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1.
Metab Brain Dis ; 38(3): 1035-1050, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36576692

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease characterized by the pathological loss of nigrostriatal dopaminergic neurons, which causes an insufficient release of dopamine (DA) and then induces motor and nonmotor symptoms. Hyperoside (HYP) is a lignan component with anti-inflammatory, antioxidant, and neuroprotective effects. In this study, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active neurotoxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) were used to induce dopaminergic neurodegeneration. The results showed that HYP (100 µg/mL) reduced MPTP-mediated cytotoxicity of SH-SY5Y cells in vitro, and HYP [25 mg/(kg d)] alleviated MPTP-induced motor symptoms in vivo. HYP treatment reduced the contents of nitric oxide (NO), H2O2, and malondialdehyde (MDA), as well as the mitochondrial damage of dopaminergic neurons, both in vitro and in vivo. Meanwhile, HYP treatment elevated the levels of neurotrophic factors such as glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, and recombinant cerebral dopamine neurotrophic factor in vivo, but not in vitro. Finally, Akt signaling was activated after the administration of HYP in MPP+/MPTP-induced dopaminergic neurodegeneration. However, the blockage of the Akt pathway with Akt inhibitor did not abolish the neuroprotective effect of HYP on DA neurons. These results showed that HYP protected the dopaminergic neurons from the MPP+- and MPTP-induced injuries, which did not rely on the Akt pathway.


Assuntos
Neuroblastoma , Doenças Neurodegenerativas , Fármacos Neuroprotetores , Humanos , Animais , Camundongos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Dopamina/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doenças Neurodegenerativas/metabolismo , Peróxido de Hidrogênio/farmacologia , Neuroblastoma/metabolismo , Neurônios Dopaminérgicos , Camundongos Endogâmicos C57BL , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/metabolismo , Modelos Animais de Doenças
2.
Metab Brain Dis ; 37(5): 1435-1450, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35488941

RESUMO

Wuzi Yanzong Pill (WYP) was found to play a protective role on nerve cells and neurological diseases, however the molecular mechanism is unclear. To understand the molecular mechanisms that underly the neuroprotective effect of WYP on dopaminergic neurons in Parkinson's disease (PD). PD mouse model was induced by the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Gait and hanging tests were used to assess motor behavioral function. Immunofluorescence assay was used to determine TH-positive neurons in substantia nigra (SN). Apoptosis, dopamine and neurotrophic factors as well as expression of PI3K/Akt pathway were detected by TUNEL staining, ELISA and western blotting, respectively. First, it was observed that WYP intervention improved abnormal motor function in MPTP-induced PD model, alleviated the loss of TH+ neurons in SN, and increased dopamine content in brain, revealing a potential protective effect. Second, network pharmacology was used to analyze the possible targets and pathways of WYP action in the treatment of PD. A total of 126 active components related to PD were screened in WYP, and the related core targets included ALB, GAPDH, Akt1, TP53, IL6 and TNF. Particularly, the effect of WYP on PD may be medicate through PI3K/Akt signaling pathway and apoptotic regulation. The WYP treated PD mice had higher expression of p-PI3K, p-Akt and Bcl-2 but lower expression of Bax and cleaved caspase-3 than the non-WYP treated PD mice. Secretion of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) were also increased in the treated mice. WYP may inhibit apoptosis and increase the secretion of neurotrophic factor via activating PI3K/ Akt signaling pathway, thus protecting the loss of dopamine neurons in MPTP-induced PD mice.


Assuntos
Fármacos Neuroprotetores , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos , Medicamentos de Ervas Chinesas/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Substância Negra
3.
Int J Neurosci ; : 1-18, 2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36037147

