RESUMO
PTPRT has been known to regulate synaptic formation and dendritic arborization of hippocampal neurons. PTPRT-/- null and PTPRT-D401A mutant mice displayed enhanced depression-like behaviors compared with wild-type mice. Transient knockdown of PTPRT in the dentate gyrus enhanced the depression-like behaviors of wild-type mice, whereas rescued expression of PTPRT ameliorated the behaviors of PTPRT-null mice. Chronic stress exposure reduced expression of PTPRT in the hippocampus of mice. In PTPRT-deficient mice the expression of GluR2 (also known as GRIA2) was attenuated as a consequence of dysregulated tyrosine phosphorylation, and the long-term potentiation at perforant-dentate gyrus synapses was augmented. The inhibitory synaptic transmission of the dentate gyrus and hippocampal GABA concentration were reduced in PTPRT-deficient mice. In addition, the hippocampal expression of GABA transporter GAT3 (also known as SLC6A11) was decreased, and its tyrosine phosphorylation was increased in PTPRT-deficient mice. PTPRT-deficient mice displayed reduced numbers and neurite length of newborn granule cells in the dentate gyrus and had attenuated neurogenic ability of embryonic hippocampal neural stem cells. In conclusion, our findings show that the physiological roles of PTPRT in hippocampal neurogenesis, as well as synaptic functions, are involved in the pathogenesis of depressive disorder.
Assuntos
Depressão , Neurogênese , Animais , Giro Denteado , Hipocampo , Camundongos , Camundongos Knockout , Neurogênese/genética , Neurônios , SinapsesRESUMO
Humulus japonicus is an annual plant belonging to the Cannabacea family, and it has been traditionally used to treat pulmonary tuberculosis, dysentery, chronic colitis, and hypertension. We investigated the active components against Parkinson's disease from H. japonicus fraction (HJF) using high performance liquid chromatography (HPLC) coupled with quadruple-time-of-flight mass spectroscopy (qTOF-MS) and NMR. Fourteen compounds were isolated from HJF, including one new compound, using HPLC-qTOF-MS and NMR. The major compounds of HJF were luteolin-7-O-glucoside and apigenin-7-O-glucoside, and there was approximately 12.57- and 9.68-folds increase in the contents of these flavonoids compared to those of the 70% EtOH extract. Apigenin and luteolin exhibited the strongest inhibitory effects on monoamine oxidase (MAO) B enzyme activity. In animal studies, limb-use behavior was significantly reduced by unilateral 6-OHDA lesion and ipsilateral rotations. These results indicated that oral administration of 300 mg/kg HJF resulted in the improvement of motor asymmetry and motor impairment in unilateral 6-OHDA-lesioned mice. HJF, including active components leads to an improvement of motor behavior in a Parkinson's disease mouse model.
Assuntos
Humulus/química , Atividade Motora/efeitos dos fármacos , Doença de Parkinson Secundária/tratamento farmacológico , Extratos Vegetais/química , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Flavonas/administração & dosagem , Flavonas/química , Regulação da Expressão Gênica/efeitos dos fármacos , Glucosídeos/administração & dosagem , Glucosídeos/química , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Monoaminoxidase/genética , Atividade Motora/genética , Oxidopamina/toxicidade , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Doença de Parkinson Secundária/patologia , Extratos Vegetais/administração & dosagem , Espectrometria de Massas em TandemRESUMO
Histone acetylation is a key regulatory factor for gene expression in cells. Modulation of histone acetylation by targeting of histone acetyltransferases (HATs) effectively alters many gene expression profiles and synaptic plasticity in the brain. However, the role of HATs on L-DOPA-induced dyskinesia of Parkinson's disease (PD) has not been reported. Our aim was to determine whether HAT inhibitors such as anacardic acid, garcinol, and curcumin from natural plants reduce severity of L-DOPA-induced dyskinesia using a unilaterally 6-hydroxydopamine (6-OHDA)-lesioned PD mouse model. Anacardic acid 2 mg/kg, garcinol 5 mg/kg, or curcumin 100 mg/kg co-treatment with L-DOPA significantly reduced the axial, limb, and orofacial (ALO) score indicating less dyskinesia with administration of HAT inhibitors in 6-OHDA-lesioned mice. Additionally, L-DOPA's efficacy was not altered by the compounds in the early stage of treatment. The expression levels of c-Fos, Fra-2, and Arc were effectively decreased by administration of HAT inhibitors in the ipsilateral striatum. Our findings indicate that HAT inhibitor co-treatment with L-DOPA may have therapeutic potential for management of L-DOPA-induced dyskinesia in patients with PD.
