg/kg, 200 mg/kg) through oral administration for 42 days. The rats were given a single bilateral dosage of MPTP (0.1 mg/nostril) intranasally once before the drug treatment to induce PD. On day 42, the animals were subjected to various behavioral paradigms. Post-treatment with BFT for 42 days significantly improved the motor and nonmotor fluctuations of MPTP. The results demonstrated that treatment with BFT ameliorated MPTP-induced disorders in behavior, body balance, and dopamine levels in the mid-brain. Among the post-treated groups, a high dose of BFT was the most effective treatment. Mean values are indicated in ±SEM, n = 5***(p < 0.001) when compared with the vehicle control, n = 5 ### (p < 0.001) when compared with the disease control; (p < 0.001) when compared with the BFT per se; (p < 0.001) when compared with the low dose of BFT; (p < 0.001) when compared with the high dose of BFT. Our finding suggests that BFT contributed to superior antioxidant, and anti-inflammatory and could be a novel therapeutic method for PD management. In conclusion, BFT could be a potential drug candidate for curbing and preventing PD.

Asunto(s)

Intoxicación por MPTP , Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratas , Animales , Ratones , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología , Administración Oral , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Intoxicación por MPTP/tratamiento farmacológico

RESUMEN

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characteristized by the presence of dyskinesia and the progressive loss of dopaminergic neurons. Although certain drugs can mitigate the symptoms of PD, they are unable to delay the disease progression, and their prolonged use may result in complications. Therefore, there exists an urgent necessity to identify potential agents that can effectively delay PD progression with fewer side effects. Recent research has unveiled that several traditional Chinese medicines (TCM) exhibit neuroprotective properties in various models pertinent to PD. Forsythoside A (FSA), the primary bioactive compound derived from TCM Lianqiao, has undergone extensive research in animal models of Alzheimer's disease and cerebral ischemia. However, the investigation into the impact of FSA on PD is limited in existing research. In this study, we aimed to evaluate the neuroprotective effects of FSA on MPTP-induced PD mouse model. FSA demonstrated significant improvements in the behavioral and neuropathological changes triggered by MPTP in mice. Furthermore, it exerted a suppressive effect on the activations of astrocyte and microglia. Meanwhile, Tandem mass tag (TMT)-based quantitative proteomics of striatal tissue and bioinformatics analysis were performed to elucidate the underlying mechanisms of FSA on PD mouse model. Proteomics demonstrated a total of 68 differentially expressed proteins (DEPs) were identified between HFSA and MPTP groups including 26 upregulated and 42 downregulated. Systematic bioinformatics analysis of the 68 DEPs illustrated that they were predominantly related to estrogen signaling pathway and calcium signaling pathway. The related DEPs (PLCß4, Grm2, HPAC and Cox4i1) expression levels were verified by Western blot. FSA effectively restored the altered expression of the four DEPs induced by MPTP. Summarily, FSA exerted remarkable neuroprotective effects in MPTP-induced mice. Further, our research may provide proteomics insights that contribute to the further exploration of FSA as a potential treatment for PD.

Asunto(s)

Medicamentos Herbarios Chinos , Forsythia , Glicósidos , Intoxicación por MPTP , Fármacos Neuroprotectores , Enfermedad de Parkinson , Animales , Ratones , Enfermedad de Parkinson/metabolismo , Intoxicación por MPTP/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/metabolismo , Proteómica , Neuronas Dopaminérgicas/patología , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología

RESUMEN

Butyrate (BU), a gut microbiota-derived metabolite, has been reported to play a neuroprotective role in Parkinson's disease (PD). However, the specific molecular mechanism of BU has not been fully interpreted. This work aimed to verify the protective effects of BU against MPTP/MPP+ -induced neurotoxicity and explore the mechanisms involved. The results showed that BU protected against MPTP-induced motor dysfunction and decreased tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels. Additionally, BU pretreatment improved PC12 cell viability and reduced MPP+ -induced PC12 cell apoptosis. BU treatment also attenuated MPP+ -stimulated oxidative stress and inflammatory response in PC12 cells. Furthermore, BU inhibited MPTP/MPP+ -induced hyperactivation of the JAK2/STAT3 signaling in mice and PC12 cells. Besides, a JAK2 agonist, Coumermycin A1 (C-A1), substantially reversed BU-mediated inhibition on JAK2/STAT3 phosphorylation in MPP+ -challenged PC12 cells and abated BU-induced repression on MPP+ -triggered apoptosis, oxidative stress, and inflammatory response in PC12 cells. To sum up, BU might exert neuroprotective effects against MPP+ /MPTP-induced neurotoxicity by inactivating the JAK2/STAT3 signaling.