RESUMO

Background: The etiology of Parkinson's disease (PD), a chronic and progressive neurodegenerative disease, is multifactorial but not fully unknown. Until now, no drug has been proven to have neuroprotective or neuroregenerative effects in patients with PD.Objectives: To observe the therapeutic potential of Bilobalide (BB), a constituent of ginkgo biloba, in MPTP-induced PD model, and explore its possible mechanisms of action.Material and Methods: Mice were randomly divided into three groups: healthy group, MPTP group and MPTP + BB group. PD-related phenotypes were induced by intraperitoneal injection of MPTP into male C57BL/6 mice, and BB (40 mg/kg/day) was intraperitoneally given for 7 consecutive days at the end of modeling. The injection of saline was set up as the control in a similar manner.Results: BB induced M2 polarization of microglia, accompanied by inhibition of neuroinflammation in the brain. Simultaneously, BB promoted the expression of BDNF in astrocytes and neurons, and expression of GDNF in neurons. Most interestingly, BB enhanced the formation of GFAP+ astrocytes expressing nestin, Brn2 and Ki67, as well as the transformation of GFAP+ astrocytes expressing tyrosine hydroxylase around subventricular zone, providing experimental evidence that BB could promote the conversion of astrocytes into TH+ dopamine neurons in vivo and in vitro.Conclusions: These results suggest the natural product BB may utilize multiple pathways to modify degenerative process of TH+ neurons, revealing an exciting opportunity for novel neuroprotective therapeutics. However, its multi-target and important mechanisms need to be further explored.

4.
J Neurophysiol ; 126(5): 1756-1771, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34669500

RESUMO

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system (CNS). Here we report the temporal and spatial evolution of various functional neurons during demyelination in a cuprizone (CPZ)-induced mouse model. CPZ did not significantly induce the damage of axons and neurons after 2 wk of feeding. However, after 4-6 wk of CPZ feeding, axons and neurons were markedly reduced in the cortex, posterior thalamic nuclear group, and hippocampus. Simultaneously, the expression of TPH+ tryptophan neurons and VGLUT1+ glutamate neurons was obviously decreased, and the expression of TH+ dopaminergic neurons was slightly decreased in the tail part of the substantia nigra striatum, whereas the number of ChAT+ cholinergic neurons was not significantly different in the brain. In the second week of feeding, CPZ caused a higher level of glutamate secretion and upregulated the expression of EAAT2 on astrocytes, which should contribute to rapid and sufficient glutamate uptake and removal. This finding reveals that astrocyte-driven glutamate reuptake protected the CNS from excitotoxicity by rapid reuptake of glutamate in 4-6 wk of CPZ feeding. At this stage, although NG2+ oligodendroglia progenitor cells (OPCs) were enhanced in the demyelination foci, the myelin sheath was still absent. In conclusion, we comprehensively observed the temporal and spatial evolution of various functional neurons. Our results will assist with understanding how demyelination affects neurons during CPZ-induced demyelination and provide novel information for neuroprotection in myelin regeneration and demyelinating diseases.NEW & NOTEWORTHY Our results further indicate temporal and spatial evolution of various functional neurons during the demyelination in a cuprizone (CPZ)-induced mouse model, which mainly occur 4-6 wk after CPZ feeding. At the same time, the axonal compartment is damaged and, consequently, neuronal death occurs, while glutamate neurons are lost obviously. The astrocyte-mediated glutamate reuptake could protect the neurons from the excitatory effects of glutamate.


Assuntos
Astrócitos , Cuprizona/farmacologia , Doenças Desmielinizantes , Ácido Glutâmico/metabolismo , Inibidores da Monoaminoxidase/farmacologia , Bainha de Mielina , Neurônios , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Axônios/efeitos dos fármacos , Axônios/metabolismo , Axônios/patologia , Cuprizona/administração & dosagem , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/metabolismo , Modelos Animais de Doenças , Camundongos , Inibidores da Monoaminoxidase/administração & dosagem , Esclerose Múltipla/metabolismo , Bainha de Mielina/efeitos dos fármacos , Bainha de Mielina/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia
5.
Metab Brain Dis ; 35(5): 793-807, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32215835

RESUMO

Inflammatory demyelination in the central nervous system (CNS) is a hallmark of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Besides MS disease-modifying therapy, targeting myelin sheath protection/regeneration is currently a hot spot in the treatment of MS. Here, we attempt to explore the therapeutic potential of Bilobalide (BB) for the myelin protection/regeneration in EAE model. The results showed that BB treatment effectively prevented worsening and demyelination of EAE, accompanied by the inhibition of neuroinflammation that should be closely related to T cell tolerance and M2 macrophages/microglia polarization. BB treatment substantially inhibited the infiltration of T cells and macrophages, thereby alleviating the enlargement of neuroinflammation and the apoptosis of oligodendrocytes in CNS. The accurate mechanism of BB action and the feasibility of clinical application in the prevention and treatment of demyelination remain to be further explored.