Assuntos
Ácidos Anacárdicos/uso terapêutico , Antiparkinsonianos/toxicidade , Curcumina/uso terapêutico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Histona Acetiltransferases/antagonistas & inibidores , Levodopa/toxicidade , Transtornos Parkinsonianos/tratamento farmacológico , Terpenos/uso terapêutico , Ácidos Anacárdicos/farmacologia , Animais , Curcumina/farmacologia , Proteínas do Citoesqueleto/biossíntese , Proteínas do Citoesqueleto/genética , Avaliação Pré-Clínica de Medicamentos , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/genética , Inibidores Enzimáticos/farmacologia , Antígeno 2 Relacionado a Fos/biossíntese , Antígeno 2 Relacionado a Fos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Oxidopamina/toxicidade , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Organismos Livres de Patógenos Específicos , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Terpenos/farmacologiaRESUMO
The dopamine precursor 3,4-dihydroxyphenyl-l-alanine (L-DOPA) is currently the most efficacious pharmacotherapy for Parkinson's disease (PD). However, long-term L-DOPA treatment leads to the development of abnormal involuntary movements (AIMs) in patients and animal models of PD. Recently, involvement of growth arrest and DNA damage-inducible 45ß (Gadd45ß) was reported in neurological and neurobehavioral dysfunctions. However, little is known about the role of Gadd45ß in the dopaminergic nigrostriatal pathway or L-DOPA-induced dyskinesia (LID). To address this issue, we prepared an animal model of PD using unilateral 6-hydroxydopamine (6-OHDA) lesions in the substantia nigra of Gadd45ß(+/+) and Gadd45ß(-/-) mice. Dyskinetic symptoms were triggered by repetitive administration of L-DOPA in these 6-OHDA-lesioned mice. Whereas dopamine denervation in the dorsal striatum decreased Gadd45ß mRNA, chronic L-DOPA treatment significantly increased Gadd45ß mRNA expression in the 6-OHDA-lesioned striatum of wild-type mice. Using unilaterally 6-OHDA-lesioned Gadd45ß(+/+) and Gadd45ß(-/-) mice, we found that mice lacking Gadd45ß exhibited long-lasting increases in AIMs following repeated administration of L-DOPA. By contrast, adeno-associated virus-mediated expression of Gadd45ß in the striatum reduced AIMs in Gadd45ß knockout mice. The deficiency of Gadd45ß in LID increased expression of ΔFosB and c-Fos in the lesioned striatum 90 min after the last administration of L-DOPA following 11days of daily L-DOPA treatments. These data suggest that the increased expression of Gadd45ß induced by repeated administration of L-DOPA may be beneficial in patients with PD.
Assuntos
Antígenos de Diferenciação/metabolismo , Discinesia Induzida por Medicamentos/metabolismo , Levodopa/toxicidade , Transtornos Parkinsonianos/metabolismo , Animais , Antígenos de Diferenciação/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Oxidopamina , Transtornos Parkinsonianos/patologia , RNA Mensageiro/metabolismo , Receptores de Dopamina D1/metabolismo , Substância Negra/metabolismo , Substância Negra/patologiaRESUMO
The dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA) is widely used as a therapeutic choice for the treatment of patients with Parkinson's disease. However, the long-term use of L-DOPA leads to the development of debilitating involuntary movements, called L-DOPA-induced dyskinesia (LID). The cAMP/protein kinase A (PKA) signaling in the striatum is known to play a role in LID. However, from among the nine known adenylyl cyclases (ACs) present in the striatum, the AC that mediates LID remains unknown. To address this issue, we prepared an animal model with unilateral 6-hydroxydopamine lesions in the substantia nigra in wild-type and AC5-knock-out (KO) mice, and examined behavioral responses to short-term or long-term treatment with L-DOPA. Compared with the behavioral responses of wild-type mice, LID was profoundly reduced in AC5-KO mice. The behavioral protection of long-term treatment with L-DOPA in AC5-KO mice was preceded by a decrease in the phosphorylation levels of PKA substrates ERK (extracellular signal-regulated kinase) 1/2, MSK1 (mitogen- and stress-activated protein kinase 1), and histone H3, levels of which were all increased in the lesioned striatum of wild-type mice. Consistently, FosB/ΔFosB expression, which was induced by long-term L-DOPA treatment in the lesioned striatum, was also decreased in AC5-KO mice. Moreover, suppression of AC5 in the dorsal striatum with lentivirus-shRNA-AC5 was sufficient to attenuate LID, suggesting that the AC5-regulated signaling cascade in the striatum mediates LID. These results identify the AC5/cAMP system in the dorsal striatum as a therapeutic target for the treatment of LID in patients with Parkinson's disease.
