RESUMO
The pathological characteristics of Parkinson's disease (PD) include dopaminergic neuron damage, specifically disorders caused by dopamine synthesis, in vivo. Plastrum testudinis extract (PTE) and its bioactive ingredient ethyl stearate (PubChem CID: 8122) were reported to be correlated with tyrosine hydroxylase (TH), which is a biomarker of dopaminergic neurons. This suggests that PTE and its small-molecule active ingredient ethyl stearate have potential for development as a therapeutic drug for PD. In this study, we treated 6-hydroxydopamine (6-OHDA)-induced model rats and PC12 cells with PTE. The mechanism of action of PTE and ethyl stearate was investigated by western blotting, bisulfite sequencing PCR (BSP), real-time PCR, immunofluorescence and siRNA transfection. PTE effectively upregulated the TH expression and downregulated the alpha-synuclein expression in both the substantia nigra and the striatum of the midbrain in a PD model rat. The PC12 cell model showed that both PTE and its active monomer ethyl stearate significantly promoted TH expression and blocked alpha-synuclein, agreeing with the in vivo results. BSP showed that PTE and ethyl stearate increased the methylation level of the Snca intron 1 region. These findings suggest that some of the protective effects of PTE on dopaminergic neurons are mediated by ethyl stearate. The mechanism of ethyl stearate may involve disrupting the abnormal aggregation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) with alpha-synuclein by releasing DNMT1, upregulating Snca intron 1 CpG island methylation, and ultimately, reducing the expression of alpha-synuclein.
Assuntos
Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos de Tecidos/química , alfa-Sinucleína/metabolismo , Animais , DNA (Citosina-5-)-Metiltransferase 1/efeitos dos fármacos , Hidroxidopaminas , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Células PC12 , Doença de Parkinson Secundária/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Estearatos/farmacologia , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , alfa-Sinucleína/efeitos dos fármacosRESUMO
The number of functionally active synapses provides a measure of neural integrity, with reductions observed in neurodegenerative disorders. [11C]UCB-J binds to synaptic vesicle 2A (SV2A) transmembrane protein located in secretory vesicles. We aimed to assess [11C]UCB-J PET as an in vivo biomarker of regional cerebral synaptic SV2A density in rat lesion models of neurodegeneration. Healthy anesthetized rats had [11C]UCB-J PET and arterial blood sampling. We compared different models describing [11C]UCB-J brain uptake kinetics to determine its regional distribution. Blocking studies were performed with levetiracetam (LEV), an antiepileptic SV2A antagonist. Tracer binding was measured in rodent unilateral acute lesion models of Parkinsonism and Huntington's disease, induced with 6-hydroxydopamine (6-OHDA) and quinolinic acid (QA), respectively. [3H]UCB-J autoradiography was performed in postmortem tissue. Rat brain showed high and fast [11C]UCB-J uptake and washout with up to 80% blockade by LEV. [11C]UCB-J PET showed a 6.2% decrease in ipsilateral striatal SV2A binding after 6-OHDA and 39.3% and 55.1% decreases after moderate and high dose QA confirmed by autoradiography. In conclusion, [11C]UCB-J PET provides a good in vivo marker of synaptic SV2A density which can potentially be followed longitudinally along with synaptic responses to putative neuroprotective agents in models of neurodegeneration.
