Lactulose and Melibiose Inhibit α-Synuclein Aggregation and Up-Regulate Autophagy to Reduce Neuronal Vulnerability

Chen, Chiung Mei; Lin, Chin‐Feng; Wu, Yih Ru; Yen, Chien Yu; Huang, Yu‐Ting; Lin, Jia Lan; Chen, Wan Ling; Chao, Chuck C.‐K.; Lee-Chen, Guey Jen; Su, Ming; Chang, Kuo Hsuan

doi:10.3390/cells9051230

Cited by 13 publications

(18 citation statements)

References 61 publications

(81 reference statements)

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“…Indole derivative NC001-8 also protects DAergic neurons derived from SH-SY5Y or iPSCs carrying PRKN mutation against MPP + and H 2 O 2 -induced neurotoxicity by up-regulating NRF2 and NQO1 [ 98 ]. By up-regulating autophagy and NRF2 pathway, disaccharides, including trehalose, lactulose and melibiose, demonstrate neuroprotective effects against α-synuclein-induced neurotoxicity [ 283 ]. Several natural compounds, such as kahweol [ 284 ], luteolin [ 285 ], ginsenoside Rb1 [ 286 ], eriodictyol [ 287 ], licochalcone A [ 288 ], genipin [ 97 ] and gastrodin [ 289 ] also demonstrate neuroprotective effects by up-regulating NRF2 pathway in different PD models.…”

Section: Potentials Of Antioxidants In Treating Parkinson’s Diseasmentioning

confidence: 99%

The Role of Oxidative Stress in Parkinson’s Disease

2020

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Parkinson’s disease (PD) is caused by progressive neurodegeneration of dopaminergic (DAergic) neurons with abnormal accumulation of α-synuclein in substantia nigra (SN). Studies have suggested the potential involvement of dopamine, iron, calcium, mitochondria and neuroinflammation in contributing to overwhelmed oxidative stress and neurodegeneration in PD. Function studies on PD-causative mutations of SNCA, PRKN, PINK1, DJ-1, LRRK2, FBXO7 and ATP13A2 further indicate the role of oxidative stress in the pathogenesis of PD. Therefore, it is reasonable that molecules involved in oxidative stress, such as DJ-1, coenzyme Q10, uric acid, 8-hydroxy-2’-deoxyguanosin, homocysteine, retinoic acid/carotenes, vitamin E, glutathione peroxidase, superoxide dismutase, xanthine oxidase and products of lipid peroxidation, could be candidate biomarkers for PD. Applications of antioxidants to modulate oxidative stress could be a strategy in treating PD. Although a number of antioxidants, such as creatine, vitamin E, coenzyme Q10, pioglitazone, melatonin and desferrioxamine, have been tested in clinical trials, none of them have demonstrated conclusive evidence to ameliorate the neurodegeneration in PD patients. Difficulties in clinical studies may be caused by the long-standing progression of neurodegeneration, lack of biomarkers for premotor stage of PD and inadequate drug delivery across blood–brain barrier. Solutions for these challenges will be warranted for future studies with novel antioxidative treatment in PD patients.

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Section: Potentials Of Antioxidants In Treating Parkinson’s Diseasmentioning

confidence: 99%

The Role of Oxidative Stress in Parkinson’s Disease

2020

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“…However, orally administrated trehalose could be greatly digested by intestinal trehalase before entering into the brain, resulting in its pharmacological ineffectiveness [ 21 , 22 , 23 ]. Melibiose (MEL), an analogue of trehalose, might be maintained with a high therapeutic concentration in the brain by oral administration due to absence of intestinal melibiase [ 24 ]. Moreover, a study has indicated that melibiose could cross the blood-brain barrier (BBB) [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

Melibiose Confers a Neuroprotection against Cerebral Ischemia/Reperfusion Injury by Ameliorating Autophagy Flux via Facilitation of TFEB Nuclear Translocation in Neurons