Assuntos
Inibidores de Adenilil Ciclases , Antiparkinsonianos/efeitos adversos , Discinesia Induzida por Medicamentos/enzimologia , Levodopa/efeitos adversos , Transtornos Parkinsonianos/metabolismo , Adenilil Ciclases , Animais , Western Blotting , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/prevenção & controle , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Parkinson's disease (PD) is characterised by severe movement defects and the degeneration of dopaminergic neurones in the midbrain. The symptoms of PD can be managed with dopamine replacement therapy using L-3, 4-dihydroxyphenylalanine (L-dopa), which is the gold standard therapy for PD. However, long-term treatment with L-dopa can lead to motor complications. The central renin-angiotensin system (RAS) is associated with the development of neurodegenerative diseases in the brain. However, the role of the RAS in dopamine replacement therapy for PD remains unclear. Here, we tested the co-treatment of the angiotensin-converting enzyme inhibitor (ACEI) with L-dopa altered L-dopa-induced dyskinesia (LID) in a 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Perindopril, captopril, and enalapril were used as ACEIs. The co-treatment of ACEI with L-dopa significantly decreased LID development in 6-OHDA-lesioned mice. In addition, the astrocyte and microglial transcripts involving Ccl2, C3, Cd44, and Iigp1 were reduced by co-treatment with ACEI and L-dopa in the 6-OHDA-lesioned striatum. In conclusion, co-treatment with ACEIs and L-dopa, such as perindopril, captopril, and enalapril, may mitigate the severity of L-DOPA-induced dyskinesia in a mouse model of PD.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos , Levodopa , Oxidopamina , Animais , Masculino , Camundongos , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Antiparkinsonianos/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Captopril/farmacologia , Captopril/uso terapêutico , Discinesia Induzida por Medicamentos/tratamento farmacológico , Discinesia Induzida por Medicamentos/prevenção & controle , Enalapril/farmacologia , Enalapril/uso terapêutico , Levodopa/toxicidade , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Doença de Parkinson/tratamento farmacológico , Perindopril/farmacologia , Perindopril/uso terapêuticoRESUMO
Parkinson's disease (PD) is the second-most prevalent neurodegenerative disease and is characterized by dopaminergic neuronal death in the midbrain. Recently, the association between alterations in PD pathology and the gut microbiota has been explored. Microbiota-targeted interventions have been suggested as a novel therapeutic approach for PD. Agathobaculum butyriciproducens SR79T (SR79) is an anaerobic bacterium. Previously, we showed that SR79 treatment induced cognitive improvement and reduced Alzheimer's disease pathologies in a mouse model. In this study, we hypothesized that SR79 treatment may have beneficial effects on PD pathology. To investigate the therapeutic effects of SR79 on PD, 6-hydroxydopamine (6-OHDA)-induced mouse models were used. D-Amphetamine sulfate (d-AMPH)-induced behavioral rotations and dopaminergic cell death were analyzed in unilateral 6-OHDA-lesioned mice. Treatment with SR79 significantly decreased ipsilateral rotations induced by d-AMPH. Moreover, SR79 treatment markedly activated the AKT/GSK3ß signaling pathway in the striatum. In addition, SR79 treatment affected the Nrf2/ARE signaling pathway and its downstream target genes in the striatum of 6-OHDA-lesioned mice. Our findings suggest a protective role of SR79 in 6-OHDA-induced toxicity by regulating the AKT/Nrf2/ARE signaling pathway and astrocyte activation. Thus, SR79 may be a potential microbe-based intervention and therapeutic strategy for PD.