Assuntos
Ciclopentanos/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Furanos/uso terapêutico , Ginkgolídeos/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Polaridade Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Feminino , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/imunologia , Regeneração Nervosa/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Remielinização/efeitos dos fármacos , Linfócitos T/imunologia
6.
J Integr Neurosci ; 19(4): 651-662, 2020 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-33378839

RESUMO

Recent studies have shown that Nogo-A and the Nogo-A receptor affect ß-amyloid metabolism and the downstream Rho GTP enzyme signaling pathway, which may affect the levels of ß-amyloid and tau. Nogo-A may play a key role in the pathogenesis of Alzheimer's disease. However, the underlying molecular mechanisms of Fasudil treatment in Alzheimer's disease are not yet clear. Our results have found that Fasudil treatment for two months substantially ameliorated behavioral deficits, diminished ß-amyloid plaque and tau protein pathology, and alleviated neuronal apoptosis in APP/PS1 transgenic mice. More importantly, two well-established markers for synaptic function, growth-associated protein 43 and synaptophysin, were upregulated after Fasudil treatment. Finally, the levels of Nogo-A, Nogo-A receptor complex NgR/p75NTR/LINGO-1 and the downstream Rho/Rho kinase signaling pathway were significantly reduced. These findings suggest that Fasudil exerts its neuroprotective function in Alzheimer's disease by inhibiting the Nogo-A/NgR1/RhoA signaling pathway.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Proteínas tau/efeitos dos fármacos , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Nogo/efeitos dos fármacos , Receptor Nogo 1/efeitos dos fármacos , Quinases Associadas a rho/efeitos dos fármacos
7.
Clin Immunol ; 201: 35-47, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30660624

RESUMO

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system characterized by oligodendrocyte loss and progressive neurodegeneration. The cuprizone (CPZ)-induced demyelination is widely used to investigate the demyelination/remyelination. Here, we explored the therapeutic effects of Hydroxyfasudil (HF), an active metabolite of Fasudil, in CPZ model. HF improved behavioral abnormality and reduced myelin damage in the corpus callosum. Splenic atrophy and myelin oligodendrocyte glycoprotein (MOG) antibody were observed in CPZ model, which were partially restored and obviously inhibited by HF, therefore reducing pathogenic binding of MOG antibody to oligodendrocytes. HF inhibited the percentages of CD4+IL-17+ T cells from splenocytes and infiltration of CD4+ T cells and CD68+ macrophages in the brain. HF also declined microglia-mediated neuroinflammation, and promoted the production of astrocyte-derived brain derived neurotrophic factor (BDNF) and regeneration of NG2+ oligodendrocyte precursor cells. These results provide potent evidence for the therapeutic effects of HF in CPZ-induced demyelination.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Doenças Desmielinizantes/tratamento farmacológico , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/uso terapêutico , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/toxicidade , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Cuprizona , Citocinas/imunologia , Doenças Desmielinizantes/induzido quimicamente , Doenças Desmielinizantes/imunologia , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Macrófagos/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Baço/efeitos dos fármacos , Baço/patologia
8.
Eur J Immunol ; 45(1): 142-52, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25287052

RESUMO

Although Fasudil has shown therapeutic potential in EAE mice, the mechanism of action are still not fully understood. Here, we examined the immunomodulatory effect of Fasudil on encephalitogenic mononuclear cells (MNCs), and tested the therapeutic potential of Fasudil-treated MNCs in active EAE. Fasudil inhibited expression of CCL20 on T cells and migration of T cells, decreased CD4(+) IFN-γ(+) and CD4(+) IL-17(+) T cells, but increased CD4(+) IL-10(+) and CD4(+) TGF-ß(+) T cells. Fasudil reduced expression of CD16/32 and IL-12, while elevating expression of CD206, CD23, and IL-10. Fasudil also decreased levels of iNOS/NO, enhanced levels of Arg-1, and inhibited the TLR-4/NF-κB signaling and TNF-α, shifting M1 macrophage to M2 phenotype. These modulatory effects of Fasudil on T cells and macrophages were not altered by adding autoantigen MOG35-55 to the culture, i.e., autoantigen-independent. Further, we observed that, in vitro, Fasudil inhibited the capacity of encephalitogenic MNCs to adoptively transfer EAE and reduced TLR-4/p-NF-κB/p65 and inflammatory cytokines in spinal cords. Importantly, Fasudil-treated encephalitogenic MNCs exhibited therapeutic potential when injected into actively induced EAE mice. Together, our results not only provide evidence that Fasudil mediates the polarization of macrophages and the regulation of T cells, but also reveal a novel strategy for cell therapy in MS.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Encefalomielite Autoimune Experimental/terapia , Imunomodulação/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Arginase/genética , Arginase/imunologia , Terapia Baseada em Transplante de Células e Tecidos , Quimiocina CCL20/genética , Quimiocina CCL20/imunologia , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Feminino , Regulação da Expressão Gênica , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Fragmentos de Peptídeos , Cultura Primária de Células , Receptores de IgG/genética , Receptores de IgG/imunologia , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/transplante , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/imunologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/imunologia
9.
Wound Repair Regen ; 24(2): 317-27, 2016 03.
Artigo em Inglês | MEDLINE | ID: mdl-26789651