Zhang

Yuyuan

et al. 2021

Life

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Autophagic/lysosomal dysfunction is a critical pathogenesis of neuronal injury after ischemic stroke. Trehalose has been validated to restore the impaired autophagy flux by boosting transcription factor EB (TFEB) nuclear translocation, but orally administrated trehalose can be greatly digested by intestinal trehalase before entering into brain. Melibiose (MEL), an analogue of trehalose, may thoroughly exert its pharmacological effects through oral administration due to absence of intestinal melibiase. The present study was to investigate whether melibiose could also confer a neuroprotection by the similar pharmacological mechanism as trehalose did after ischemic stroke. The rats were pretreated with melibiose for 7 days before middle cerebral artery occlusion (MCAO) surgery. Twenty-four hours following MCAO/reperfusion, the cytoplasmic and nuclear TFEB, and the proteins in autophagic/lysosomal pathway at the penumbra were detected by western blot and immunofluorescence, respectively. Meanwhile, the neurological deficit, neuron survival, and infarct volume were assessed to evaluate the therapeutic outcomes. The results showed that the neurological injury was significantly mitigated in MCAO+MEL group, compared with that in MCAO group. Meanwhile, nuclear TFEB expression in neurons at the penumbra was significantly promoted by melibiose. Moreover, melibiose treatment markedly enhanced autophagy flux, as reflected by the reinforced lysosomal capacity and reduced autophagic substrates. Furthermore, the melibiose-elicited neuroprotection was prominently counteracted by lysosomal inhibitor Bafilomycin A1 (Baf-A1). Contrarily, reinforcement of lysosomal capacity with EN6 further improved the neurological performance upon melibiose treatment. Our data suggests that melibiose-augmented neuroprotection may be achieved by ameliorating autophagy flux via facilitation of TFEB nuclear translocation in neurons after ischemic stroke.

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“…In the brain, activated microglia release proinflammatory mediators in response to neuroinflammation [ 33 ]. To investigate α-synuclein induced inflammation in mouse BV-2 microglial cells, α-synuclein fibrils prepared from the Escherichia coli -derived α-synuclein [ 34 ] were used to activate BV-2 cells ( Figure 1 a). As shown in Figure 1 b, the resting BV-2 microglia exhibited a ramified morphology.…”

Section: Resultsmentioning

confidence: 99%

“…The A53T mutation is a point mutation of α-synuclein that enhances its rate of fibrillization, leading to early-onset PD [ 73 ]. A53T mutation was introduced into SNCA cDNA [ 34 ] by site-directed mutagenesis (QuikChange II XL mutagenesis kit; Stratagene, La Jolla, CA, USA) using primer 5′-GTGGTGCATGGTGTG A CAACAGTGGCTGAGAAG-3′ (mutated nucleotide underlined) and sequenced. Then the A53T SNCA cDNA acid (and GFP (from pEGFP-N1, Invitrogen) were subcloned into pcDNA5/FRT/TO (Invitrogen) to generate in-frame A53T SNCA-GFP.…”

Section: Methodsmentioning

confidence: 99%

Pathomechanism Characterization and Potential Therapeutics Identification for Parkinson’s Disease Targeting Neuroinflammation

Chen

Yen

Chen

et al. 2021

IJMS

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Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons and the presence of α-synuclein-containing Lewy bodies. The unstructured α-synuclein forms insoluble fibrils and aggregates that result in increased reactive oxygen species (ROS) and cellular toxicity in PD. Neuroinflammation engaged by microglia actively contributes to the pathogenesis of PD. In this study, we showed that VB-037 (a quinoline compound), glycyrrhetic acid (a pentacyclic triterpenoid), Glycyrrhiza inflata (G. inflata, a Chinese herbal medicine), and Shaoyao Gancao Tang (SG-Tang, a formulated Chinese medicine) suppressed the nitric oxide (NO) production and interleukin (IL)-1β maturation in α-synuclein-stimulated BV-2 cells. Mouse inflammation antibody array further revealed increased IL-1α, IL-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) expression in α-synuclein-inflamed BV-2 cells and compound pretreatment effectively reduced the expression and release of these pro-inflammatory mediators. The test compounds and herbal medicines further reduced α-synuclein aggregation and associated oxidative stress, and protected cells against α-synuclein-induced neurotoxicity by downregulating NLR family pyrin domain containing 1 (NLRP1) and 3 (NLRP3), caspase 1, IL-1β, IL-6, and associated nuclear factor (NF)-κB inhibitor alpha (IκBα)/NF-κB P65 subunit (P65), c-Jun N-terminal kinase (JNK)/proto-oncogene c-Jun (JUN), mitogen-activated protein kinase 14 (P38)/signal transducer and activator of transcription 1 (STAT1) and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathways in dopaminergic neurons derived from α-synuclein-expressing SH-SY5Y cells. Our findings indicate the potential of VB-037, glycyrrhetic acid, G. inflata, and SG-Tang through mitigating α-synuclein-stimulated neuroinflammation in PD, as new drug candidates for PD treatment.

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Lactulose and Melibiose Inhibit α-Synuclein Aggregation and Up-Regulate Autophagy to Reduce Neuronal Vulnerability

Cited by 13 publications

References 61 publications

The Role of Oxidative Stress in Parkinson’s Disease

The Role of Oxidative Stress in Parkinson’s Disease

Melibiose Confers a Neuroprotection against Cerebral Ischemia/Reperfusion Injury by Ameliorating Autophagy Flux via Facilitation of TFEB Nuclear Translocation in Neurons

Pathomechanism Characterization and Potential Therapeutics Identification for Parkinson’s Disease Targeting Neuroinflammation

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