Assuntos
Corpo Estriado/diagnóstico por imagem , Corpo Estriado/lesões , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Sinapses/metabolismo , Animais , Anticonvulsivantes/farmacologia , Autorradiografia , Feminino , Doença de Huntington/induzido quimicamente , Doença de Huntington/patologia , Doença de Huntington/psicologia , Hidroxidopaminas/farmacocinética , Cinética , Levetiracetam/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/patologia , Doença de Parkinson Secundária/psicologia , Ácido Quinolínico/farmacocinética , Compostos Radiofarmacêuticos , Ratos , Ratos Sprague-DawleyRESUMO
INTRODUCTION: Parkinson's Disease (PD) is a progressive neurodegenerative disorder, hallmark of which is loss of nigral dopaminergic neurons. Since a Hypericum polyanthemum extract inhibits monoamine reuptake and some of its constituents present cytotoxic properties, the aim of this study was to evaluate the effect of this extract in an animal PD model. METHODS: Adult Wistar rats (110 days old) received 6-hydroxydopamine (6-OHDA) infusions into the right medial forebrain bundle. A cyclohexane extract from aerial parts of H. polyanthemum (POL; 90 mg/kg/administration; gavage) was administered in three different regimens. In Regimens 1 and 2, rats received 3 administrations of POL starting 4 or 24 h after 6-OHDA infusion, respectively. In Regimen 3, these administrations were carried out 1 day before any evaluation of ipsilateral rotational activity induced by methylphenidate (MP, 20 mg/kg, i.p.). MP was administered 10, 45, and 85 days after 6-OHDA infusion in all groups. Nigral tyrosine hydroxylase (TH) immunocontent was evaluated 120 days after 6-OHDA infusion in animals submitted to Regimen 2 only. The effect of POL on apomorphine-induced climbing behavior in non-lesioned adult CF1 mice (60 days old) treated with POL was also evaluated. RESULTS: Regimen 2 increased MP-induced rotational activity and decreased nigral TH levels in 6-OHDA-lesioned rats. Rotational activity was not altered in regimens 1 and 3. In addition, no change in climbing behavior was observed in non-lesioned mice. CONCLUSION: Together, these results indicate that, in 6-OHDA-lesioned rats, a cyclohexane H. polyanthemum extract potentiates neurotoxicity and MP-induced motor asymmetry depending on the time of administration. In the short term, it seems to not act directly on mice dopaminergic receptors.
Assuntos
Comportamento Animal/efeitos dos fármacos , Hidroxidopaminas/farmacologia , Hypericum/metabolismo , Atividade Motora/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Dopamina/farmacologia , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/tratamento farmacológico , Ratos Wistar , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Parkinson's disease (PD) is described as a neurological condition, resulting from continuous degeneration of dopaminergic neurons. Currently, most treatments for neurodegenerative diseases are palliative. In traditional Iranian medicine, Citrus aurantium flower extract is used to treat some neural diseases, such as sleep disorders and anxiety. The tendency towards the use of medicinal herbs for the treatment of diseases (eg, seizure) is growing. Accordingly, we evaluated the antioxidant effects of C. aurantium flowers and analyzed their protective effects against 6-hydroxydopamine (6-OHDA)-mediated oxidative stress. In this study, 150 mM of 6-OHDA was used to induce cellular damage. Also, MTT assay was performed to analyze cellular viability. Fluorescence spectrophotometry was performed to measure the intracellular reactive oxygen species (ROS) and calcium levels. Based on the findings, 6-OHDA could reduce cell viability. We also analyzed the effects of C. aurantium against neurotoxicity. The intracellular levels of ROS and calcium greatly improved in cells exposed to 6-OHDA. SH-SY5Y cell incubation with C. aurantium (400 and 600 mg/mL) induced protective effects and decreased the biochemical markers of cell apoptosis. According to the findings, C. aurantium showed protective effects against neurotoxicity, caused by 6-OHDA; these protective properties were accompanied by antiapoptotic features. According to the findings, it seems that hydromethanolic C. aurantium extract can be used to prevent seizures.
La enfermedad de Parkinson (EP) se describe como una afección neurológica que resulta de la degeneración continua de las neuronas dopaminérgicas. Actualmente, la mayoría de los tratamientos para las enfermedades neurodegenerativas son paliativos. En la medicina tradicional iraní, el extracto de flor de Citrus aurantium se usa para tratar algunas enfermedades neurológicas, como los trastornos del sueño y la ansiedad. La tendencia hacia el uso de las medicinas para el tratamiento de enfermedades (por ejemplo, convulsiones) está creciendo. Por consiguiente, el objetivo de este trabajo consistió en evaluar los efectos antioxidantes de las flores de C. aurantium y analizar sus efectos protectores contra el estrés oxidativo mediado por la 6- hidroxidopamina (6-OHDA). En este estudio, se usó 150 mM de 6-OHDA para inducir daño celular. Además, se realizó un ensayo de MTT para analizar la viabilidad celular. La espectrofotometría de fluorescencia se realizó para medir las especies reactivas de oxígeno (ROS) intracelulares y los niveles de calcio. En base a los hallazgos, 6-OHDA podría reducir la viabilidad celular. También analizamos los efectos de C. aurantium contra la neurotoxicidad. Los niveles intracelulares de ROS y calcio se expandieron a las células expuestas a 6-OHDA. La incubación de células SH-SY5Y con C. aurantium (400 y 600 mg / ml) indujo efectos protectores y disminuyó los marcadores bioquímicos de la apoptosis celular. De acuerdo con los hallazgos, C. aurantium mostró efectos protectores contra la neurotoxicidad, causada por 6-OHDA; estas propiedades protectoras fueron acompañadas por características antiapoptóticas. Según los hallazgos, parece que el extracto hidrometanólico de C. aurantium se puede usar para prevenir las convulsiones.
