RESUMEN
Methamphetamine (MA) is a extremely addictive psychostimulant drug with a significant abuse potential. Long-term MA exposure can induce neurotoxic effects through oxidative stress, mitochondrial functional impairment, endoplasmic reticulum stress, the activation of astrocytes and microglial cells, axonal transport barriers, autophagy, and apoptosis. However, the molecular and cellular mechanisms underlying MA-induced neurotoxicity remain unclear. MA abuse increases the chances of developing neurotoxic conditions such as Parkinson's disease (PD), Alzheimer's disease (AD) and other neurotoxic diseases. MA increases the risk of PD by increasing the expression of alpha-synuclein (ASYN). Furthermore, MA abuse is linked to high chances of developing AD and subsequent neurodegeneration due to biological variations in the brain region or genetic and epigenetic variations. To date, there is no Food and Drug Administration (FDA)-approved therapy for MA-induced neurotoxicity, although many studies are being conducted to develop effective therapeutic strategies. Most current studies are now focused on developing therapies to diminish the neurotoxic effects of MA, based on the underlying mechanism of neurotoxicity. This review article highlights current research on several therapeutic techniques targeting multiple pathways to reduce the neurotoxic effects of MA in the brain, as well as the putative mechanism of MA-induced neurotoxicity.
Asunto(s)
Trastornos Relacionados con Anfetaminas , Estimulantes del Sistema Nervioso Central , Metanfetamina , Síndromes de Neurotoxicidad , Enfermedad de Parkinson , Trastornos Relacionados con Anfetaminas/complicaciones , Trastornos Relacionados con Anfetaminas/terapia , Astrocitos , Estimulantes del Sistema Nervioso Central/toxicidad , Humanos , Metanfetamina/toxicidad , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/terapiaRESUMEN
Parkinson's disease (PD) is a debilitating neurodegenerative condition characterized by the loss of dopaminergic neurons within the substantia nigra. The specific molecular mechanisms through which PD-associated neuronal loss occurs remain unclear, and there is no available effective treatment against PD-related neurodegeneration. Resveratrol (RSV) has exhibited promising neuroprotective effects via antioxidant and anti-inflammatory activity. However, its poor bioavailability in the brain represents a challenge for its application in PD treatment. In this study, we synthesized RSV-loaded PLGA nanoparticles (RSV-PLGA-NPs) conjugated with lactoferrin (Lf) to enhance RSV diffusion into the brain and assessed whether this formulation improved the neuroprotective effects of RSV in experimental PD models. The Lf-conjugated RSV-PLGA-NPs (Lf-RSV-PLGA-NPs) exhibited enhanced internalization into SH-SY5Y and human brain microvascular endothelial cells as compared to RSV-PLGA-NPs and free RSV. Further, Lf-RSV-PLGA-NPs were more effective than RSV-PLGA-NPs and free RSV in attenuating the MPP+-induced generation of reactive oxygen species, reduction of mitochondrial membrane potential, and cell death. Importantly, Lf conjugation specifically increased the accumulation of RSV-PLGA-NPs in the brain as determined via bioluminescent imaging analyses. Our formulation substantially enhanced the neuroprotective effects of RSV in the MPTP-induced PD model. Hence, Lf-RSV-PLGA-NPs represent a promising tool for improving RSV bioavailability and neuroprotection within the brain.
Asunto(s)
Nanopartículas , Neuroblastoma , Fármacos Neuroprotectores , Enfermedad de Parkinson , Barrera Hematoencefálica , Células Endoteliales , Humanos , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , ResveratrolRESUMEN
The neuropathological hallmark of Parkinson's disease (PD) is the preferential loss of dopaminergic neurons in the substantia nigra and presence of Lewy bodies in the dying neurons. Though specific molecular mechanisms for the neurodegeneration remains to be clarified, mitochondrial dysfunction and increased oxidative stress are major players associated with PD pathogenesis and these pathogenic mechanisms can be reproduced in cells and animals by application of various neurotoxins such as MPP+. In this study, we attempted to determine the neuroprotective effects of methylene blue (MB) against 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity, and to elucidate its action mechanism. We observed that MB attenuated MPP+-induced apoptotic cell death in SH-SY5Y cells and the mescencephalic dopaminergic neurons. In addition, MB protected the cells against MPP+-induced oxidative stress and mitochondrial dysfunction as evidenced by restoration of mitochondrial complex I activity and ATP levels, and attenuation of oxidative stress. Moreover, we demonstrated that MB induced antioxidant molecules, and activated Nrf2 pathway through AKT activation. These results indicate that MB protects the neurons from MPP+-induced toxicity through activation of antioxidant system, thereby reducing the oxidative stress and mitochondrial impairment, implying the potential use of MB in the treatment of neurodegenerative diseases such as PD.
