RESUMO
The gut microbiota and microbial metabolites influence the enteric nervous system and the central nervous system via the microbial-gut-brain axis. Increasing body of evidence suggests that disturbances in the metabolism of peripheral branched-chain amino acids (BCAAs) can contribute to the development of neurodegenerative diseases through neuroinflammatory signaling. Preliminary research has shown that longitudinal changes in serum amino acid levels in mouse models of Parkinson's disease (PD) are negatively correlated with disease progression. Therefore, the aim of the present study was to determine the changes in serum levels of short-chain fatty acids (SCFAs) in a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD after dietary BCAA supplementation. In our research, gas chromatography-mass spectrometry was used to detect serum SCFA concentrations. The data were then analyzed with principal component analysis and orthogonal partial least squares discriminant analysis. Finally, the correlations of serum SCFA levels with gut and motor function in MPTP-induced PD mice were explored. Propionic acid, acetic acid, butyric acid, and isobutyric acid concentrations were elevated in MPTP + H-BCAA mice compared with MPTP mice. Propionic acid concentration was increased the most, while the isovaleric acid concentration was decreased. Propionic acid concentration was positively correlated with fecal weight and water content and negatively correlated with the pole-climbing duration. In conclusion, these results not only suggest that propionic acid may be a potential biomarker for PD, but also indicate the possibility that PD may be treated by altering circulating levels of SCFA.
RESUMO
Neuroinflammation caused by the disorder of gut microbiota and its metabolites is associated with the pathogenesis of Parkinson's disease (PD). Thus, it is necessary to identify certain molecules derived from gut microbiota to verify whether they could become intervention targets for the treatment of PD. The branched-chain amino acids (BCAAs), as a common dietary supplement, could modulate brain function. Herein, we investigated the longitudinal shifts of microbial community in mice treated with rotenone for 0, 3 and 4 weeks by 16S rRNA gene sequencing to identify the microbial markers at different PD stages. Serum BCAAs were determined by gas chromatography-mass spectrometry. Then, rotenone-induced mice were given a high BCAA diet to evaluate the motor and non-motor functions, dopaminergic neuron loss, and inflammation levels. Using a PD mouse model, we discovered that during PD progression, the alterations of gut microbiota compositions led to the peripheral decrease of BCAAs. Based on the serum lipopolysaccharide binding protein concentrations and the levels of pro-inflammatory factors (including tumor necrosis factor-α, interleukin [IL]-1ß, and IL-6) in the colon and substantia nigra, we found that the high BCAA diet could attenuate the inflammatory levels in PD mice, and reverse motor and non-motor dysfunctions and dopaminergic neuron impairment. Together, our results emphasize the dynamic changes of gut microbiota and BCAA metabolism and propose a novel strategy for PD therapy: a high BCAA diet intervention could improve PD progression by regulating the levels of inflammation.
Assuntos
Microbioma Gastrointestinal , Doença de Parkinson , Aminoácidos de Cadeia Ramificada/metabolismo , Animais , Microbioma Gastrointestinal/fisiologia , Inflamação , Interleucina-6 , Lipopolissacarídeos , Camundongos , Doença de Parkinson/patologia , RNA Ribossômico 16S/genética , Rotenona , Fator de Necrose Tumoral alfa/metabolismoRESUMO
This study aimed to identify potential novel drug candidates and targets for Parkinson's disease. First, 970 genes that have been reported to be related to PD were collected from five databases, and functional enrichment analysis of these genes was conducted to investigate their potential mechanisms. Then, we collected drugs and related targets from DrugBank, narrowed the list by proximity scores and Inverted Gene Set Enrichment analysis of drug targets, and identified potential drug candidates for PD treatment. Finally, we compared the expression distribution of the candidate drug-target genes between the PD group and the control group in the public dataset with the largest sample size (GSE99039) in Gene Expression Omnibus. Ten drugs with an FDR < 0.1 and their corresponding targets were identified. Some target genes of the ten drugs significantly overlapped with PD-related genes or already known therapeutic targets for PD. Nine differentially expressed drug-target genes with p < 0.05 were screened. This work will facilitate further research into the possible efficacy of new drugs for PD and will provide valuable clues for drug design.
