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1.
Eur J Pharmacol ; 907: 174262, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34146589

RESUMO

Parkinson's disease (PD) is the prevalent neurodegenerative disorder characterized by the degeneration of the nigrostriatal neurons. Dynamin-related protein 1 (Drp1) is a key regulator mediating mitochondrial fission and affecting mitophagy in neurons. It has been reported that the inhibition of Drp1 may be beneficial to PD. However, the role of Drp1 and mitophagy in PD remains elusive. Therefore, in this research, we investigated the role of Drp1 and the underlying mechanisms in the mice model of PD. We used the dynasore, a GTPase inhibitor, to inhibit the expression of Drp1. We found that inhibition of Drp1 could ameliorate the motor deficits and the expression of tyrosine hydroxylase in the mice of the PD model. But Drp1 inhibition did not affect mitochondria number and morphological parameters. Moreover, suppression of Drp1 up-regulated the mitochondrial expressions of PINK1 and Parkin while not affected the expressions of NIX and BNIP3. Conclusively, our findings suggest that the inhibition of Drp1 ameliorated the mitochondrial ultrastructure at least via regulating PINK1 and Parkin in the mice of the PD model. This study also implicates that inhibition of Drp1 might impact mitophagy and recover mitochondrial homeostasis in PD.

3.
Am J Chin Med ; 49(3): 627-643, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33657988

RESUMO

Depression is a common neuropsychiatric symptom of Parkinson's disease (PD), resulting in a lower quality of life and cognitive impairment in PD patients. Traditional Chinese medicine (TCM) formulas have been widely used in neurodegenerative disease and neuropsychic disorders to improve life quality of patients in ethnomedicine. TCM formulas combined with selective serotonin reuptake inhibitors (SSRIs) also have a positive effect on depressed PD compared with SSRIs as reported by several clinical studies. However, the results are discordant and failed to be conclusive. We aim to evaluate the efficacy of TCM formulas combined with SSRIs for depressed PD in this systematic review. We searched literatures from PubMed, Web of Science, Medline, Embase, Google Scholar, Chinese National Knowledge Infrastructure, Wanfang Database, and VIP Information Database before July 2020. We included randomized controlled trials investigating the efficacy of TCM formulas combined with SSRIs on depressed PD patients. This analysis was according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Eleven randomized clinical trials involving 861 subjects were enrolled in this analysis. The overall results showed that TCM formulas combined with SSRIs significantly improved the depression score [weighted mean difference (WMD): -4.920, 95% confidence interval (CI): (-5.999, -3.840); [Formula: see text]¡ 0.001] and had a statistical significance on Unified Parkinson's Disease Rating Scale II score [WMD: -1.209, 95% CI: (-1.561, -0.857); [Formula: see text] < 0.001]. Furthermore, we observed that Chai-Hu-Shu-Gan Powder combined with SSRIs had a significant improvement on the depressive symptom in PD compared to the SSRIs alone [WMD: -5.390, 95% CI: (-7.66, -3.11); [Formula: see text] < 0.001]. No severe side events were reported in these included trials. This systematic review provided the evidences that TCM formulas combined with SSRIs might be helpful and safe in the treatment of depression of PD, including Chai-Hu-Shu-Gan Powder. Also, more randomized double-blinded trials with reliable design are required in the future.


Assuntos
Depressão/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Medicina Tradicional Chinesa , Doença de Parkinson/tratamento farmacológico , Fitoterapia , Extratos Vegetais/administração & dosagem , Inibidores de Captação de Serotonina/administração & dosagem , Depressão/etiologia , Quimioterapia Combinada , Feminino , Humanos , Masculino , Doença de Parkinson/complicações , Resultado do Tratamento
4.
Pharmacol Res ; 170: 105541, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33711434

RESUMO

Diversiform ways of intercellular communication are vital links in maintaining homeostasis and disseminating physiological states. Among intercellular bridges, tunneling nanotubes (TNTs) discovered in 2004 were recognized as potential pharmacology targets related to the pathogenesis of common or infrequent neurodegenerative disorders. The neurotoxic aggregates in neurodegenerative diseases including scrapie prion protein (PrPSc), mutant tau protein, amyloid-beta (Aß) protein, alpha-synuclein (α-syn) as well as mutant Huntington (mHTT) protein could promote TNT formation via certain physiological mechanisms, in turn, mediating the intercellular transmission of neurotoxicity. In this review, we described in detail the skeleton, the formation, the physicochemical properties, and the functions of TNTs, while paying particular attention to the key role of TNTs in the transport of pathological proteins during neurodegeneration.