RESUMO

The ROCK signaling pathway is involved in numerous fundamental cellular functions such as cell migration, apoptosis, inflammatory responses, and neurite outgrowth. Previous studies demonstrate that Fasudil exhibited therapeutic potential of experimental autoimmune encephalomyelitis (EAE) possibly through immune-modulation and anti-inflammation. In this study, we observed the effect of Fasudil on synaptic protection of EAE mice. Fasudil ameliorated the clinical severity of EAE and inhibited Rho kinase (ROCK), especially ROCK II, in brain and spinal cord of EAE mice. Protein extracts from spinal cord of Fasudil-treated EAE mice promoted the formation of neurite outgrowth when co-cultured with primary neurons, indicating that peripheral administration of Fasudil can enter the central nervous system (CNS) and exhibited its biological effect on the formation of neurite outgrowth. Synapse-related molecule synaptophysin was enhanced, and CRMP-2, AMPA receptor, and GSK-3ß were declined in spinal cord of Fasudil-treated mice. Neurotrophic factor BDNF and GDNF as well as immunomodulatory cytokine IL-10 in spinal cord were elevated in Fasudil-treated mice, while inflammatory cytokine IL-17, IL-1ß, IL-6, and TNF-α were obviously inhibited, accompanied by the decrease of inflammatory M1 iNOS and the increase of anti-inflammatory M2 Arg-1, providing a microenvironment that contributes to synaptic protection. Our results indicate that Fasudil treatment protected against synaptic damage and promoted synaptic formation, which may be related with increased neurotrophic factors as well as decreased inflammatory microenvironment in the CNS of EAE mice.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Fármacos Neuroprotetores/farmacologia , Sinapses/efeitos dos fármacos , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Western Blotting , Células Cultivadas , Citocinas , Modelos Animais de Doenças , Feminino , Quinase 3 da Glicogênio Sintase , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Crescimento Neural
10.
Int J Immunopathol Pharmacol ; 29(1): 54-64, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26634402

RESUMO

Activated microglia, especially polarized M1 cells, produce pro-inflammatory cytokines and free radicals, thereby contributing directly to neuroinflammation and various brain disorders. Given that excessive or chronic neuroinflammation within the central nervous system (CNS) exacerbates neuronal damage, molecules that modulate neuroinflammation are candidates as neuroprotective agents. In this study, we provide evidence that Safflor yellow (SY), the main active component in the traditional Chinese medicine safflower, modulates inflammatory responses by acting directly on BV2 microglia. LPS stimulated BV2 cells to upregulate expression of TLR4-Myd88 and MAPK-NF-κB signaling pathways and to release IL-1ß, IL-6, TNF-α, and COX-2. However, SY treatment inhibited expression of TLR4-Myd88 and p-38/p-JNK-NF-κB, downregulated expression of iNOS, CD16/32, and IL-12, and upregulated CD206 and IL-10. In conclusion, our results demonstrate that SY exerts an anti-inflammatory effect on BV2 microglia, possibly through TLR-4/p-38/p-JNK/NF-κB signaling pathways and the conversion of microglia from inflammatory M1 to an anti-inflammatory M2 phenotype.