Asunto(s)
1-Metil-4-fenilpiridinio/toxicidad , Azul de Metileno/farmacología , Mitocondrias/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Neuroprotección/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Animales , Antioxidantes/farmacología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Herbicidas/toxicidad , Humanos , Ratones , Ratones Endogámicos C57BL , Mitocondrias/efectos de los fármacos , Factor 2 Relacionado con NF-E2/agonistas , Neuroprotección/fisiología , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo/fisiologíaRESUMEN
Oxidative stress and mitochondrial dysfunction are now widely accepted as the major factors involved in the pathogenesis of Parkinson's disease (PD). Rotenone, a commonly used environmental toxin also reproduces these principle pathological features of PD. Hence, it is used frequently to induce experimental PD in cells and animals. In this study, we evaluated the neuroprotective effects of metformin against rotenone-induced toxicity in SH-SY5Y cells. Metformin treatment clearly rescued these cells from rotenone-mediated cell death via the reduction of the cytosolic and mitochondrial levels of reactive oxygen species and restoration of mitochondrial function. Furthermore, metformin upregulated PGC-1α, the master regulator of mitochondrial biogenesis and key antioxidant molecules, including glutathione and superoxide dismutase. We demonstrated that the drug exerted its cytoprotective effects by activating nuclear factor erythroid 2-related factor 2 (Nrf2)/heme-oxygenase (HO)-1 pathway, which in turn, is dependent on AKT activation by metformin. Thus, our results implicate that metformin provides neuroprotection against rotenone by inhibiting oxidative stress in the cells by inducing antioxidant system via upregulation of transcription mediated by Nrf2, thereby restoring the rotenone-induced mitochondrial dysfunction and energy deficit in the cells.
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Hipoglucemiantes/farmacología , Metformina/farmacología , Enfermedades Mitocondriales/prevención & control , Factor 2 Relacionado con NF-E2/genética , Proteína Oncogénica v-akt/genética , Estrés Oxidativo/efectos de los fármacos , Rotenona/antagonistas & inhibidores , Rotenona/toxicidad , Transducción de Señal/efectos de los fármacos , Desacopladores/toxicidad , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Suntamide A (1), a new cyclic peptide, was isolated from Cicadidae Periostracum. The gross structure of 1 was elucidated by detailed analysis of HRMS and 1D/2D NMR spectra, and the absolute configuration was established by C3 Marfey's method. We extended our study to examine biological activity of 1, and found that 1 protected SH-SY5Y cells against rotenone-induced neurotoxicity. This effect of 1 seemed to be attributed to antioxidant induction and protection of mitochondria from rotenone-caused injury. Along with augmentation of the antioxidant system by 1, there was an evident activation of Nrf2, a transcription factor involved in the activation of the antioxidant system. These results indicate that 1 rescued the cells from rotenone-mediated neurotoxicity by enhancing antioxidant capacity via induction of Nrf2, suggesting that the compound could be used as a therapeutic intervention in neurodegenerative diseases such as Parkinson's disease.