Assuntos
Humanos , Doença de Parkinson , Extratos Vegetais/farmacologia , Citrus/química , Antioxidantes/farmacologia , Espectrometria de Fluorescência , Sobrevivência Celular/efeitos dos fármacos , Western Blotting , Espécies Reativas de Oxigênio , Apoptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fármacos Neuroprotetores , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Hidroxidopaminas/toxicidade , NeuroblastomaRESUMO
BACKGROUND: While the Albizia adianthifolia (Schumach.) W. Wright (Fabaceae) is a traditional herb largely used in the African traditional medicine as analgesic, purgative, antiinflammatory, antioxidant, antimicrobial, memory-enhancer, anxiolytic and antidepressant drug, there are no scientific data that clarify the anxiolytic and antidepressant-like effects in 6-hydroxydopamine (6-OHDA)-lesioned animal model of Parkinson's disease. This study was undertaken in order to identify the effects of aqueous extract of A. adianthifolia leaves on 6-hydroxydopamine-induced anxiety, depression and oxidative stress in the rat amygdala. METHODS: The effect of the aqueous extract of A. adianthifolia leaves (150 and 300 mg/kg, orally, daily, for 21 days) on anxiety and depression was assessed using elevated plus-maze and forced swimming tests, as animal models of anxiety and depression. Also, the antioxidant activity in the rat amygdala was assessed using assessed using superoxide dismutase, glutathione peroxidase and catalase specific activities, the total content of the reduced glutathione, protein carbonyl and malondialdehyde levels. Statistical analyses were performed using by one-way analysis of variance (ANOVA). Significant differences were determined by Tukey's post hoc test. F values for which p < 0.05 were regarded as statistically significant. Pearson's correlation coefficient and regression analysis were used in order to evaluate the connection between behavioral measures, the antioxidant defence and lipid peroxidation. RESULTS: 6-OHDA-lesioned rats exhibited the following: decrease of the exploratory activity, the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming time and increase of immobility time within forced swimming test. Administration of the aqueous extract significantly exhibited anxiolytic- and antidepressant-like effects and also antioxidant potential in the rat amygdala. CONCLUSIONS: Our results suggest that the aqueous extract ameliorates 6-OHDA-induced anxiety and depression by attenuation of the oxidative stress in the rat amygdala. These pieces of evidence accentuate its use in traditional medicine.
Assuntos
Albizzia/química , Tonsila do Cerebelo/efeitos dos fármacos , Ansiolíticos/administração & dosagem , Antidepressivos/administração & dosagem , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Tonsila do Cerebelo/enzimologia , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/induzido quimicamente , Ansiedade/metabolismo , Depressão/induzido quimicamente , Depressão/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Hidroxidopaminas/efeitos adversos , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Folhas de Planta/química , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
OBJECTIVE: Parkinson's disease (PD) may be caused by the interaction of a number of factors, including genetics, toxins, oxidative stress, mitochondrial abnormalities, and aging. Studies have shown that consumption of an antioxidant-rich diet may reduce the incidence of neurodegenerative diseases. The aim of this study was to evaluate the role of the flavonoid hesperidin in an animal model of PD induced by 6-hidroxidopamine (6-OHDA). METHODS: Aged mice were treated with hesperidin (50 mg/kg) during 28 d after an intracerebroventricular injection of 6-OHDA. The enzymatic activities of superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase, and glutathione S-transferase, the levels of glutathione, reactive oxygen species, total reactive antioxidant potential, dopamine and its levels of metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid, was analyzed in the striatum. The behavioral parameters (depressive-like, memory, and locomotor) were measured. RESULTS: This study demonstrated that hesperidin (50 mg/kg) treatment was effective in preventing memory impairment in the Morris water maze test, as well as, depressive-like behavior in the tail suspension test. Hesperidin attenuated the 6-OHDA-induced reduction in glutathione peroxidase and catalase activity, total reactive antioxidant potential and the dopamine and its metabolite levels in the striatum of aged mice. 6-OHDA increased reactive oxygen species levels and glutathione reductase activity in the striatum, and these alterations were mitigated by chronic administration of hesperidin. CONCLUSION: This study demonstrated a protective effect of hesperidin on the neurotoxicity induced by 6-OHDA in aged mice, indicating that it could be useful as a therapy for the treatment of PD.