5.
Cell Mol Neurobiol ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33528716

RESUMO

Parkinson's disease (PD) is a severe neurodegenerative disorder caused by the progressive loss of dopaminergic neurons in the substantia nigra and affects millions of people. Currently, mitochondrial dysfunction is considered as a central role in the pathogenesis of both sporadic and familial forms of PD. Mitophagy, a process that selectively targets damaged or redundant mitochondria to the lysosome for elimination via the autophagy devices, is crucial in preserving mitochondrial health. So far, aberrant mitophagy has been observed in the postmortem of PD patients and genetic or toxin-induced models of PD. Except for mitochondrial dysfunction, mitophagy is involved in regulating several other PD-related pathological mechanisms as well, e.g., oxidative stress and calcium imbalance. So far, the mitophagy mechanisms induced by PD-related proteins, PINK1 and Parkin, have been studied widely, and several other PD-associated genes, e.g., DJ-1, LRRK2, and alpha-synuclein, have been discovered to participate in the regulation of mitophagy as well, which further strengthens the link between mitophagy and PD. Thus, in this view, we reviewed mitophagy pathways in belief and discussed the interactions between mitophagy and several PD's pathological mechanisms and how PD-related genes modulate the mitophagy process.

6.
Brain Res Bull ; 168: 100-109, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33387636

RESUMO

Current treatments for Parkinson's disease (PD) are mainly dopaminergic drugs. However, dopaminergic drugs are only symptomatic treatments and limited by several side effects. Recent studies into drug development focused on emerging new molecular mechanisms, including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, nuclear receptor-related 1 (Nurr1), adenosine receptor A2, nicotine receptor, metabotropic glutamate receptors (mGluRs), and glucocerebrosidase (GCase). Also, immunotherapy and common pathological mechanisms shared with Alzheimer's Disease (AD) and diabetes have attracted much attention. In this review, we summarized the development of preclinical and clinical studies of novel drugs and the improvement of dopaminergic drugs to provide a prospect for PD treatment.

7.
Eur J Neurosci ; 53(9): 2946-2959, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32031280

RESUMO

The critical role of mitochondrial dysfunction in the pathological mechanisms of neurodegenerative disorders, particularly Parkinson's disease (PD), is well established. Compelling evidence indicates that Parkinson's proteins (e.g., α-synuclein, Parkin, PINK1, DJ-1, and LRRK2) are associated with mitochondrial dysfunction and oxidative stress in PD. Significantly, there is a possible central role of alpha-synuclein (α-Syn) in the occurrence of mitochondrial dysfunction and oxidative stress by the mediation of different signaling pathways. Also, tau, traditionally considered as the main component of neurofibrillary tangles, aggregates and amplifies the neurotoxic effects on mitochondria by interacting with α-Syn. Moreover, oxidative stress caused by mitochondrial dysfunction favors assembly of both α-Syn and tau and also plays a key role in the formation of protein aggregates. In this review, we provide an overview of the relationship between these two pathological proteins and mitochondrial dysfunction in PD, and also summarize the underlying mechanisms in the interplay of α-Syn aggregation and phosphorylated tau targeting the mitochondria, to find new strategies to prevent PD processing.


Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo
8.
Cell Mol Neurobiol ; 41(7): 1395-1411, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32623547

RESUMO

Parkinson's disease (PD), as one of the complex neurodegenerative disorders, affects millions of aged people. Although the precise pathogenesis remains mostly unknown, a significant number of studies have demonstrated that mitochondrial dysfunction acts as a major role in the pathogeny of PD. Both nuclear and mitochondrial DNA mutations can damage mitochondrial integrity. Especially, mutations in several genes that PD-linked have a closed association with mitochondrial dysfunction (e.g., Parkin, PINK1, DJ-1, alpha-synuclein, and LRRK2). Parkin, whose mutation causes autosomal-recessive juvenile parkinsonism, plays an essential role in mitochondrial quality control of mitochondrial biogenesis, mitochondrial dynamics, and mitophagy. Therefore, we summarized the advanced studies of Parkin's role in mitochondrial quality control and hoped it could be studied further as a therapeutic target for PD.