Assuntos
Anti-Inflamatórios/farmacologia , Chalcona/análogos & derivados , Lipopolissacarídeos/farmacologia , Microglia/efeitos dos fármacos , Polaridade Celular , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Chalcona/farmacologia , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Microglia/fisiologia , Fator 88 de Diferenciação Mieloide/fisiologia , NF-kappa B/fisiologia , Receptor 4 Toll-Like/fisiologia
12.
Exp Mol Pathol ; 99(2): 220-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26112093

RESUMO

The Rho-kinase (ROCK) inhibitor Fasudil has proven beneficial in experimental autoimmune encephalomyelitis (EAE). Given the small safety window of Fasudil, we are looking for novel ROCK inhibitors, which have similar or stronger effect on EAE with greater safety. In this study, we report that WAR-5, a Y-27632 derivative, alleviates the clinical symptoms, attenuates myelin damage and reduces CNS inflammatory responses in EAE C57BL/6 mice at an extent similar to Fasudil, while exhibits less vasodilator and adverse reaction in vivo. WAR-5 inhibits ROCK activity, and selectively suppresses the expression of ROCK II in spleen, brain and spinal cord of EAE mice, especially in spinal cord, accompanied by decreased expression of Nogo. WAR-5 also regulates the imbalance of Th1/Th17 T cells and regulatory T cells, inhibits inflammatory microenvironment induced with NF-κB-IL-1ß pathway. Importantly, WAR-5 converts M1 toward M2 microglia/macrophages that are positively correlated with BDNF and NT-3 production. Taken together, WAR-5 exhibits therapeutic potential in EAE by more selectively inhibits ROCK II, with a greater safety than Fasudil, and is worthy of further clinical study to clarify its clinical value.


Assuntos
Aminopiridinas/farmacologia , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/prevenção & controle , Inflamação/imunologia , Fatores de Crescimento Neural/metabolismo , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Amidas/farmacologia , Animais , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Immunoblotting , Técnicas Imunoenzimáticas , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/metabolismo , Piridinas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Quinases Associadas a rho/metabolismo
13.
Cell Biol Toxicol ; 31(1): 29-38, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25656842

RESUMO

Recombinant human erythropoietin (EPO), a glycohormone, is one of the leading biopharmaceutical products, while carbamylated erythropoietin (CEPO), an EPO derivative, is attracting widespread interest due to its neuroprotective effects without erythropoiesis in several cells and animal models. However, exogenous EPO promotes an angiogenic response from tumor cells and is associated with tumor growth, but knowledge of CEPO on tumor growth is lacking. Here we show that CEPO, but not EPO, inhibited Neuro-2a growth and viability. As expected, CEPO--unlike EPO--did not activate JAK-2 either in primary neurons or in Neuro-2a cells. Interestingly, CEPO did not induce GDNF expression and subsequent AKT activation in Neuro-2a cells. Before CEPO/EPO treatment, glial cell line-derived neurotrophic factor (GDNF) neutralization and GFR receptor blocking decreased the viability of EPO-treated Neuro-2a cells but did not influence CEPO-treated Neuro-2a cells. As compared to primary neurons, the expression of CD131, as a receptor complex binding to CEPO, is almost lacking in Neuro-2a cells. In BABL/C-nu mice, CEPO did not promote the growth of Neuro-2a cells nor extended the survival time compared to mice treated with EPO. The results indicate that CEPO did not promote tumor growth because of lower expression of CD131 and subsequent dysfunction of CD131/GDNF/AKT pathway in Neuro-2a cells, revealing its therapeutic potential in future clinical application.


Assuntos
Subunidade beta Comum dos Receptores de Citocinas/metabolismo , Eritropoetina/análogos & derivados , Animais , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Eritropoetina/farmacologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial/biossíntese , Janus Quinase 2/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias
14.
Metab Brain Dis ; 30(5): 1217-26, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26084861

RESUMO

Parkinson's disease (PD) is a chronic neurodegenerative disease of the central nervous system (CNS), characterized by a loss of dopaminergic neurons, which is thought to be caused by both genetic and environmental factors. Recent findings suggest that neuroinflammation may be a pathogenic factor in the onset and progression of sporadic PD. Here we explore the potential therapeutic effect of lipoic acid (LA) on a lipolysaccharide (LPS)-induced inflammatory PD model. Our results for the first time showed that LA administration improved motor dysfunction, protected dopaminergic neurons loss, and decreased α-synuclein accumulation in the substantia nigra (SN) area of brain. Further, LA inhibited the activation of nuclear factor-κB (NF-κB) and expression of pro-inflammatory molecules in M1 microglia. Taken together, these results suggest that LA may exert a profound neuroprotective effect and is thus a promising anti-neuroinflammatory and anti-oxidative agent for halting the progression of PD. Interventions aimed at either blocking microglia-derived inflammatory mediators or modulating the polarization of microglia may be potentially useful therapies that are worth further investigation.