Assuntos
Doenças Neurodegenerativas , Fármacos Neuroprotetores , Doença de Parkinson , Animais , Composição de Bases , Clostridiales , Dextroanfetamina/metabolismo , Dextroanfetamina/farmacologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Oxidopamina/metabolismo , Oxidopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Filogenia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Ribossômico 16S/metabolismo , Análise de Sequência de DNARESUMO
As global plastic production continues to grow, microplastics released from a massive quantity of plastic wastes have become a critical environmental concern. These microplastic particles are found in a wide range of living organisms in a diverse array of ecosystems. In this study, we investigated the biological effects of polystyrene nanoplastic (PSNP) on development of the central nervous system using cultured neural stem cells (NSCs) and mice exposed to PSNP during developmental stages. Our study demonstrates that maternal administration of PSNP during gestation and lactating periods altered the functioning of NSCs, neural cell compositions, and brain histology in progeny. Similarly, PSNP-induced molecular and functional defects were also observed in cultured NSCs in vitro. Finally, we show that the abnormal brain development caused by exposure to high concentrations of PSNP results in neurophysiological and cognitive deficits in a gender-specific manner. Our data demonstrate the possibility that exposure to high amounts of PSNP may increase the risk of neurodevelopmental defects.
Assuntos
Microplásticos , Poluentes Químicos da Água , Animais , Encéfalo , Ecossistema , Feminino , Humanos , Lactação , Exposição Materna/estatística & dados numéricos , Camundongos , Plásticos/toxicidade , Poliestirenos/toxicidade , Poluentes Químicos da Água/análiseRESUMO
The dopamine precursor 3,4dihydroxyphenyl lalanine (LDOPA) is the most widely used symptomatic treatment for Parkinson's disease (PD); however, its prolonged use is associated with LDOPAinduced dyskinesia in more than half of patients after 10 years of treatment. The present study investigated whether cotreatment with ßLapachone, a natural compound, and LDOPA has protective effects in a 6hydroxydopamine (6OHDA)induced mouse model of PD. Unilateral 6OHDAlesioned mice were treated with vehicle or ßLapachone (10 mg/kg/day) and LDOPA for 11 days. Abnormal involuntary movements (AIMs) were scored on days 5 and 10. ßLapachone (10 mg/kg) cotreatment with LDOPA decreased the AIMs score on both days 5 and 10. ßLapachone was demonstrated to have a beneficial effect on the axial and limb AIMs scores on day 10. There was no significant suppression in dopamine D1 receptorrelated and ERK1/2 signaling in the DAdenervated striatum by ßLapachonecotreatment with LDOPA. Notably, ßLapachonecotreatment with LDOPA increased phosphorylation at the Ser9 site of glycogen synthase kinase 3ß (GSK3ß), indicating suppression of GSK3ß activity in both the unlesioned and 6OHDAlesioned striata. In addition, astrocyte activation was markedly suppressed by ßLapachonecotreatment with LDOPA in the striatum and substantia nigra of the unilateral 6OHDA model. These findings suggest that ßLapachone cotreatment with LDOPA therapy may have therapeutic potential for the suppression or management of the development of LDOPAinduced dyskinesia in patients with PD.
Assuntos
Discinesias , Levodopa/efeitos adversos , Naftoquinonas/farmacologia , Oxidopamina/efeitos adversos , Doença de Parkinson Secundária , Animais , Discinesias/tratamento farmacológico , Discinesias/metabolismo , Discinesias/patologia , Levodopa/farmacologia , Masculino , Camundongos , Oxidopamina/farmacologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologiaRESUMO
Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by deficits in social interaction and restrictive, repetitive, and stereotypical patterns of behavior. However, there is no pharmacological drug that is currently used to target these core ASD symptoms. Sodium phenylbutyrate (NaPB) is a well-known long-term treatment of urea cycle disorders in children. In this study, we assessed the therapeutic effects of NaPB, which is a chemical chaperone as well as histone deacetylase inhibitor on a BTBR T + Itpr3tf/J (BTBR) mice model of ASD. We found that acute and chronic treatment of NaPB remarkably improved, not only core ASD symptoms, including repetitive behaviors and sociability deficit, but also cognitive impairment in the BTBR mice. NaPB substantially induced histone acetylation in the brain of the BTBR mice. Intriguingly, the therapeutic effects of NaPB on autistic-like behaviors, such as repetitive behaviors, impaired sociability, and cognitive deficit also showed in the valproic acid (VPA)-induced mouse model of autism. In addition, pentylenetetrazole (PTZ)-induced seizure was significantly attenuated by NaPB treatment in C57BL/6J and BTBR mice. These findings suggest that NaPB may provide a novel therapeutic approach for the treatment of patients with ASD.
Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Asseio Animal/efeitos dos fármacos , Fenilbutiratos/uso terapêutico , Comportamento Social , Comportamento Estereotipado/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/psicologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Feminino , Asseio Animal/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Transgênicos , Fenilbutiratos/farmacologia , Comportamento Estereotipado/fisiologia , Ácido Valproico/toxicidadeRESUMO
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, and is characterized by the accumulation and presence of amyloid plaques (Aß), tangles, dementia, and cognitive impairment. Currently, there is no known cure for AD; however, recently, the association between alteration of the gut microbiota and AD pathology has been explored to find novel therapeutic approaches. Microbiota-targeted intervention has been suggested as an attractive therapeutic approach for AD. Agathobaculum butyriciproducens (SR79) is a strict anaerobic and butyric acid-producing bacteria. We hypothesized that administration of SR79 might have a beneficial effect on cognitive deficits and AD pathologies. To determine the therapeutic effects of SR79 on AD pathologies, APP/PS1 transgenic and lipopolysaccharide -induced cognitive impairment mouse models were used. In the lipopolysaccharide -induced cognitive deficit model, the administration of SR79 improved cognitive function and decreased microglia activation. In addition, the administration of SR79 to APP/PS1 mice significantly improved novel object recognition and percent alteration results in novel object recognition and Y-maze alteration tests. Furthermore, Aß plaque deposition and microglial activation were markedly reduced in the parietal cortex and hippocampus after SR79 treatment in APP/PS1 mice. SR79 treatment significantly decreased gene expression levels of IL-1ß and C1QB and increased the gene expression levels of IGF-1 and thereby the downstream signaling pathway in the cortex of APP/PS1 mice. In conclusion, SR79 administration improved cognitive function and AD pathologies through the regulation of neuroinflammation and IGF-1 signaling in an animal model.
Assuntos
Doença de Alzheimer/terapia , Clostridiales/fisiologia , Cognição , Disfunção Cognitiva/terapia , Microbioma Gastrointestinal/fisiologia , Probióticos , Doença de Alzheimer/microbiologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Humanos , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Lipopolissacarídeos , Aprendizagem em Labirinto , Camundongos , Camundongos Transgênicos , Microglia/fisiologia , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Placa Amiloide/terapia , Reconhecimento PsicológicoRESUMO
Humulus japonicus (HJ) is a traditional herbal medicine that exhibits antiinflammatory, antimicrobial and antitumor effects that is used for the treatment of hypertension, pulmonary disease and leprosy. Recently, it has also been reported that HJ demonstrates neuroprotective properties in animal models of neurodegenerative diseases. The current study hypothesised that the administration of HJ would exhibit therapeutic effects in autism spectrum disorder (ASD), a neurodevelopmental disorder with lifelong consequences. The BTBR T+ Itpr3tf/J mouse model of ASD was used to investigate the antiautistic like behavioural effects of HJ. Chronic oral administration of the ethanolic extract of HJ significantly increased social interaction, attenuated repetitive grooming behaviour and improved novelobject recognition in BTBR mice. Antiinflammatory effects of HJ in the brain were analysed using immunohistochemistry and reversetranscription quantitative PCR analysis. Microglia activation was markedly decreased in the striatum and hippocampus, and proinflammatory cytokines, including CC Motif Chemokine Ligand 2, interleukin (IL)1ß and IL6, were significantly reduced in the hippocampus following HJ treatment. Moreover, HJ treatment normalised the phosphorylation levels of: NmethylDaspartate receptor subtype 2B and calcium/calmodulindependent protein kinase type II subunit α in the hippocampus of BTBR mice. The results of the present study demonstrated that the administration of HJ may have beneficial potential for ameliorating behavioural deficits and neuroinflammation in ASD.