9.
Acta Pharmacol Sin ; 42(9): 1409-1421, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33214696

RESUMO

Huntington's disease (HD) is one of main neurodegenerative diseases, characterized by striatal atrophy, involuntary movements, and motor incoordination. Ginsenoside Rg1 (Rg1), an active ingredient in ginseng, possesses a variety of neuroprotective effects with low toxicity and side effects. In this study, we investigated the potential therapeutic effects of Rg1 in a mouse model of HD and explored the underlying mechanisms. HD was induced in mice by injection of 3-nitropropionic acid (3-NP, i.p.) for 4 days. From the first day of 3-NP injection, the mice were administered Rg1 (10, 20, 40 mg·kg-1, p.o.) for 5 days. We showed that oral pretreatment with Rg1 alleviated 3-NP-induced body weight loss and behavioral defects. Furthermore, pretreatment with Rg1 ameliorated 3-NP-induced neuronal loss and ultrastructural morphological damage in the striatum. Moreover, pretreatment with Rg1 reduced 3-NP-induced apoptosis and inhibited the activation of microglia, inflammatory mediators in the striatum. We revealed that Rg1 exerted neuroprotective effects by suppressing 3-NP-induced activation of the MAPKs and NF-κΒ signaling pathways in the striatum. Thus, our results suggest that Rg1 exerts therapeutic effects on 3-NP-induced HD mouse model via suppressing MAPKs and NF-κΒ signaling pathways. Rg1 may be served as a novel therapeutic option for HD.

10.
Int Immunopharmacol ; 91: 107269, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33340781

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease with complicated pathogenesis. A novel bibenzyl compound 2-[4-hydroxy-3-(4-hydroxyphenyl)benzyl]-4-(4-hydroxyphenyl)phenol (20C) has been shown to have some neuroprotective effects, and its mechanism still needs further research. In this study, we used a 6-hydroxydopamine (6-OHDA)-induced PD rat model to evaluate the protective effect of 20C. Our study found that 20C could improve behavioral defects in 6-OHDA-lesion rats, decrease neuroinflammation and protect their DA neurons. It could inhibit the activity of inducible nitric oxide synthase (iNOS) induced by 6-OHDA, and lead to a decrease in the expression of nitrated-α-synuclein. When exposed to AMT-an inhibitor of iNOS, the nitrated-α-synuclein in PC12 decreased, and 20C demonstrated the same function on nitrated-α-synuclein as AMT. Besides, we also found that nitrated-α-synuclein was displayed in microglia. And 20C could decrease the expression of antigen-presenting molecule major histocompatibility complex I (MHC I) in dopamine (DA) neurons and MHC II in microglia induced by 6-OHDA. So, these imply that nitrated-α-synuclein might act as an endogenous antigen activating adaptive immunity, and the neuroprotection of 20C might be associated with inhibiting the activity of iNOS, decreasing the expression of the antigen molecule nitrated-α-synuclein and the antigen presenting molecule MHC. Our results indicated that inhibiting iNOS might be an effective strategy to protect neurons from oxidative stress.


Assuntos
Bibenzilas/farmacologia , Encéfalo/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Microglia/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/imunologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Endocitose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Mediadores da Inflamação/metabolismo , Masculino , Microglia/imunologia , Microglia/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxidopamina , Células PC12 , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/imunologia , Transtornos Parkinsonianos/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , alfa-Sinucleína/metabolismo
11.
Bioorg Chem ; 97: 103659, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32078940

RESUMO

Seven flavonoid dimers, biflavocochins A-G, together with six known compounds were isolated from the red resins of Dracaena cochinchinensis (Chinese dragon's blood). Their structures were elucidated based on extensive spectroscopic analysis. The absolute configurations of 1-7 was assigned by experimental and quantum chemical calculated ECD spectra, and that of 4 was further established by X-ray diffraction analysis using Cu Kα radiation. Compounds 1-3 are novel dimers of homoisoflavonoid and dihydrochalcone with a unique dibenzopyran ring. Compounds 2, 6, 7 exhibited moderate PTP1B inhibitory activities in an enzyme assay. Compound 1 showed neuroprotective effect on serum deficiency-induced cellular damage in PC12 cells.