Assuntos
Antioxidantes/uso terapêutico , Neurônios Dopaminérgicos/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/prevenção & controle , Ácido Tióctico/uso terapêutico , Animais , Antioxidantes/farmacologia , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Transtornos Parkinsonianos/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologia , Ácido Tióctico/farmacologia
15.
Immunology ; 143(2): 219-29, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24749492

RESUMO

Viewing multiple sclerosis (MS) as both neuroinflammation and neurodegeneration has major implications for therapy, with neuroprotection and neurorepair needed in addition to controlling neuroinflammation in the central nervous system (CNS). While Fasudil, an inhibitor of Rho kinase (ROCK), is known to suppress experimental autoimmune encephalomyelitis (EAE), an animal model of MS, it relies on multiple, short-term injections, with a narrow safety window. In this study, we explored the therapeutic effect of a novel ROCK inhibitor FSD-C10, a Fasudil derivative, on EAE. An important advantage of this derivative is that it can be used via non-injection routes; intranasal delivery is the preferred route because of its efficient CNS delivery and the much lower dose compared with oral delivery. Our results showed that intranasal delivery of FSD-C10 effectively ameliorated the clinical severity of EAE and CNS inflammatory infiltration and promoted neuroprotection. FSD-C10 effectively induced CNS production of the immunoregulatory cytokine interleukin-10 and boosted expression of nerve growth factor and brain-derived neurotrophic factor proteins, while inhibiting activation of p-nuclear factor-κB/p65 on astrocytes and production of multiple pro-inflammatory cytokines. In addition, FSD-C10 treatment effectively induced CD4(+) CD25(+) , CD4(+) FOXP3(+) regulatory T cells. Together, our results demonstrate that intranasal delivery of the novel ROCK inhibitor FSD-C10 has therapeutic potential in EAE, through mechanisms that possibly involve both inhibiting CNS inflammation and promoting neuroprotection.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Anti-Inflamatórios/administração & dosagem , Sistema Nervoso Central/efeitos dos fármacos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/administração & dosagem , Administração Intranasal , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Sistema Nervoso Central/enzimologia , Sistema Nervoso Central/imunologia , Proteínas de Ligação a DNA , Encefalomielite Autoimune Experimental/enzimologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-10/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Neural/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Índice de Gravidade de Doença , Baço/efeitos dos fármacos , Baço/enzimologia , Baço/imunologia , Fatores de Tempo , Fator de Transcrição RelA/metabolismo , Quinases Associadas a rho/metabolismo
16.
Acta Pharmacol Sin ; 35(11): 1428-38, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25263338