Assuntos
Antioxidantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Depressão/tratamento farmacológico , Hesperidina/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Encéfalo/metabolismo , Depressão/etiologia , Modelos Animais de Doenças , Dopamina/metabolismo , Feminino , Hesperidina/farmacologia , Elevação dos Membros Posteriores , Hidroxidopaminas , Peroxidação de Lipídeos/efeitos dos fármacos , Aprendizagem em Labirinto , Memória/efeitos dos fármacos , Transtornos da Memória/etiologia , Camundongos Endogâmicos C57BL , Doença de Parkinson/complicações , Doença de Parkinson/metabolismo , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Espécies Reativas de Oxigênio/metabolismoRESUMO
3,4-Dihydroxyphenyl-L-alanine (L-DOPA)-induced dyskinesia (LID) is a debilitating side effect of long-term dopamine replacement therapy in Parkinson's Disease. At present, there are few therapeutic options for treatment of LID and mechanisms contributing to the development and maintenance of these drug-induced motor complications are not well understood. We have previously shown that pharmacological reduction of cholinergic tone attenuates the expression of LID in parkinsonian mice with established dyskinesia after chronic L-DOPA treatment. The present study was undertaken to provide anatomically specific evidence for the role of striatal cholinergic interneurons by ablating them before initiation of L-DOPA treatment and determining whether it decreases LID. We used a novel approach to ablate striatal cholinergic interneurons (ChIs) via Cre-dependent viral expression of the diphtheria toxin A subunit (DT-A) in hemiparkinsonian transgenic mice expressing Cre recombinase under control of the choline acetyltransferase promoter. We show that Cre recombinase-mediated DT-A ablation selectively eliminated ChIs when injected into striatum. The depletion of ChIs markedly attenuated LID without compromising the therapeutic efficacy of L-DOPA. These results provide evidence that ChIs play a key and selective role in LID and that strategies to reduce striatal cholinergic tone may represent a promising approach to decreasing L-DOPA-induced motor complications in Parkinson's disease.
Assuntos
Antiparkinsonianos/toxicidade , Discinesia Induzida por Medicamentos/terapia , Levodopa/toxicidade , Neostriado/fisiologia , Sistema Nervoso Parassimpático/fisiologia , Transtornos Parkinsonianos/terapia , Adenoviridae/genética , Animais , Comportamento Animal/efeitos dos fármacos , DNA Complementar/biossíntese , DNA Complementar/genética , Denervação , Toxina Diftérica/farmacologia , Discinesia Induzida por Medicamentos/fisiopatologia , Hidroxidopaminas/toxicidade , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neostriado/citologia , Sistema Nervoso Parassimpático/citologia , Transtornos Parkinsonianos/fisiopatologiaRESUMO
The hypothalamic neurochemicals neuropeptide Y (NPY), orexin-A (ORX), and oxytocin (OXY) exert glucoregulatory effects upon intracerebral administration, findings that support their potential function within neural pathways that maintain glucostasis. Current understanding of how these neurotransmitter systems respond to the diabetes mellitus complication, insulin-induced hypoglycemia, is limited to knowledge of neuropeptide gene transcriptional reactivity. We investigated the hypothesis that hypoglycemia elicits hypothalamic site-specific alterations in levels of these neurochemicals, and that adjustments in local neurotransmitter availability may be regulated by catecholaminergic (CA) input from the caudal dorsomedial hindbrain. The arcuate (ARH) and paraventricular (PVH) hypothalamic nuclei and lateral hypothalamic area (LHA) were each microdissected from adult male rats pretreated by caudal fourth ventricular administration of the selective CA neurotoxin, 6-hydroxydopamine (6-OHDA), or vehicle prior to insulin (INS)-induced hypoglycemia. Hypoglycemia stimulated ARH NPY gene expression and NPY accumulation in the ARH and LHA, but not PVH. 6-OHDA pretreatment did not modify the positive NPY mRNA response to INS, but blunted hypoglycemic augmentation of ARH and LHA NPY content while increasing PVH NPY levels in response to hypoglycemia. INS-treated rats exhibited diminished LHA ORX gene expression and increased [ARH; LHA] or decreased [PVH] tissue ORX protein levels. 6-OHDA+INS animals showed a comparable decline in ORX transcripts, but attenuated augmentation of ARH and LHA ORX content and elevated PVH ORX levels. OT mRNA and protein were respectively decreased or unchanged during hypoglycemia, responses that were uninfluenced by hindbrain CA nerve cell destruction. These results illustrate divergent adjustments in glucoregulatory neurotransmitter gene expression and site-specific protein accumulation in the hypothalamus during hypoglycemia. Evidence that 6-OHDA pretreatment does not modify NPY or ORX transcriptional reactivity to hypoglycemia, but alters hypoglycemic patterns of NPY and ORX accretion implicates dorsomedial hindbrain CA neurons in regulation of translation/post-translational processing and site-specific availability of these neurotransmitters in the hypothalamus during hypoglycemia.