Assuntos
Dracaena/química , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Animais , Cristalografia por Raios X , Dimerização , Inibidores Enzimáticos/química , Flavonoides/química , Humanos , Modelos Moleculares , Fármacos Neuroprotetores/química , Células PC12 , Extratos Vegetais/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , Ratos
12.
Toxicol Lett ; 324: 20-29, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31987890

RESUMO

Similar to other types of neuronal degeneration, Parkinson's disease (PD) is characterized by the aggregation of a pathological protein, α-synuclein. The endoplasmic reticulum (ER) is the principal site of protein synthesis, quality control and degradation. Genetic mutants, environmental insults and other factors disturb ER balance and induce the accumulation of misfolded/unfolded proteins, which initiate ER stress and disturb normal cell function. ER stress perturbs Ca2+ homeostasis and initiates the activation of autophagy and inflammasomes, which have been identified as risk factors for the development of PD. However, the mechanisms by which ER stress contributes to the processed of PD pathogenesis and development remain unclear. This review summarizes current knowledge of ER stress and highlights the principal role of ER stress in PD pathogenesis which may help reveal novel sight to illustrate the pathomechanism of PD.


Assuntos
Estresse do Retículo Endoplasmático/fisiologia , Doença de Parkinson/etiologia , Fator 6 Ativador da Transcrição/fisiologia , Adaptação Fisiológica , Animais , Autofagia , Cálcio/metabolismo , Endorribonucleases/fisiologia , Humanos , Doença de Parkinson/fisiopatologia , Proteínas Serina-Treonina Quinases/fisiologia , Resposta a Proteínas não Dobradas , Proteína 1 de Ligação a X-Box/fisiologia , eIF-2 Quinase/fisiologia
13.
Artigo em Inglês | MEDLINE | ID: mdl-31442553

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease and its characteristic is the progressive degeneration of dopaminergic neurons within the substantia nigra (SN) of the midbrain. There is hardly any clinically proven efficient therapeutics for its cure in several recent preclinical advances proposed to treat PD. Recent studies have found that the endocannabinoid signaling system in particular the comprised two receptors, CB1 and CB2 receptors, has a significant regulatory function in basal ganglia and is involved in the pathogenesis of PD. Therefore, adding new insights into the biochemical interactions between cannabinoids and other signaling pathways may help develop new pharmacological strategies. Factors of the endocannabinoid system (ECS) are abundantly expressed in the neural circuits of basal ganglia, where they interact interactively with glutamatergic, γ-aminobutyric acid-ergic (GABAergic), and dopaminergic signaling systems. Although preclinical studies on PD are promising, the use of cannabinoids at the clinical level has not been thoroughly studied. In this review, we evaluated the available evidence and reviewed the involvement of ECS in etiologies, symptoms and treatments related to PD. Since CB1 and CB2 receptors are the two main receptors of endocannabinoids, we primarily put the focus on the therapeutic role of CB1 and CB2 receptors in PD. We will try to determine future research clues that will help understand the potential therapeutic benefits of the ECS in the treatment of PD, aiming to open up new strategies and ideas for the treatment of PD.


Assuntos
Agonistas de Receptores de Canabinoides/metabolismo , Antagonistas de Receptores de Canabinoides/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Animais , Ácidos Araquidônicos/metabolismo , Ácidos Araquidônicos/uso terapêutico , Agonistas de Receptores de Canabinoides/uso terapêutico , Antagonistas de Receptores de Canabinoides/uso terapêutico , Moduladores de Receptores de Canabinoides/metabolismo , Moduladores de Receptores de Canabinoides/uso terapêutico , Canabinoides/metabolismo , Canabinoides/uso terapêutico , Capsaicina/análogos & derivados , Capsaicina/metabolismo , Capsaicina/uso terapêutico , Endocanabinoides/metabolismo , Endocanabinoides/uso terapêutico , Humanos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores
14.
Pharmacol Res ; 151: 104553, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760107