Asunto(s)
Antioxidantes/farmacología , Hemípteros/química , Factor 2 Relacionado con NF-E2/metabolismo , Fármacos Neuroprotectores/farmacología , Péptidos Cíclicos/farmacología , Animales , Antioxidantes/química , Antioxidantes/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estructura Molecular , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/aislamiento & purificación , Péptidos Cíclicos/química , Péptidos Cíclicos/aislamiento & purificación , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Especies Reactivas de Oxígeno/metabolismo , Rotenona/antagonistas & inhibidores , Rotenona/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Parkinson's disease (PD) is the second most common neurodegenerative disease, which is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, leading to a decrease in striatal dopamine. There is no antiparkinsonian therapy that offers a true disease-modifying treatment till date and there is an urgent need for a safe and effective neuroprotective or neurorestorative therapy. Our previous study demonstrated that metformin upregulated dopamine in the mouse brain and provided significant neuroprotection in animal model of PD. Therefore, we designed this study to investigate the molecular mechanism underlying such pharmacological effect of metformin. Herein, we found that metformin enhanced the phosphorylation of tyrosine hydroxylase (TH) which was accompanied by increase in brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and activation of their downstream signaling pathways in the mouse brain and SH-SY5Y cells. We further investigated the role of the neurotrophic factors in the activation of TH and observed that both BDNF and GDNF-induction were essential for metformin-induced TH activation. We found that the AMPK/aPKCζ/CREB pathway was essential for metformin-induced GDNF upregulation and TH activation. Thus, this study reveals the TH-activating property of metformin in the brain via induction of neurotrophic factors along with the signaling mechanism. These results potentiate the candidacy of metformin not only as a neuroprotective agent, but also as restorative therapy for the treatment of PD.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Dopamina/biosíntesis , Factor Neurotrófico Derivado de la Línea Celular Glial/biosíntesis , Metformina/farmacología , Proteína Quinasa C/metabolismo , Animales , Línea Celular Tumoral , Humanos , Hipoglucemiantes/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
BACKGROUND: AMP-activated protein kinase (AMPK) exerts its anti-inflammatory effects by suppressing redox-sensitive nuclear factor kappa B (NF-κB) and pro-inflammatory cytokines including TNF-α. However, it is unclear whether AMPK regulates anti-inflammatory cytokine expressions in the presence of oxidative stress-induced inflammation. We sought to elucidate the mechanisms whereby AMPK regulates inflammatory cytokine expressions under NADPH oxidase (NOX)-induced oxidative stress. METHODS: HT-29 human colonic epithelial cells transfected with AMPKα shRNA and mouse models with AMPKα knocked out in epithelial cells (AMPKαfl/fl-Vil-Cre) or macrophages (AMPKαfl/fl-Lyz2-Cre) were used to examine the effects of AMPK and NOX on signaling pathways and cytokine expressions. RESULTS: In HT-29 cells, 5-hydroxytryptamine (5-HT)-induced NOX activity was enhanced by AMPKα silencing, and resulted in inflammatory cell death. AMPKα deletion specific for colon epithelial cells (AMPKαfl/fl-Vil-Cre) or macrophages (AMPKαfl/fl-Lyz2-Cre) intensified 5-HT- or dextran sulfate sodium (DSS)-induced upregulations of NOX2, TNF-α, and IL-6, but completely abolished basal and 5-HT- or DSS-induced upregulation of IL-10 in colon epithelium. Furthermore, 5-HT- and DSS-induced changes were accompanied by marked upregulations of increased inflammatory signaling pathways linked to NF-κB, AP-1, and STAT3 transcription factors, and to GATA, a cell fate-directing signaling. In addition, AMPKα deletion significantly fortified 5-HT- or DSS-induced downregulations of cytoprotective signaling pathways (Nrf2, HIF-1α, and KLF4). CONCLUSION: Basal AMPKα maintains an anti-inflammatory state by inhibiting NOX, balancing pro-/anti-inflammatory signaling pathways, and directing IL-10 production. When these regulatory roles of AMPK are diminished by oxidative stress, colon epithelium undergoes inflammation despite IL-10 production.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Inflamación/metabolismo , Interleucina-10/biosíntesis , Proteínas Quinasas Activadas por AMP/genética , Silenciador del Gen , Células HT29 , Humanos , Factor 4 Similar a Kruppel , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/metabolismo , Transducción de SeñalRESUMEN
Two new chlorinated secondary metabolites, saccharochlorines A and B (1 and 2), were isolated from the saline cultivation of a marine-derived bacterium Saccharomonospora sp. (KCTC-19160). The chemical structures of the saccharochlorines were elucidated by 2D NMR and MS spectroscopic data. Saccharochlorines A and B (1 and 2) exhibit weak inhibition of ß-secretase (BACE1) in biochemical inhibitory assay, but they induced the release of Aß (1-40) and Aß (1-42) in H4-APP neuroglial cells. This discrepancy might be derived from the differences between the cellular and sub-cellular environments or the epigenetic stimulation of BACE1 expression.