Assuntos
Transtorno Autístico/tratamento farmacológico , Humulus/química , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Transtorno do Espectro Autista/tratamento farmacológico , Transtorno Autístico/genética , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Fosforilação/efeitos dos fármacosRESUMO
Parkinson's disease (PD) is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra, leading to motor symptoms. Despite the remarkable improvements in the management of PD in recent decades, many patients remain significantly disabled. Metformin is a primary medication for the management of type 2 diabetes. We previously showed that co-treatment with metformin and 3,4-dihydroxyphenyl-l-alanine (l-DOPA) prevented the development of l-DOPA-induced dyskinesia in a 6-hydroxydopamine (6-OHDA)-lesioned animal model of PD. However, effects of metformin on PD- and aging-induced genes in reactive astrocytes remain unknown. In this study, we assessed the effect of metformin on motor function, neuroprotection, and reactive astrocytes in the 6-OHDA-induced PD animal model. In addition, the effects of metformin on the genes expressed by specific types of astrocytes were analyzed in PD model and aged mice. Here, we showed that metformin treatment effectively improves the motor symptoms in the 6-OHDA-induced PD mouse model, whereas metformin had no effect on tyrosine hydroxylase-positive neurons. The activation of AMPK and BDNF signaling pathways was induced by metformin treatment on the 6-OHDA-lesioned side of the striatum. Metformin treatment caused astrocytes to alter reactive genes in a PD animal model. Moreover, aging-induced genes in reactive astrocytes were effectively regulated or suppressed by metformin treatment. Taken together, these results suggest that metformin should be evaluated for the treatment of Parkinson's disease and related neurologic disorders characterized by astrocyte activation.
Assuntos
Envelhecimento/fisiologia , Astrócitos/efeitos dos fármacos , Astrócitos/fisiologia , Corpo Estriado/fisiologia , Metformina/administração & dosagem , Doença de Parkinson/fisiopatologia , Animais , Corpo Estriado/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacosRESUMO
The NAD(P)H:quinone oxidoreductase 1 (NQO1) gene encodes a cytosolic flavoenzyme that catalyzes the two-electron reduction of quinones to hydroquinones. A polymorphic form of NQO1 is associated with mood disorders such as schizophrenia. However, the role of NQO1 in dopaminergic system has not yet been elucidated. To determine the role of NQO1 in the dopaminergic system, we investigated pharmaco-behavioral effects of d-amphetamine using NQO1-deficienct mice. According to our comparative study involving NQO1+/+ and NQO1-/- mice, NQO1 deficiency increased d-amphetamine-induced psychomotor activity and psychological dependency compared to wild-type mice. Basal and d-amphetamine-induced dopamine levels were also enhanced by NQO1 deficiency. In NQO1-/- mice, neural activation induced by d-amphetamine was higher in dorsolateral striatum, but not in dorsomedial and ventral striata. Although protein level of CaMKIIα, which is a key player in amphetamine-induced dopamine efflux, was decreased in striata of NQO1-/- mice, phosphorylation of CaMKIIα was markedly enhanced in NQO1-/- mice compared to wild-type mice. Interestingly, experiments with pharmacological antagonist showed that D2 antagonist-induced suppression of locomotion required activation of NQO1. Moreover, the rewarding effect in response to D1 agonist was increased by NQO1 deficiency. These results suggest that striatal NQO1 is of considerable interest to understand the mechanism of dopaminergic regulation of psychiatric disorders.
Assuntos
Corpo Estriado/metabolismo , Dextroanfetamina/farmacologia , Dopamina/metabolismo , NAD(P)H Desidrogenase (Quinona)/deficiência , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/agonistasRESUMO
Metformin is a medication that is widely prescribed for the management of type 2 diabetes. In addition to its anti-diabetic uses, metformin has been proposed as a therapeutically effective drug candidate in various central nervous system disorders, including Parkinson's disease (PD). PD is characterized by severe movement defects and is commonly treated with the dopamine (DA) precursor 3,4-dihydroxyphenyl-l-alanine (L-DOPA). However, prolonged use of L-DOPA can lead to the development of L-DOPA-induced dyskinesia (LID). Here, we hypothesized that metformin co-treatment would improve LID in the 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Metformin did not interfere the pharmacotherapeutic effects of L-DOPA in the cylinder test. Furthermore, metformin co-treatment with L-DOPA attenuated the development of LID in unilaterally 6-OHDA-lesioned mice. Metformin showed a long-lasting effect on axial, limb, and orofacial abnormal involuntary movement scores for up to 20 days after treatment initiation. Interestingly, persistent enhancement of the mammalian target of rapamycin, dopamine D1 receptor, and extracellular signaling-regulated kinase 1/2 signaling was maintained in the DA-denervated striatum during metformin treatment. Metformin globally normalized the increased glycogen synthase kinase 3ß activity induced by chronic treatment of L-DOPA in a manner associated with Akt activation in unilaterally 6-OHDA-lesioned mice. These findings suggest that metformin may have therapeutic potential for the suppression or management of L-DOPA-induced motor complications in patients with PD.