RESUMO

Parkinson's disease (PD) that afflicts millions of individuals worldwide is associated with deposits of aggregate-prone proteins (e.g., α-synuclein) and with mitochondrial dysfunction in neuronal cells. Mitochondria are the main source of reactive oxygen species, provide energy for neuronal cells, and are regarded as dynamic organelles that are determined by mitochondrial fission, fusion, and mitophagy to maintain mitochondrial homeostasis. Growing evidence reveals that several dynamics-related proteins, such as dynamin-related protein 1 (Drp1), mediate mitochondrial fission, fusion, and mitophagy, to protect against neurodegeneration in PD. More importantly, not only is Drp1-mediated fission required for mitophagy that exerts a protective effect on neurons, but abnormal mitochondrial fission and mitophagy can drive neuronal survival or cell death (i.e., autophagy, apoptosis, and necroptosis), suggesting that Drp1 may play a pivotal role in the pathogenesis of PD. Also, PD-related proteins such as α-synuclein, leucine-rich repeat kinase-2, PTEN-induced putative kinase 1, and Parkin have been proven to interact with Drp1, thus contributing to mitochondrial dynamics and clearance, as well as neuronal fate. Here, we review the roles of Drp1 in mitochondrial fission, dynamics, mitophagy, bulk autophagy, apoptosis, and necroptosis for a better understanding of mitochondrial disturbances in PD-associated neurodegeneration and summarize the advances of novel chemical compounds targeting Drp1 to provide new insight into potential PD therapies.


Assuntos
Dinaminas/metabolismo , Dinâmica Mitocondrial , Mitofagia , Neurônios/patologia , Doença de Parkinson/patologia , Animais , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Morte Celular/efeitos dos fármacos , Descoberta de Drogas , Dinaminas/análise , Humanos , Dinâmica Mitocondrial/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Terapia de Alvo Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo
15.
Acta Pharmacol Sin ; 40(12): 1503-1512, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31388087

RESUMO

Parkinson's disease (PD) is a multifactorial disorder characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (LBs) consisting of misfolded α-synuclein protein. The etiology of PD is still not clear but systemic inflammation is proved to trigger and exacerbate DA neurons degeneration. Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) and plays a major role in promoting the host immune. TLR4-mediated signal pathways induce the release of many inflammatory cytokines. It is reasonable to hypothesize that TLR4 is the mediator in microglia contributing to the damage of DA neurons in the SNpc. In this study, we evaluated the role of TLR4 in the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid mouse model. Both TLR4-deficient and wild-type (WT) mice were injected with probenecid (250 mg/kg, i.p.) followed by injection of MPTP (25 mg/kg, s.c.) every 4 days for 10 times. From D43 to D47, the behavioral performance in pole test and wire hang test was assessed. Then the mice were euthanized, and SN and striatum were dissected out for biochemical tests. We showed that compared with MPTP-treated WT mice, TLR4 deficiency significantly attenuated MPTP-induced motor deficits and TH-protein expression reduction in SNpc and striatum, suppressed MPTP-induced α-synuclein abnormality and neuroinflammation mediated through oxidative stress, glial activation, NF-κB and the NLRP3 inflammasome signaling pathways. These findings highlight the neuroprotective effect of TLR4-pathways in the chronic MPTP-induced PD mouse model.


Assuntos
Doença de Parkinson Secundária/fisiopatologia , Receptor 4 Toll-Like/fisiologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Inflamassomos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/metabolismo , Microglia/patologia , Subunidade p50 de NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Probenecid , Transdução de Sinais/fisiologia , Receptor 4 Toll-Like/genética , Tirosina 3-Mono-Oxigenase/metabolismo , alfa-Sinucleína/metabolismo
16.
Pharmacol Res ; 146: 104336, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31271846