Assuntos
Catecolaminas/metabolismo , Glucose/metabolismo , Hipoglicemia/metabolismo , Hipotálamo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Neuropeptídeo Y/biossíntese , Neuropeptídeos/biossíntese , Ocitocina/biossíntese , Rombencéfalo/metabolismo , Animais , Glicemia/metabolismo , Western Blotting , Hidroxidopaminas/farmacologia , Hipoglicemia/induzido quimicamente , Hipoglicemiantes , Imuno-Histoquímica , Insulina , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Neuropeptídeo Y/genética , Neuropeptídeos/genética , Neurotoxinas/metabolismo , Neurotransmissores/metabolismo , Orexinas , Ocitocina/genética , Reação em Cadeia da Polimerase , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Simpatectomia QuímicaRESUMO
Three dimensional maps of iron (Fe), zinc (Zn), copper (Cu), manganese (Mn) and phosphorous (P) in a 6-hydroxydopamine (6-OHDA) lesioned mouse brain were constructed employing a novel quantitative laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging method known as elemental bio-imaging. The 3D maps were produced by ablating serial consecutive sections taken from the same animal. Each section was quantified against tissue standards resulting in a three dimensional map that represents the variation of trace element concentrations of the mouse brain in the area surrounding the substantia nigra (SN). Damage caused by the needle or the toxin did not alter the distribution of Zn, and Cu but significantly altered Fe in and around the SN and both Mn and Fe around the needle track. A 20% increase in nigral Fe concentration was observed within the lesioned hemisphere. This technique clearly shows the natural heterogeneous distributions of these elements throughout the brain and the perturbations that occur following trauma or intoxication. The method may applied to three-dimensional modelling of trace elements in a wide range of tissue samples.
Assuntos
Química Encefálica , Cobre/análise , Hidroxidopaminas/química , Ferro/análise , Manganês/análise , Fósforo/análise , Zinco/análise , Animais , Imageamento Tridimensional , Espectrometria de Massas/métodos , Camundongos , Modelos BiológicosRESUMO
Neurodegeneration is one of the primary etiologies in the onset of Parkinson's disease. In the quest for a new antiparkinsonism treatment the potential benefits of puerarin from the roots of Pueraria lobata have been recognized. Thus, we examined whether puerarin is capable to protect dopaminergic neurons of the substantia nigra against 6-hydroxydopamine induced neuronal cell death. Our data showed that the intraperitoneal administration of 0.12 mg/kg/day puerarin over 10 days reduced the 6-hydroxydopamine-induced decrease of tyrosine hydroxylase-positive cell counts. Analysis of apoptosis via DNA fragmentation by the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay proved that puerarin could prevent 6-hydroxydopamine-induced apoptosis. As an additional apoptotic cell death marker, the BAX and BCL-2 expression levels were investigated using immunohistochemistry. Whereas 6-hydroxydopamine increased the level of Bax (p < 0.05), the coadministrated puerarin significantly antagonized this effect in a dose-dependent manner. Bcl-2 expression was not affected. Analysis of the dopamine, dihydroxyphenylacetic acid, and L-dihydroxy-phenyl-alanine contents of 6-hydroxydopamine-treated animals by HPLC revealed that puerarin was capable to restore the contents of dopamine and its metabolites. Moreover, the expression level of glial cell line-derived neurotrophic factor in the striatum was higher in puerarin than in rats treated with 6-hydroxydopamine alone. These results suggest that puerarin develops its neuroprotective effect against 6-hydroxydopamine-induced neurotoxicity in the substantia nigra through the inhibition of apoptotic signaling pathways and upregulation of glial cell line-derived neurotrophic factor expression in the striatum.