Assuntos
Antiparkinsonianos/isolamento & purificação , Descoberta de Drogas , Terapia de Alvo Molecular , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/farmacologia , Linhagem Celular , Mineração de Dados/métodos , Bases de Dados Genéticas , Bases de Dados de Produtos Farmacêuticos , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos , Transporte de Elétrons/genética , Metabolismo Energético/genética , Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Humanos , Transporte de Íons/genética , Redes e Vias Metabólicas/genética , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/genética , Doença de Parkinson/genética , Mapeamento de Interação de ProteínasRESUMO
Schisandrin, an active component extracted from Schisandra chinensis (Turcz.) Baill has been reported to alleviate the cognitive impairment in neurodegenerative disorder like Alzheimer's disease (AD). However, the mechanism by which schisandrin regulates the cognitive decline is still unclear. In our study, intracerebroventricular injection of streptozotocin (STZ) was employed to establish AD model in male Wistar rats, and indicated dose of schisandrin was further administered. The Morris water maze test was performed to evaluate the ability of learning and memory in rats with schisandrin treatment. The results indicated that schisandrin improved the capacity of cognition in STZ-induced rats. The contents of pro-inflammatory cytokines in brain tissue were determined by ELISA, and the expressions of these cytokines were assessed by western-blot and immunohistochemistry. The results showed that treatment of schisandrin significantly reduced the production of inflammation mediators including tumor necrosis factor-α, interleukin-1ß and interleukin-6. Further study suggested a remarkable decrease in the expressions of ER stress maker proteins like C/EBP-homologous protein, glucose-regulated protein 78 and cleaved caspase-12 in the presence of schisandrin, meanwhile the up-regulation of sirtuin 1 (SIRT1) was also observed in the same group. Additionally, the results of western-blot and EMSA demonstrated that schisandrin inhibited NF-κB signaling in the brain of STZ-induced rats. In conclusion, schisandrin ameliorated STZ-induced cognitive dysfunction, ER stress and neuroinflammation which may be associated with up-regulation of SIRT1. Our study provides novel mechanisms for the neuroprotective effect of schisandrin in AD treatment.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Ciclo-Octanos/farmacologia , Ciclo-Octanos/uso terapêutico , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Lignanas/farmacologia , Lignanas/uso terapêutico , Fitoterapia , Compostos Policíclicos/farmacologia , Compostos Policíclicos/uso terapêutico , Schisandra/química , Estreptozocina , Animais , Modelos Animais de Doenças , Masculino , Ratos Wistar , Sirtuína 1/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
The aim of the present study was to investigate the effect of electroacupuncture (EA) at the Zusanli (ST36) acupoint on somatostatin mRNA expression in the rat brainstem. A total of 96 Sprague-Dawley rats were randomly assigned to a control (n = 24), restraint (n = 24), pseudopoint-EA (n = 24), or Zusanli-EA (n = 24) group. The rats received stimulation for 30 min at 2, 4, 6, and 8 h after stimulation. Brainstem samples (n = 6 for each group at each time point) were collected, and somatostatin expression was assessed by reverse transcription polymerase chain reaction, northern blot, and immunohistochemical staining. Somatostatin mRNA expression was inhibited at 2 h after EA stimulation, but an increase was seen at 6 and 8 h in the Zusanli-EA group compared to the three control groups. With respect to immunohistochemical staining, the number of somatostatin-positive cells in the brainstem was increased in the Zusanli-EA group at 6 and 8 h after stimulation compared to the 2- and 4-h time point. These results indicate that Zusanli-EA increased somatostatin mRNA and protein expression in the brainstem. Somatostatin may therefore be involved in some of the analgesic effects of Zusanli-EA.