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Acrilatos/química , Actinobacteria/química , Acrilatos/aislamiento & purificación , Acrilatos/metabolismo , Acrilatos/farmacología , Actinobacteria/metabolismo , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Conformación Molecular , Neuroglía/citología , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Fragmentos de Péptidos/metabolismoRESUMEN
Adiponectin, an adipokine predominantly derived from adipose tissue, exhibits potent antitumor properties in breast cancer cells. However, its mechanisms of action remain elusive. Inflammasomes-intracellular multimeric protein complexes-modulate cancer cell growth in a complicated manner, as well as playing a role in the innate immune system. Herein, we examined the potential role of inflammasomes in the antitumor activity of adiponectin and found that globular adiponectin (gAcrp) significantly suppressed inflammasomes activation in breast cancer cells both in vitro and in vivo conditions, as determined by decreased expression of inflammasomes components, including NOD-like receptor pyrin domain-containing protein 3 (NLRP3) and the apoptosis-associated speck-like protein containing a CARD (ASC), and inhibition of interleukin-1ß and caspase-1 activation. Treatment with pharmacological inhibitors of inflammasomes caused decrease in cell viability, apoptosis induction, and G0/G1 cell cycle arrest, suggesting that inflammasomes activation is implicated in the growth of breast cancer cells. In addition, treatment with gAcrp generated essentially similar results to those of inflammasomes inhibitors, further indicating that suppression of breast cancer cell growth by gAcrp is mediated via modulation of inflammasomes. Mechanistically, gAcrp suppressed inflammasomes activation through sestrin2 (SESN2) induction, liver kinase B1 (LKB-1)-dependent AMP-activated protein kinase (AMPK) phosphorylation, and alleviation of endoplasmic reticulum (ER) stress. Taken together, these results demonstrate that gAcrp inhibits growth of breast cancer cells by suppressing inflammasomes activation, at least in part, via SESN2 induction and AMPK activation-dependent mechanisms.
RESUMEN
Host immune response remains an obstacle in cell-replacement therapy for treating type I diabetes. Long-term systemic immunosuppression results in suboptimal efficacy and adverse reactions. Thus, "cell-particle hybrids" of pancreatic islets and tissue-adhesive, polydopamine-coated, FK506-loaded biodegradable microspheres (PD-FK506-MS) were developed to locally modulate the immune response at the transplantation site. Coating of FK506-MS with PD enabled the rapid formation of stable cell-particle hybrids without significant changes in islet viability and functionality. Extremely low quantities of FK506 (approximately 600â¯ng per recipient) sustainably released from cell-particle hybrids effectively prolonged survival of xenogeneic islet graft. Interestingly, FK506 exhibited extended bioavailability in the grafts but was undetectable in systemic circulation and other tissues. Moreover, mRNA expression of inflammatory cytokines was significantly inhibited in the PD-FK506-MS-containing grafts but not in lymphoid organs. This study presents a promising platform that facilitates the translation of local immunomodulation towards an effective strategy with improved safety profiles for treating type I diabetes.