RESUMO

Alzheimer's disease (AD) and Parkinson's disease (PD) are recognized as the universal neurodegenerative diseases, with the involvement of misfolded proteins pathology, leading to oxidative stress, glial cells activation, neuroinflammation, mitochondrial dysfunction, and cellular apoptosis. Several discoveries indicate that accumulation of pathogenic proteins, i.e. amyloid ß (Aß), the microtubule-binding protein tau, and α-synuclein, are parallel with oxidative stress, neuroinflammation, and mitochondrial dysfunction. Whether the causative factors are misfolded proteins or these pathophysiological changes, leading to neurodegeneration still remain ambiguous. Importantly, directing pharmacological researches towards the prevention of AD and PD seem a promising approach to detect these complicating mechanisms, and provide new insight into therapy for AD and PD patients. Mangiferin (MGF, 2-C-ß-D-glucopyranosyl-1, 3, 6, 7-tetrahydroxyxanthone), well-known as a natural product, is detached from multiple plants, including Mangifera indica L. With the structure of C-glycosyl and phenolic moiety, MGF possesses multipotent properties starting from anti-oxidant effects, to the alleviation of mitochondrial dysfunction, neuroinflammation, and cellular apoptosis. In particular, MGF can cross the blood-brain barrier to exert neuronal protection. Different researches implicate that MGF is able to protect the central nervous system from oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis under in vitro and in vivo models. Additional facts support that MGF plays a role in improving the declined memory and cognition of rat models. Taken together, the neuroprotective capacity of MGF may stand out as an agent candidate for AD and PD therapy.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Xantonas/farmacologia , Xantonas/uso terapêutico , Animais , Antioxidantes/fisiologia , Antioxidantes/uso terapêutico , Humanos , Estresse Oxidativo/efeitos dos fármacos
17.
Acta Pharmacol Sin ; 40(8): 991-998, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30728466

RESUMO

Olfactory bulb, as one of sensory organs opening to the outside, is susceptible to toxic environment and easy to deteriorate. Recent studies in Parkinson's disease (PD) patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys have shown that abnormal α-synuclein is accumulated in the olfactory glomeruli, suggesting that the lesions of PD are not only confined to the substantia nigra (SN) but also located in the olfactory bulb. Thus, olfactory bulb might be the region of onset in PD pathogenesis and a targeted region for diagnosis and treatment of PD. However, the relationship between olfactory bulb and pathogenesis of PD remains unclear. In the present study, we investigated the inflammatory pathological alterations in olfactory bulb and the underlying mechanisms in chronic MPTP mice. Mice were treated with MPTP/P, i.e., MPTP (25 mg/kg, s.c.) plus probenecid (250 mg/kg, i.p.) every 4 days, for ten times. The mice displayed typical parkinsonian syndrome. Then we examined their olfactory function and the pathologic changes in olfactory bulb. The mice showed obvious olfactory dysfunction in a buried pellet test. Immunohistochemical studies revealed that tyrosine hydroxylase (TH) protein levels were significantly decreased, whereas abnormal α-synuclein was significantly increased in the olfactory bulbs. Furthermore, the olfactory bulbs in MPTP/P-treated mice showed significantly increased levels of interleukin-1ß (IL-1ß), caspase-1, glial fibrillary acidic protein (GFAP), Toll receptor 4 (TLR4), phosphorylation of p65, as well as activated molecules of NOD-like receptor protein 3 (NLRP3) that were associated with neuroinflammation. Our results demonstrate that MPTP/P-caused olfactory bulb damage might be related to NLRP3-mediated inflammation.


Assuntos
Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Bulbo Olfatório/efeitos dos fármacos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Masculino , Camundongos Endogâmicos C57BL , Bulbo Olfatório/patologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/etiologia , Probenecid/farmacologia , Multimerização Proteica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , alfa-Sinucleína/metabolismo
18.
Neuropharmacology ; 144: 388-399, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29634982