Assuntos
Apoptose/efeitos dos fármacos , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Isoflavonas/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Pueraria/química , Substância Negra/efeitos dos fármacos , Animais , Contagem de Células , Fragmentação do DNA , Modelos Animais de Doenças , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Hidroxidopaminas/toxicidade , Isoflavonas/uso terapêutico , Masculino , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/metabolismo , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Raízes de Plantas , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Coloração e Rotulagem , Substância Negra/citologia , Substância Negra/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Regulação para Cima , Proteína X Associada a bcl-2/metabolismoRESUMO
AIM: Our previous study indicated petroleum ether layer of Cnidium monnieri L. Cuss. (CM) and its ingredient osthole could alleviate scopolamine-induced amnesia in female rats. MATERIALS AND METHODS: Hence, this study was desired to investigate the mechanism of the ameliorating effects of petroleum ether layer of CM on the performance impairment of inhibitory avoidance task and Morris water maze induced by scopolamine in male rats. RESULTS: CM at 0.1-0.6g/kg orally administered 60 min before the training trial ameliorated the scopolamine-induced performance impairment on inhibitory avoidance learning and water maze in male rats. Only adrenalectomy but not peripheral cholinergic antagonist scopolamine methylbromide and catecholaminergic neurotoxin 6-hydroxydopamine blocked the ameliorating effects of CM on scopolamine-induced performance impairment in rats. CONCLUSION: Therefore, we demonstrated that the ameliorating effects of CM on scopolamine-induced performance impairment may be related to activating the adrenal gland and central acetylcholingeric neuron, instead of peripheral nervous system.
Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Cnidium/química , Antagonistas Muscarínicos , Escopolamina , Glândulas Suprarrenais/fisiologia , Adrenalectomia , Alcanos , Amnésia/psicologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Hidroxidopaminas , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/fisiologia , Extratos Vegetais , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Solventes , Simpatectomia QuímicaRESUMO
In the present studies, the effect of paeoniflorin (PF), one of the main compounds extracted from Paeoniae radix, in alleviating the neurological impairment following unilateral striatal 6-hydroxydopamine (6-OHDA) lesion was examined in Sprague-Dawley rats. Sub-chronic PF (2.5, 5 and 10 mg/kg, s.c., twice daily for 11 days) administration dose-dependently reduced apomorphine (APO)-induced rotation, suggesting that PF had an ameliorative effect on the 6-OHDA-induced neurological impairment. Notably, PF had no direct action on dopamine D(1) receptor or dopamine D(2) receptor indicated by the competitive binding experiments. These results suggest that PF, an active component of Paeoniae radix, might provide an opportunity to introduce a non-dopaminergic management of Parkinson's disease.
Assuntos
Comportamento Animal/efeitos dos fármacos , Benzoatos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Glucosídeos/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , Doença de Parkinson Secundária/psicologia , Animais , Apomorfina/farmacologia , Benzazepinas/metabolismo , Benzoatos/administração & dosagem , Benzoatos/química , Ligação Competitiva/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/química , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/metabolismo , Glucosídeos/administração & dosagem , Glucosídeos/química , Hidroxidopaminas , Técnicas In Vitro , Masculino , Membranas/efeitos dos fármacos , Membranas/metabolismo , Microinjeções , Monoterpenos , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Doença de Parkinson Secundária/induzido quimicamente , Racloprida/metabolismo , Ratos , Ratos Sprague-Dawley , Comportamento Estereotipado/efeitos dos fármacosRESUMO
Antioxidants and iron chelating molecules are known as neuroprotective agents in animal models of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). In this study, we designed and synthesized a novel bifunctional molecule (M10) with radical scavenging and iron chelating ability on an amino acid carrier likely to be a substrate for system L, thus targeting the compound to the central nervous system (CNS). M10 had a moderate iron affinity in HEPES buffer (pH 7.4) with logK(3)=12.25+/-0.55 but exhibited highly inhibitory action against iron-induced lipid peroxidation, with an IC(50) value (12microM) comparable to that of desferal (DFO). EPR studies indicated that M10 was a highly potent *OH scavenger with an IC(50) of about 0.3 molar ratio of M10 to H(2)O(2). In PC12 cell culture, M10 was at least as potent as the anti-Parkinson drug rasagiline in protecting against cell death induced by serum-deprivation and by 6-hydroxydopamine (6-OHDA). These results suggest that M10 deserves further investigation as a potential agent for the treatment of neurodegenerative disorders such as AD and PD.