Asunto(s)
Terapia de Inmunosupresión/métodos , Trasplante de Islotes Pancreáticos/métodos , Islotes Pancreáticos/metabolismo , Microesferas , Trasplante Heterólogo/métodos , Animales , Citometría de Flujo , Prueba de Tolerancia a la Glucosa , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Polímeros/química , TacrolimusRESUMEN
Microbiota in the gut affect brain physiology via various pathways, and dysbiosis seems to play a role in the pathogenesis of Parkinson's disease (PD). Probiotics showed pleiotropic effects on functions of the central nervous system via microbiota-gut-brain axis. However, no studies displayed the neuroprotective effects of probiotics in the Parkinson's disease. This study aimed to test the neuroprotective effects of probiotics in two different models of PD. We evaluated neuroprotective effects of a probiotic cocktail containing Lactobacillus rhamnosus GG, Bifidobacterium animalis lactis, and Lactobacillus acidophilus in PD models induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone utilizing behavioral tests, immunohistochemistry and neurochemical analysis. To assure the neuroprotection came from increased production of butyrate, we further determined beneficial effects of butyrate in the MPTP-mediated PD model. The probiotic mixture overtly protected the dopaminergic neurons against MPTP neurotoxicity. However, the probiotics downregulated expression of monoamine oxidase (MAO) B in the striatum, which was accompanied by a lower level of 1-methyl-4-phenylpyridinium (MPP+), the main neurotoxic metabolite of MPTP. Thus, we extended the investigation into the rotenone-induced PD model. Rescuing effects of the probiotics were observed in the setup, which came with increased levels of neurotrophic factors and butyrate in the brain. Lactobacillus rhamnosus GG was identified to be a major contributor to the induction of neurotrophic factors and downregulation of MAO B. Finally, we demonstrated that sodium butyrate attenuated MPTP-induced neuronal loss in the nigrostriatal pathway. Probiotics could ameliorate neurodegeneration at least partially by increasing butyrate level. These data highlight the role of probiotics for brain health, and their potential as a preventive measure for neurodegenerative diseases such as PD.
Asunto(s)
Butiratos/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Síndromes de Neurotoxicidad/tratamiento farmacológico , Probióticos/farmacología , Rotenona/toxicidad , Acetilación/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Modelos Animales de Enfermedad , Dopamina , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Histonas/metabolismo , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/metabolismo , Masculino , Ratones Endogámicos C57BL , Monoaminooxidasa/metabolismo , Neuroglía/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/metabolismo , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
Animal models for Parkinson's disease (PD) are very useful in understanding the pathogenesis of PD and screening for new therapeutic approaches. 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP) and rotenone are common neurotoxins used for the development of experimental PD models, and both inhibit complex I of mitochondria; this is thought to be an instrumental mechanism for dopaminergic neurodegeneration in PD. In this study, we treated mice with MPTP (30 mg/kg/day) or rotenone (2.5 mg/kg/day) for 1 week and compared the neurotoxic effects of these toxins. MPTP clearly produced dopaminergic lesions in both the substantia nigra and the striatum as shown by loss of dopaminergic neurons, depletion of striatal dopamine, activation of glial cells in the nigrostriatal pathway and behavioral impairment. In contrast, rotenone treatment did not show any significant neuronal injury in the nigrostriatal pathway, but it caused neurodegeneration and glial activation only in the hippocampus. MPTP showed no such deleterious effects in the hippocampus suggesting the higher susceptibility of the hippocampus to rotenone than to MPTP. Interestingly, rotenone caused upregulation of the neurotrophic factors and their downstream PI3K-Akt pathway along with adenosine monophosphate-activated protein kinase (AMPK) activation. These results suggest that MPTP-induced dopaminergic neurotoxicity is more acute and specific in comparison to rotenone toxicity, and compensatory brain-derived neurotrophic factor (BDNF) induction and AMPK activation in the rotenone-treated brain might suppress the neuronal injury.