Assuntos
Discinesia Induzida por Medicamentos/complicações , Discinesia Induzida por Medicamentos/tratamento farmacológico , Metformina/uso terapêutico , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Amantadina/farmacologia , Amantadina/uso terapêutico , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/patologia , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/patologia , Levodopa , Masculino , Metformina/farmacologia , Camundongos Endogâmicos C57BL , Doença de Parkinson/patologia , Transdução de SinaisRESUMO
Piperlongumine (PL), a biologically active compound from the Piper species, has been shown to exert various pharmacological effects in a number of conditions, including tumours, diabetes, pain, psychiatric disorders and neurodegenerative disease. In this study, we evaluated the therapeutic effects of PL on hippocampal function and cognition decline in aged mice. PL (50 mg/kg/day) was intragastrically administrated to 23monthold female C57BL/6J mice for 8 weeks. Novel object recognition and nest building behaviour tests were used to assess cognitive and social functions. Additionally, immunohistochemistry and western blot analysis were performed to examine the effects of PL on the hippocampus. We found that the oral administration of PL significantly improved novel object recognition and nest building behaviour in aged mice. Although neither the percentage area occupied by astrocytes and microglia nor the level of 4hydroxynonenal protein, a specific marker of lipid peroxidation, were altered by PL treatment, the phosphorylation levels of NmethylDaspartate receptor subtype 2B (NR2B), calmodulindependent protein kinase II alpha (CaMKIIα) and extracellular signalregulated kinase 1/2 (ERK1/2) were markedly increased in the hippocampus of aged mice following the administration of PL. We also found that PL treatment resulted in a CA3specific increase in the phosphorylation level of cyclic AMP response element binding protein, which is recognized as a potent marker of neuronal plasticity, learning and memory. Moreover, the number of doublecortinpositive cells, a specific marker of neurogenesis, was significantly increased following PL treatment in the dentate gyrus of the hippocampus. On the whole, these data demonstrate that PL treatment may be a potential novel approach in the treatment of agerelated cognitive impairment and hippocampal changes.
Assuntos
Envelhecimento/metabolismo , Astrócitos/metabolismo , Região CA3 Hipocampal/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Dioxolanos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Envelhecimento/patologia , Animais , Astrócitos/patologia , Região CA3 Hipocampal/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Camundongos , Proteína Quinase 3 Ativada por Mitógeno/metabolismoRESUMO
Humulus japonicus (HJ), popularly known as Japanese hops, is a traditional herbal medicine widely used for the treatment of pulmonary disease, skin disease, and hypertension in Korea. HJ exerts scavenging effects against reactive oxygen species (ROS), such as superoxide radical, hydroxyl radical, and hydrogen peroxide. Moreover, dysfunction and damage of mitochondria elicited by ROS are of critical importance in the pathogenesis of Parkinson's disease (PD). The present study aimed to examine neuroprotective potential of extracts of HJ using in vitro and in vivo 6-hydroxydopamine (6-OHDA) models. SH-SY5Y cells were cultured to explore the mechanisms for the neuroprotective effect of HJ in vitro. Unilateral 6-OHDA-induced mouse model of PD was established to investigate the neuroprotective effect of HJ on dopaminergic neurons in substantia nigra pars compacta (SNc) and striatum in vivo. Methanol extract of HJ (HJM) significantly attenuated cytotoxicity and the mitochondrial apoptosis pathway caused by 6-OHDA in SH-SY5Y cells. In addition, HJM significantly increased glutathione levels and decreased phosphorylation of ERK1/2 in SH-SY5Y cells exposed to 6-OHDA. In the in vivo study, the administration of methanol or ethanol extract of HJ improved the motor dysfunction and notably reduced dopaminergic cell death and fiber loss in the SNc and striatum caused by 6-OHDA. Our findings demonstrate that HJ may have therapeutic potential to protect dopaminergic neuron degeneration in Parkinson's disease.