Assuntos
Aminoácidos/metabolismo , Quelantes de Ferro/farmacologia , Ferro/metabolismo , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Alanina/análogos & derivados , Alanina/química , Alanina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Meios de Cultura Livres de Soro/farmacologia , Avaliação Pré-Clínica de Medicamentos , Sequestradores de Radicais Livres/farmacologia , Hidroxidopaminas/farmacologia , Radical Hidroxila/metabolismo , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacologia , Quelantes de Ferro/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Estrutura Molecular , Neurônios/metabolismo , Células PC12 , RatosRESUMO
Green tea polyphenols exert a wide range of biochemical and pharmacological effects, and have been shown to possess antimutagenic and anticarcinogenic properties. Oxidative stress is involved in the pathogenesis of Parkinson's disease. However, although green tea polyphenols may be expected to inhibit the progression of Parkinson's disease on the basis of their known antioxidant activity, this has not previously been established. In the present study, we evaluated the neuroprotective effects of green tea polyphenols in the Parkinson's disease pathological cell model. The results show that the natural antioxidants have significant inhibitory effects against apoptosis induced by oxidative stress. 6-Hydroxydopamine (6-OHDA)-induced apoptosis in catecholaminergic PC12 cells was chosen as the in vitro model of Parkinson's disease in our study. Apoptotic characteristics of PC12 cells were assessed by MTT assay, flow cytometry, fluorescence microscopy and DNA fragmentation. Green tea polyphenols and their major component, EGCG at a concentration of 200 microM, exert significant protective effects against 6-OHDA-induced PC12 cell apoptosis. EGCG is more effective than the mixture of green tea polyphenols. The antioxidant function of green tea polyphenols may account for this neuroprotective effect. The present study supports the notion that green tea polyphenols have the potential to be effective as neuropreventive agents for the treatment of neurodegenerative diseases.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Catequina/análogos & derivados , Catequina/farmacologia , Flavonoides , Hidroxidopaminas/farmacologia , Extratos Vegetais/farmacologia , Chá , Animais , Sobrevivência Celular/efeitos dos fármacos , Cinética , Células PC12 , Fenóis/farmacologia , Feocromocitoma , Polímeros/farmacologia , RatosRESUMO
PURPOSE: Although vagus nerve stimulation (VNS) is now marketed throughout most of the world as a treatment for drug-resistant epilepsy, the therapeutic mechanism of action of VNS-induced seizure suppression has not yet been established. Elucidation of this mechanism is an important first step in the development of strategies to improve VNS efficacy. Because the locus coeruleus (LC) has been implicated in the antinociceptive effects of VNS, we chemically lesioned the LC in the present study to determine if it is a critical structure involved in the anticonvulsant mechanisms of VNS. METHODS: Rats were chronically depleted of norepinephrine (NE) by a bilateral infusion of 6-hydroxydopamine (6-OHDA) into the LC. Two weeks later, they were tested with maximal electroshock (MES) to assess VNS-induced seizure suppression. In another experiment, the LC was acutely inactivated with lidocaine, and seizure suppression was tested in a similar fashion. RESULTS: VNS significantly reduced seizure severities of control rats. However, in animals with chronic or acute LC lesions, VNS-induced seizure suppression was attenuated. CONCLUSIONS: Our data indicate that the LC is involved in the circuitry necessary for the anticonvulsant effects of VNS. Seizure suppression by VNS may therefore depend on the release of NE, a neuromodulator that has anticonvulsant effects. These data suggest that noradrenergic agonists might enhance VNS-induced seizure suppression.
Assuntos
Terapia por Estimulação Elétrica , Locus Cerúleo/fisiologia , Convulsões/prevenção & controle , Nervo Vago/fisiologia , Animais , Terapia por Estimulação Elétrica/normas , Eletrochoque , Feminino , Hidroxidopaminas/farmacologia , Lidocaína/farmacologia , Locus Cerúleo/efeitos dos fármacos , Norepinefrina/agonistas , Norepinefrina/metabolismo , Norepinefrina/fisiologia , Ratos , Ratos Sprague-Dawley , Convulsões/etiologia , Convulsões/terapia , Índice de Gravidade de DoençaRESUMO
UNLABELLED: Sex-specific peculiarities of catecholamine (CA) content and turnover in neuroendocrine brain areas and their modification with neonatal steroids or prenatal stress (PS) in Wistar rats were studied. No changes in noradrenaline (NA) content and turnover rate were found in the preoptic area (POA), meanwhile dopamine (DA) turnover rates in the POA and mediobasal hypothalamus (MBH) were increased in neonatally androgenized 10-day-old females. Treatment of female neonates with various catecholestrogens increased hypothalamic NA content by 30-95% but only 4-hydroxyestradiol-17 beta induced anovulation. 6-Hydroxydopamine had no significant impact on hypothalamic CA content in neonates and did not prevent testosterone-induced persistent estrous. Maternal stress (restriction for 1 h a day, 15-21st days of pregnancy) resulted in a decrease of hypothalamic NA and blood plasma corticosterone response to acute stress in adult male offspring. Sex differences in CA content in the POA and MBH disappeared in 10-day-old prenatally stressed rats. CONCLUSIONS: (1) sexual brain differentiation needs co-operative actions of sex steroids and CA to be completed; and (2) early changes in CA content and turnover induced by PS or neonatal steroid exposure predetermine long-term alterations of the stress responsiveness, reproductive behaviour and neuroendocrine control of ovulation.