Asunto(s)
Encéfalo/efectos de los fármacos , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/patología , Neuronas/efectos de los fármacos , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/patología , Rotenona/toxicidad , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Dopamina/metabolismo , Masculino , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neuronas/patología , Trastornos Parkinsonianos/inducido químicamenteRESUMEN
IL-32 is a proinflammatory cytokine, and involved in various diseases including infection, inflammation, and cancer. However, effects of IL-32 on neuroinflammation remain obscure. Herein, we examined the effects of IL-32ß on systemic LPS-induced neuroinflammation using IL-32ß transgenic (Tg) mice. IL-32ß wild type (WT) and Tg mice received LPS injection (5 mg/kg, i.p.), and then neuroinflammatory responses were evaluated. Systemic LPS caused remarkable gliosis in the brain at 12 h regardless of genotypes. The gliosis in WT mice was sustained by 24 h, whereas it became more severe in Tg mice by 24 h. Proinflammatory cytokines and proteins were increased at 12 h both in WT and Tg brains. The elevated levels of TNFα and VCAM-1were not altered over time, while levels of IL-6, IL-1ß and iNOS were dropped in WT mice. In contrast, elevated levels IL-6, IL-1ß, iNOS and VCAM-1 were sustained, and level of TNFα was augmented in Tg brains by 24 h. Interestingly, level of IL-10 mRNA in Tg mice was remarkably higher than in WT mice at 0 h, which was decreased at 12 h and maintained by 24 h. In WT brain, mRNA level of IL-10 was raised at 12 h after LPS injection, and further increased at 24 h. Activation of NF-κB signaling pathway was detected in glia cells after LPS injection which was exaggerated at 24 h in Tg mice in comparison to WT mice. These results indicate that IL-32ß enhances neuroinflammatory responses caused by systemic LPS, and this might be attributable to prolonged activation of NF-κB signaling pathway.
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Encéfalo/patología , Gliosis/patología , Inflamación/patología , Interleucinas/genética , Lipopolisacáridos , Animales , Encéfalo/metabolismo , Citocinas/metabolismo , Gliosis/inducido químicamente , Gliosis/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Interleucinas/metabolismo , Ratones , Ratones Transgénicos , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Transducción de Señal , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
The relatively old, yet clinically used, drug methylene blue (MB) is known to possess neuroprotective properties by reducing aggregated proteins, augmenting the antioxidant response, and enhancing mitochondrial function and survival in various models of neurodegenerative diseases. In this study, we aimed to examine the effects of MB in Parkinson's disease (PD) in vivo and in vitro models by using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/1-methyl-4-phenylpyridinium (MPP+ ) with a focus on possible effects on induction of neurotrophic factors. Our results indicate that pretreatment with MB significantly attenuated MPTP-induced loss of dopaminergic neurons, glial cell activation, and depletion of dopamine. We also found that MB upregulated brain-derived neurotrophic factor (BDNF) and activated its downstream signaling pathways, suggesting that BDNF might be a contributor to MB-associated neuroprotection. Specific inhibition of the BDNF receptor or extracellular signal-regulated kinase (Erk) reversed the MB-mediated protection against MPP+ toxicity, thus implying a role for BDNF and the Erk pathway in the neuroprotective effects. Taken together, our data suggest that MB protects neurons from MPTP neurotoxicity via induction of BDNF. Further study to determine whether MB preserves dopaminergic neurons in the brains of PD patients is warranted.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Intoxicación por MPTP/prevención & control , Azul de Metileno/farmacología , Fármacos Neuroprotectores/farmacología , Regulación hacia Arriba/efectos de los fármacos , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Intoxicación por MPTP/metabolismo , Masculino , Azul de Metileno/uso terapéutico , Ratones , Fármacos Neuroprotectores/uso terapéutico , Fosforilación/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The pathogenesis of inflammatory bowel disease (IBD) is associated with production of immense pro-inflammatory cytokines including TNF-α. Once generated, TNF-α stimulates production of various pro-inflammatory cytokines and disrupts mucosal barrier by inducing inflamed mucosal epithelial cell death. In the present study, we investigated inhibitory effects of TI-1-162, a hydroxyindenone derivative, against TNF-α-induced and TNBS-induced colon inflammation. TI-1-162 showed inhibitory effect on the TNF-α-induced adhesion of U937 monocytic cells to HT-29 colonic epithelial cells (IC50 =â¯0.83⯱â¯0.12⯵M), which is an in vitro model representing the initial step of colitis. In addition, TI-1-162 suppressed TNF-α-stimulated caspase-3 activation and HT-29 cell apoptosis. These in vitro inhibitory activities of TI-1-162 correlated to recovery changes in in vivo colon tissues, such as downregulation of adhesion molecules (ICAM-1, VCAM-1) and chemokines (CCL11, CXCL1, CXCL2, CXCL3, CX3CL1) revealed by gene expression array and Western blot analyses. Such molecular recovery of colon epithelium from TNBS-treated rats corresponded to the recovery in body weight, colon weight/length, and myeloperoxidase level by TI-1-162 (10 and 30â¯mg/kg/day, orally). In relation to action mechanism, TI-1-162 did not disturb TNF-α binding to its receptor, but suppressed phosphorylation of RIP-1, ASK-1, JNK and p38, and nuclear translocation of NF-kB and AP-1, which corresponded to down regulation of inflammatory cytokines in TNF-α-treated cells (HT-29 and U937) and TNBS-treated rat colon tissues. Taken together, the results indicate that the protective effects of TI-1-162 against colon inflammation and epithelial cell death are associated with its inhibitory action in RIP/ASK-1/MAPK signaling pathway downstream to TNF receptor 1.