RESUMO

AIM: Fasudil, a selective Rho kinase (ROCK) inhibitor, has been shown to alleviate the severity of experimental autoimmune encephalomyelitis (EAE) via attenuating demyelination and neuroinflammation. The aim of this study was to investigate the effects of fasudil on interactions between macrophages/microglia and T cells in a mice EAE model. METHODS: Mouse BV-2 microglia were treated with IFN-γ and fasudil. Cell viability was detected with MTT assay. BV-2 microglia polarization was analyzed using flow cytometry. Cytokines and other proteins were detected with ELISA and Western blotting, respectively. Mice were immunized with MOG35-55 to induce EAE, and then treated with fasudil (40 mg/kg, ip) every other day from d 3 to d 27 pi. Encephalomyelitic T cells were prepared from the spleen of mice immunized with MOG35-55 on d 9 pi. RESULTS: Treatment of mouse BV-2 microglia with fasudil (15 µg/mL) induced significant phenotype polarization and functional plasticity, shifting M1 to M2 polarization. When co-cultured with the encephalomyelitic T cells, fasudil-treated BV-2 microglia significantly inhibited the proliferation of antigen-reactive T cells, and down-regulated IL-17-expressing CD4(+) T cells and IL-17 production. Furthermore, fasudil-treated BV-2 microglia significantly up-regulated CD4(+)CD25(high) and CD4(+)IL-10(+) regulatory T cells (Tregs) and IL-10 production, suggesting that the encephalomyelitic T cells had converted to Tregs. In EAE mice, fasudil administration significantly decreased both CD11b(+)iNOS(+) and CD11b(+)TNF-α(+) M1 microglia, and increased CD11b(+)IL-10(+) M2 microglia. CONCLUSION: Fasudil polarizes BV-2 microglia into M2 cells, which convert the encephalomyelitic T cells into Tregs in the mice EAE model.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Anti-Inflamatórios/farmacologia , Encefalomielite Autoimune Experimental/tratamento farmacológico , Microglia/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Cocultura , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/enzimologia , Encefalomielite Autoimune Experimental/imunologia , Feminino , Mediadores da Inflamação/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos Endogâmicos C57BL , Microglia/enzimologia , Microglia/imunologia , Glicoproteína Mielina-Oligodendrócito , Fragmentos de Peptídeos , Fenótipo , Linfócitos T Reguladores/imunologia , Quinases Associadas a rho/metabolismo
17.
J BUON ; 19(3): 650-5, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25261647

RESUMO

PURPOSE: Our previous data have shown that emodin azide methyl anthraquinone derivative (AMAD) triggered mitochondrial- dependent cell apoptosis involving caspase-8-mediated Bid cleavage, and induced proteasomal degradation of HER2/neu by blocking Her2/neu binding to Hsp90. In the present study, we futher investigated the effect of this compound on the cell cycle and related molecular mechanisms in HER2/neu-overexpressing MDA-MB-453 breast cancer cells. METHODS: The cell cycle distribution was tested by flow cytometry. The expression of cell cycle-related proteins was determined by Western blot analysis; DNA agarose gel electrophoresis was used to examine the apoptosis of MDAMB- 453 cells induced by emodin AMAD. RESULTS: After MDA-MB-453 cells were treated with different concentrations of emodin AMAD for 24 hrs, cells were arrested in G0/G1 phase, and the expression of G0/G1 related proteins c/Myc, Cyclin D1, CDK4 and p-Rb changed. DNA fragmentation appeared on the agarose gel in a concentration- dependent manner. CONCLUSION: Emodin AMAD induced G0/G1 arrest in Her2/ neu-overexpressing MDA-MB-453 cancer cells. This G0/G1 arrest was associated with decreasing protein expression of c-Myc, Cyclin D1, CDK4, and p-Rb.


Assuntos
Antraquinonas/farmacologia , Antineoplásicos/farmacologia , Azidas/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Emodina/análogos & derivados , Emodina/farmacologia , Receptor ErbB-2/análise , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ciclina D1/análise , Quinase 4 Dependente de Ciclina/análise , Feminino , Fase G1/efeitos dos fármacos , Humanos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos
18.
J Neurosci Res ; 91(1): 73-82, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23074165

RESUMO

Carbamylated erythropoietin (CEPO) is attracting widespread interest because of its neuroprotective effects without influencing erythropoiesis. Here we show that CEPO, unlike EPO, does not stimulate erythropoiesis. Both CEPO and EPO inhibit the death/apoptosis of neurons in the hypoxic model of primary neurons and induce neuron proliferation and differentiation in hypoxic mice. Hypoxic mice show apparent memory deficits at 3 and 30 days after hypoxia. The administration of CEPO/EPO significantly improves cognitive and behavioral defects after hypoxic insults. Further investigation shows that CEPO/EPO induces neuron proliferation and differentiation and promotes the generation of choline acetyltransferase (ChAT)(+) neurons in hypoxic mice. Phosphorylated AKT was colabeled with ChAT(+) neurons and coexpressed in bromodeoxyuridine-positive cells, suggesting that the PI3K/AKT pathway may play a pivotal role in CEPO/EPO-cholinergic neuron generation. These results reveal that CEPO/EPO ameliorates hypoxia-induced cognitive and behavioral defects possibly through the generation of ChAT-positive neurons.