Assuntos
Morte Celular/efeitos dos fármacos , Neurônios Dopaminérgicos/efeitos dos fármacos , Humulus/química , Fármacos Neuroprotetores/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Animais , Dopamina/metabolismo , Neurônios Dopaminérgicos/citologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxidopamina/efeitos adversos , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Humulus japonicus Siebold & Zucc. (HJ) has traditionally been administered to patients with pulmonary disease, skin disease and hypertension in Korea, and it is considered to exert anti-inflammatory, antioxidant, antimicrobial and antimycobacterial effects. However, its effects against Alzheimer's disease (AD) have yet to be explored. Thus, this study was carried out to investigate whether HJ has a beneficial effect on the progression of AD in an animal model. A methanolic extract of HJ (500 mg/kg/day) was intragastrically administered to 5-month-old APP/PS1 transgenic (Tg-APP/PS1) mice for 2.5 months. Novel object recognition and Y-maze alteration tests were used to assess cognitive function, and an immunohistochemical assay was performed to assess amyloid ß (Aß)deposition, tau phosphorylation and gliosis. An in vitro assay using a microglial cell line was also performed to investigate the anti-inflammatory effects of HJ. Our results revealed that HJ significantly decreased the mRNA and protein expression levels of tumor necrosis factor-α (TNFα), interleukin (IL)-1ß, IL-6 and inducible nitric oxide synthase (iNOS) induced by lipopolysaccharide in the microglial cell line. The administration of HJ for 2 months improved the cognitive function of Tg-APP/PS1 mice. HJ notably reduced the area occupied by Aß and neurofibrillary tangles, and the number of activated astrocytes and microglia in the cortex of Tg-APP/PS1 mice. The findings of our study suggest that HJ has the therapeutic potential to inhibit the progression of AD and to improve cognitive deterioration in Tg-APP/PS1 mice.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Progressão da Doença , Humulus/química , Extratos Vegetais/uso terapêutico , Presenilina-1/genética , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Linhagem Celular , Cognição/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Humanos , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Insulisina , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Óxido Nítrico/biossíntese , Fosforilação/efeitos dos fármacos , Extratos Vegetais/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas tau/metabolismoRESUMO
L-3,4-dihydroxyphenylalanine (L-DOPA) is the most common treatment for patients with Parkinson's disease (PD). However, long term use of L-DOPA for PD therapy lead to abnormal involuntary movements (AIMs) known as dyskinesia. Fatty acid amide hydrolase (FAAH) is enriched protein in basal ganglia, and inhibition of the protein reduces dyskinetic behavior of mice. Palmitoyl serotonin (PA-5HT) is a hybrid molecule patterned after arachidonoyl serotonin, antagonist of FAAH. However, the effect of PA-5HT on L-DOPA-induced dyskinesia (LID) in PD have not yet been elucidated. To investigate whether PA-5HT relieve LID in PD and decrease hyperactivation of dopamine D1 receptors, we used the 6-hydroxydopomine (6-OHDA)-lesioned mouse model of PD and treated the L-DOPA (20 mg/kg) for 10 days with PA-5HT (0.3 mg/kg/day). The number of wall contacts with the forelimb in the cylinder test was significantly decreased by 6-OHDA lesion in mice and the pharmacotherapeutic effect of L-DOPA was also revealed in PA-5HT-treated mice. Moreover, in AIMs test, PA-5HT-treated mice showed significant reduction of locomotive, axial, limb, and orofacial AIMs score compared to the vehicle-treated mice. LID-induced hyper-phosphorylation of ERK1/2 and overexpression of FosB/ΔFosB was markedly decreased in 6-OHDA-lesioned striatum of PA-5HT-treated mice, indicating that PA-5HT decreased the dopamine D1 receptor-hyperactivation induced by chronic treatment of L-DOPA in dopamine-denervated striatum. These results suggest that PA-5HT effectively attenuates the development of LID and enhance of ERK1/2 phosphorylation and FosB/ΔFosB expression in the hemi-parkinsonian mouse model. PA-5HT may have beneficial effect on the LID in PD.