Asunto(s)
Compuestos de Bencilideno/farmacología , Colitis/tratamiento farmacológico , Colitis/patología , Indenos/uso terapéutico , MAP Quinasa Quinasa Quinasa 5/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Ácido Trinitrobencenosulfónico/efectos adversos , Animales , Compuestos de Bencilideno/uso terapéutico , Adhesión Celular/efectos de los fármacos , Colitis/inducido químicamente , Colitis/metabolismo , Colon/efectos de los fármacos , Colon/patología , Citocinas/metabolismo , Epitelio/efectos de los fármacos , Epitelio/patología , Regulación de la Expresión Génica/efectos de los fármacos , Células HT29 , Humanos , Indenos/farmacología , RatasRESUMEN
Neurotrophic factors are essential for neuronal survival, plasticity, and development and have been implicated in the action mechanism of antidepressants. In this study, we assessed the neurotrophic factor-inducing and neuroprotective properties of antidepressants. In the first part of the study, we found that fluoxetine, imipramine, and milnacipran (i.p., 20 mg/kg/day for 1 week or 3 weeks) upregulated brain-derived neurotrophic factor in the striatum and substantia nigra both at 1 week and 3 weeks. In contrast, an increase in the glial-derived neurotrophic factor was more obvious at 3 weeks after the antidepressants treatment. Specifically, it was found that fluoxetine and imipramine are more potent in raising the levels of neurotrophic factors than milnacipran. Furthermore, antidepressants elevated the phosphorylation of extracellular signal-regulated-protein kinase (ERK1/2) and the serine/threonine kinase Akt. In the second part of the study, we compared the neuroprotective effects of fluoxetine, imipramine, and milnacipran in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Pretreament with fluoxetine, imipramine or milnacipran for 3 weeks reduced MPTP-induced dopaminergic neurodegeneration and microglial activation in the nigrostriatal pathway. Neurochemical analysis by HPLC exhibited that antidepressants attenuated the depletion of striatal dopamine. In consistent, beam test showed that behavioral impairment was ameliorated by antidepressants. Neuroprotective effects were more prominent in the fluoxetine or imipramine treatment group than in milnacipran treatment group. Finally, we found that neuroprotection of the antidepressants against 1-methyl-4-phenylpyridinium neurotoxicity in SH-SY5Y cells was attenuated by ERK or Akt inhibitor. These results indicate that neuroprotection by antidepressants might be associated with the induction of neurotrophic factors, and antidepressant could be a potential therapeutic intervention for treatment of Parkinson's disease.