Assuntos
Proliferação de Células/efeitos dos fármacos , Transtornos Cognitivos/prevenção & controle , Eritropoetina/análogos & derivados , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Transtornos Cognitivos/etiologia , Eritropoetina/farmacologia , Citometria de Fluxo , Hipóxia/complicações , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo
19.
Neural Regen Res ; 18(5): 947-954, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36254973

RESUMO

Microglia are resident immune cells in the central nervous system. During the pathogenesis of Alzheimer's disease, stimulatory factors continuously act on the microglia causing abnormal activation and unbalanced phenotypic changes; these events have become a significant and promising area of research. In this review, we summarize the effects of microglial polarization and crosstalk with other cells in the central nervous system in the treatment of Alzheimer's disease. Our literature search found that phenotypic changes occur continuously in Alzheimer's disease and that microglia exhibit extensive crosstalk with astrocytes, oligodendrocytes, neurons, and penetrated peripheral innate immune cells via specific signaling pathways and cytokines. Collectively, unlike previous efforts to modulate microglial phenotypes at a single level, targeting the phenotypes of microglia and the crosstalk with other cells in the central nervous system may be more effective in reducing inflammation in the central nervous system in Alzheimer's disease. This would establish a theoretical basis for reducing neuronal death from central nervous system inflammation and provide an appropriate environment to promote neuronal regeneration in the treatment of Alzheimer's disease.

20.
Chin J Integr Med ; 29(5): 394-404, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36607588

RESUMO

OBJECTIVE: To examine the anti-inflammatory effect of grape seed extract (GSE) in animal and cellular models and explore its mechanism of action. METHODS: This study determined the inhibitory effect of GSE on macrophage inflammation and Th1 and Th17 polarization in vitro. Based on the in vitro results, the effects and mechanisms of GSE on multiple sclerosis (MS)-experimental autoimmune encephalomyelitis (EAE) mice model were further explored. The C57BL/6 mice were intragastrically administered with 50 mg/kg of GSE once a day from the 3rd day to the 27th day after immunization. The activation of microglia, the polarization of Th1 and Th17 and the inflammatory factors such as tumor necrosis factor- α (TNF- α), interleukin-1 ß (IL-1 ß), IL-6, IL-12, IL-17 and interferon-γ (IFN-γ) secreted by them were detected in vitro and in vivo by flow cytometry, enzyme linked immunosorbent assay (ELISA), immunofluorescence staining and Western blot, respectively. RESULTS: GSE reduced the secretion of TNF-α, IL-1 ß and IL-6 in bone marrow-derived macrophages stimulated by lipopolysaccharide (P<0.01), inhibited the secretion of TNF-α, IL-1 ß, IL-6, IL-12, IL-17 and IFN-γ in spleen cells of EAE mice immunized for 9 days (P<0.05 or P<0.01), and reduced the differentiation of Th1 and Th17 mediated by CD3 and CD28 factors (P<0.01). GSE significantly improved the clinical symptoms of EAE mice, and inhibited spinal cord demyelination and inflammatory cell infiltration. Peripherally, GSE downregulated the expression of toll-like-receptor 4 (TLR4) and Rho-associated kinase (ROCKII, P<0.05 or P<0.01), and inhibited the secretion of inflammatory factors (P<0.01 or P<0.05). In the central nervous system, GSE inhibited the infiltration of CD45+CD11b+ and CD45+CD4+ cells, and weakened the differentiation of Th1 and Th17 (P<0.05). Moreover, it reduced the secretion of inflammatory factors (P<0.01), and prevented the activation of microglia (P<0.05). CONCLUSION: GSE had a beneficial effect on the pathogenesis and progression of EAE by inhibiting inflammatory response as a potential drug and strategy for the treatment of MS.


Assuntos
Encefalomielite Autoimune Experimental , Extrato de Sementes de Uva , Camundongos , Animais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Extrato de Sementes de Uva/farmacologia , Extrato de Sementes de Uva/uso terapêutico , Interleucina-17 , Interleucina-1beta , Fator de Necrose Tumoral alfa/metabolismo , Interleucina-6/metabolismo , Células Th1 , Camundongos Endogâmicos C57BL , Interferon gama/metabolismo , Interferon gama/farmacologia , Interferon gama/uso terapêutico , Células Th17/metabolismo , Interleucina-12/farmacologia , Interleucina-12/uso terapêutico , Citocinas/metabolismo
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