Asunto(s)

Microbioma Gastrointestinal , Intoxicación por MPTP , Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratas , Ratones , Animales , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Butiratos , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Transducción de Señal , Células PC12 , Ratones Endogámicos C57BL

RESUMEN

Mutations in the GBA1 gene represent the major genetic risk factor for Parkinson's disease (PD). The lysosomal enzyme beta-glucocerebrosidase (GCase) encoded by the GBA1 gene participates in both the endolysosomal pathway and the immune response. Disruption of these mechanisms is involved in PD pathogenesis. However, molecular mechanisms of PD associated with GBA1 mutations (GBA-PD) are unknown today in particular due to the partial penetrance of GBA1 variants in PD. The modifiers of GBA1 penetrance have not been elucidated. We characterized the transcriptomic profiles of cells from the substantia nigra (SN) of mice with co-injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and selective inhibitor of GCase activity (conduritol-ß-epoxide, (CBE)) to mimic PD bearing GCase dysfunction (MPTP+CBE), mice treated with MPTP, mice treated with CBE and control mice treated with injection of sodium chloride (NaCl) (vehicle). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Functional clustering of differentially represented transcripts revealed more processes associated with the functioning of neurogenesis, inflammation, apoptosis and autophagy in MPTP+CBE and MPTP mice than in vehicle mice, with a more pronounced alteration of autophagy processes in MPTP+CBE mice than in MPTP mice. The PI3K-Akt-mTOR signaling pathway may be considered a potential target for therapy in PD with GCase dysfunction.

Asunto(s)

Intoxicación por MPTP , Enfermedad de Parkinson , Trastornos Parkinsonianos , Animales , Ratones , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Glucosilceramidasa/genética , Glucosilceramidasa/metabolismo , Ratones Endogámicos C57BL , Intoxicación por MPTP/patología , Enfermedad de Parkinson/patología , Trastornos Parkinsonianos/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Sustancia Negra/metabolismo

RESUMEN

Parkinson's disease (PD) is the second most frequent neurodegenerative disease associated with motor dysfunction secondary to the loss of dopaminergic neurons in the nigrostriatal axis. Actual therapy consists mainly of levodopa; however, its long-term use promotes secondary effects. Consequently, finding new therapeutic alternatives, such as neuroprotective molecules, is necessary. Among these alternatives is silybin (Sb), the major bioactive flavonolignan in silymarin. Both exert neuroprotective effects, preserving dopamine levels and dopaminergic neurons when administered in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model, being probably Sb the potential therapeutic molecule behind this effect. To elucidate the role of Sb in the PD model, we determined the dose-dependent conservation of striatal dopamine content following Sb oral administration. Then, we evaluated motor deficit tests using the best dopamine conservative dose of Sb and determined a cytokine-dependent inflammatory profile status, malondialdehyde as an oxidative stress product, and neurotrophic factors content in the MPTP-induced mouse PD model. Our results show that oral Sb at 100 mg/kg dose conserved about 60% dopamine levels. Also, Sb improved motor deficits, preserved neurotrophic factors content and mitochondrial function, reduced lipid peroxidation, diminished proinflammatory cytokines to basal levels, enhanced fractalkine production in the striatum and substantia nigra, and increased IL-10 and IL-4 levels in the substantia nigra in the MPTP mice. Thus, oral Sb may be a potential pharmacological PD treatment alternative.

Asunto(s)

Intoxicación por MPTP , Enfermedades Neurodegenerativas , Animales , Ratones , Citocinas , Silibina/farmacología , Silibina/uso terapéutico , Factor Neurotrófico Derivado del Encéfalo , Dopamina , Administración Oral , Modelos Animales de Enfermedad

RESUMEN

Neuroinflammation mediated by brain glial cells is one of the pathological drivers of Parkinson's disease (PD). Recent studies have shown that higher circulating trimethylamine N-oxide (TMAO, a gut microbiota-derived metabolite) can induce neuroinflammation and are strongly related to a variety of central nervous system diseases and adverse brain events. Herein, we explored the effect of pre-existing higher circulating TMAO on dopamine system and neuroinflammation in acute PD model mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP). TMAO pretreatment was given by adding 3% (w/v) TMAO to drinking water of mice for 21 days to induce higher circulating TMAO status, then mice were administered with MPTP (20 mg/kg, i.p) for four times in one day to construct an acute PD model mice and treated with TMAO continuously until the end of the experiment. Results demonstrated that TMAO treatment significantly increased serum TMAO levels. Moreover, high serum TMAO significantly increased activation of microglia and astrocytes both in striatum and in substantia nigra. And strikingly, high serum TMAO significantly promoted the metabolism of striatal dopamine (DA) of PD model mice, although it had no significant effect on the number of dopaminergic neurons or the content of DA. Furthermore, immunofluorescence, ELISA, and RT-qPCR results of the hippocampus also showed that high serum TMAO significantly promoted the activation of microglia and astrocytes in the dentate gyrus, increased the levels of TNF-α and IL-1ß, and upregulated gene expression of M1 microglia-related markers (including CD16, CD32, and iNOS) and A2 astrocyte-related markers (including S100a10, Ptx3, and Emp1) in mRNA levels. In summary, we found that pre-existing high serum levels of TMAO worsened the PD-related brain pathology by promoting DA metabolism, aggravating neuroinflammation and regulating glial cell polarization.

Asunto(s)

Intoxicación por MPTP , Enfermedad de Parkinson , Ratones , Animales , Enfermedad de Parkinson/patología , Dopamina/metabolismo , Intoxicación por MPTP/metabolismo , Enfermedades Neuroinflamatorias , Microglía/metabolismo , Neuronas Dopaminérgicas/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/farmacología