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Antidepresivos/uso terapéutico , Factores de Crecimiento Nervioso/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Regulación hacia Arriba , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Animales , Antidepresivos/farmacología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/enzimología , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patología , Sustancia Negra/fisiopatología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
In spite of the massive research for the identification of neurorestorative or neuroprotective intervention for curing Parkinson's disease (PD), there is still lack of clinically proven neuroprotective agents. Metformin, a common anti-hyperglycemic drug has been known to possess neuroprotective properties. However, specific mechanisms by which metformin protects neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity remain to be elucidated. In this study, we assessed the neuroprotective effects of metformin in the subchronic MPTP model of PD, and explored its feasible mechanisms for neuroprotection. Animals received saline or MPTP injection (30 mg/kg/day) for the first 7 days, and then saline or metformin (200 mg/kg/day) for the next 7 days. Immunohistochemical stainings showed that metformin rescued the tyrosine hydroxylase-positive neurons and attenuated astroglial activation in the nigrostriatal pathway. In parallel, metformin restored dopamine depletion and behavioral impairments exerted by MPTP. Western blot analysis revealed that metformin ameliorated MPTP-induced α-synuclein phosphorylation which was accompanied by increased methylation of protein phosphatase 2A (PP2A), a phosphatase related to α-synuclein dephosphorylation. Moreover, the metformin regimen significantly increased the level of brain derived neurotrophic factor in the substantia nigra, and activated signaling pathways related to cell survival. Proof of concept study revealed that inhibition of PP2A or tropomyosin receptor kinase B reversed neuroprotective property of metformin in SH-SY5Y cells. Our results indicate that metformin provides neuroprotection against MPTP neurotoxicity, which might be mediated by inhibition of α-synuclein phosphorylation and induction of neurotrophic factors.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Intoxicación por MPTP/tratamiento farmacológico , Intoxicación por MPTP/metabolismo , Metformina/farmacología , Fármacos Neuroprotectores/farmacología , alfa-Sinucleína/metabolismo , Animales , Antiparkinsonianos/farmacología , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Astrocitos/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Neuronas Dopaminérgicas/patología , Humanos , Intoxicación por MPTP/patología , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/metabolismo , Ratones Endogámicos C57BL , Fosforilación/efectos de los fármacos , Prueba de Estudio Conceptual , Proteína Fosfatasa 2/antagonistas & inhibidores , Proteína Fosfatasa 2/metabolismo , Receptor trkB/antagonistas & inhibidores , Receptor trkB/metabolismo , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
HPLC-UV guided isolation of the culture broth of a marine bacterium Saccharomonospora sp. CNQ-490 has led to the isolation of two new natural products, lodopyridones B and C (1 and 2) along with the previously reported lodopyridone A (3). Their chemical structures were established from the interpretation of 2D NMR spectroscopic data and the comparison of NMR data with the lodopyridone A (3). Lodopyridones B and C (1 and 2) possess the thiazole, and chloroquinoline groups which are characteristic features of these molecules. Lodopyridones A-C show weak inhibitory activities on the ß-site amyloid precursor protein cleaving enzyme 1 (BACE1).
Asunto(s)
Actinobacteria/metabolismo , Sedimentos Geológicos/microbiología , Piridonas/química , Alcaloides/química , Alcaloides/aislamiento & purificación , Alcaloides/farmacología , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Línea Celular Tumoral , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Humanos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fragmentos de Péptidos/metabolismo , Piridonas/aislamiento & purificación , Piridonas/farmacologíaRESUMEN
Parkinson's disease (PD) is a neurodegenerative disorder characterized by prominent loss of the nigral dopaminergic neurons and motor symptoms, such as resting tremor and bradykinesia. Evidence suggests that neuroinflammation may play a critical role in PD pathogenesis. Interleukin (IL)-32 is a newly-identified proinflammatory cytokine, which regulates innate and adaptive immune responses by activating p38 MAPK and NF-κB signaling pathways. The cytokine has been implicated in cancers and autoimmune, inflammatory, and infectious diseases. In this study, we attempted to identify the effects of IL-32ß on dopaminergic neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), using IL-32ß transgenic mice. Male wild type and IL-32ß transgenic mice received intraperitoneal injections of vehicle or MPTP (15 mg/kg × 4). Immunohistochemistry showed that overexpression of IL-32ß significantly increased MPTP-mediated loss of dopaminergic neurons in the substantia nigra and deletion of tyrosine hydroxylase-positive fibers in the striatum. Dopamine depletion in the striatum and deficit in locomotor activity were enhanced in IL-32ß transgenic mice. These results were accompanied by higher neuroinflammatory responses in the brains of transgenic mice. Finally, we found that IL-32ß exaggerated MPTP-mediated activation of p38 MAPK and JNK pathways, which have been shown to be involved in MPTP neurotoxicity. These results suggest that IL-32ß exacerbates MPTP neurotoxicity through enhanced neuroinflammatory responses.