RESUMO

Parkinson's disease (PD) is a multi-factorial neurodegenerative disease. Abnormal α-synuclein protein aggregate and sustained microglia activation contribute to the pathogenic processes of PD. However, the relationship between α-synuclein and microglia-mediated neuroinflammation remains unclear. We purified α-synuclein after overexpression in Escherichia coli and then used it to stimulate BV-2 cells or primary microglia cells from wild type or toll-like receptor 4 (TLR4)-defective mice. Enzyme linked immunosorbent assay (ELISA) and real-time PCR results confirmed that α-synuclein could enhance the production of tumor necrosis factor α (TNF-α) through TLR4 activation. Western blotting results confirmed the involvement of the TLR4/PI3K/AKT/GSK3ß signal pathway in the inflammatory response. Nuclear factor kappa B (NF-κB) could translocate to the nucleus, promoting the expression of TNF-α when stimulated by α-synuclein in BV-2 cells. Nurr1 suppressed the production of TNF-α via interaction with NF-κB/p65 and inhibiting its nuclear translocation. In addition, both NF-κB and Nurr1 appeared to be regulated by the TLR4-mediated signal pathway. Our work demonstrated that TLR4 recognized α-synuclein and activated downstream signaling mechanisms leading to the release of pro-inflammatory mediators that are contra-balanced by Nurr1 expression. In conclusion, Nurr1 is a novel participant in the neuroinflammation stimulated by α-synuclein, thus the regulation of Nurr1 may be a novel neuroprotective target for PD treatment.


Assuntos
Inflamação/metabolismo , Microglia/metabolismo , NF-kappa B/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Receptor 4 Toll-Like/metabolismo , alfa-Sinucleína/metabolismo , Transporte Ativo do Núcleo Celular/fisiologia , Animais , Linhagem Celular , Núcleo Celular/metabolismo , Córtex Cerebral/metabolismo , Escherichia coli , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuroimunomodulação/fisiologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/genética , alfa-Sinucleína/genética
19.
Exp Gerontol ; 116: 37-45, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30553024

RESUMO

The Chinese tree shrew (TS) has many unique advantages that make it suitable for use as an experimental animal model for human disease including moderate body size, low cost of feeding, short reproductive cycle and lifespan, and close phylogenetic relationship to primates. Our previous studies have shown that TS treated with the mitochondrial inhibitor MPTP displayed classic Parkinsonian symptoms. Additionally, the structure of TS alpha-synuclein (α-syn) is highly homologous to that found in humans. Previous studies have concluded that misfolded, fibrillar α-syn is a hallmark of α-synucleinopathies. In this study, we examined the distribution and expression levels of α-syn in different TS brain regions. We also obtained recombinant TS α-syn protein to study its aggregation and cytotoxic properties in primary neurons. Our results showed that α-syn was expressed in numerous different brain regions in TS but was most abundant in the hippocampus and midbrain. The recombinant α-syn of TS displayed straight fibrils when incubated for 72 h in vitro, which is very similar to human α-syn. When exposed to primary neurons, the TS and human α-syn fibrils led to cytotoxicity and Lewy-like pathology. Our findings indicated that TS could be a potential animal model to study the pathology of α-synucleinopathies.


Assuntos
Encéfalo/metabolismo , Neurônios/metabolismo , Sinucleinopatias/etiologia , Tupaia/metabolismo , alfa-Sinucleína/metabolismo , Sequência de Aminoácidos , Animais , Encéfalo/patologia , Humanos , Neurônios/patologia , Sinucleinopatias/patologia
20.
Int Immunopharmacol ; 67: 458-464, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30594776

RESUMO

Parkinson's disease (PD) is a typical neurodegenerative disease and the pathological feature of which is the death of dopamine neurons in the substantia nigra region. At present, neuronal death caused by inflammatory cytokine-mediated neuroinflammation is being extensively studied. The nucleotide-binding oligomerization domain-, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome is an inflammatory complex existing in microglia. Its activation promotes the secretion of the inflammatory cytokine interleukin-1ß/18 (IL-1ß/18) and induces pyroptosis, a type of cell death that possesses the potential for inflammation, to rupture microglia to further release IL-1ß. In this review we focus on the mechanisms of activation of the NLRP3 inflammasome and pyroptosis and their inflammatory effects on the development of PD. In addition, we focus on some inhibitors of NLRP3 inflammatory pathways to alleviate the progression of PD by inhibiting central inflammation and provide new therapeutic strategies for the treatment of PD.


Assuntos
Inflamassomos/fisiologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Doença de Parkinson/metabolismo , Piroptose/fisiologia , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Doença de Parkinson/fisiopatologia
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