Assuntos
Encéfalo/crescimento & desenvolvimento , Catecolaminas/fisiologia , Hipotálamo/metabolismo , Área Pré-Óptica/metabolismo , Animais , Animais Recém-Nascidos , Estrogênios de Catecol/farmacologia , Feminino , Humanos , Hidroxidopaminas/farmacologia , Recém-Nascido , Masculino , Gravidez , Complicações na Gravidez/metabolismo , Complicações na Gravidez/psicologia , Complicações na Gravidez/veterinária , Ratos , Ratos Wistar , Estresse Fisiológico/metabolismo , Testosterona/farmacologiaRESUMO
Long-term results are presented of 28 patients who were diagnosed with neuroblastoma at more than 12 months of age and who received melphalan 180 mg/m2 (n = 6) or 240 mg/m2 (n = 22) to consolidate remissions of Stage IV disease or to control refractory disease. Twenty-four patients also received dianhydrogalactitol 180 to 240 mg/m2, and 11 received total body irradiation 450 to 600 cGy. Autologous bone marrow transplantation (ABMT) was performed with marrow that was unpurged (n = 2) or purged ex vivo (n = 26) with 6-hydroxydopamine (6-OHDA) 20 micrograms/ml plus ascorbate 200 micrograms/ml. The median time to an absolute neutrophil count of 500/microliters was 21 days and to self-sustaining platelet counts more than 20,000/microliters, 28 days. One patient required infusion of unpurged reserve marrow. Two groups of patients underwent ABMT: (1) 17 patients (Group I) who were in first remission a median of 7 months after diagnosis; and (2) 11 patients (Group II) who had refractory disease or were in second remission. For Group I, event-free survival was 29% at 12 months and 6% at 24 months post-ABMT. All Group II patients died of disease or ABMT-related toxicity. Overall, of the 28 patients, one is a long-term relapse-free survivor; five died of ABMT-related toxicity; ten patients with tumors present at ABMT had progressive disease within 6 months of ABMT; and 12 patients with no measurable disease at ABMT relapsed 4 to 32 months (median, 12) post-ABMT. Among the latter, six relapses involved the primary site, and six were restricted to distant sites. These results--in accord with the long-term outcome in other series--suggest that for neuroblastoma high-dose melphalan cannot be relied on to ablate residual disease or to salvage patients with refractory tumors. In addition, the pattern of relapse in several patients could be explained by infusion of incompletely purged autografts; this would support recent laboratory evidence that 6-OHDA/ascorbate is a suboptimal purging method.
Assuntos
Transplante de Medula Óssea , Melfalan/uso terapêutico , Neuroblastoma/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ácido Ascórbico , Criança , Pré-Escolar , Terapia Combinada , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Dianidrogalactitol/uso terapêutico , Doxorrubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Hidroxidopaminas , Hidroxiureia/administração & dosagem , Lactente , Masculino , Estadiamento de Neoplasias , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Oxidopamina , Prognóstico , Dosagem Radioterapêutica , Indução de Remissão , Taxa de Sobrevida , Vincristina/administração & dosagem , Irradiação Corporal TotalRESUMO
In this study we examined the role of the noradrenergic innervation of the hypothalamus on the adrenalectomy-induced changes in median eminence (ME) CRF-41 and serum ACTH. 6-Hydroxydopamine (6-OHDA), the catecholaminergic neurotoxin, or vehicle was injected into the ventral noradrenergic bundle of male rats. One week later animals underwent adrenalectomy or sham operation and were sacrificed 18 or 120 h later. In sham-operated rats 6-OHDA did not affect ME CRF-41 content or serum ACTH. In vehicle-injected adrenalectomized rats ACTH was increased approximately 3-fold at 18 h and almost 6-fold at 120 h. At 18 h CRF-41 content was markedly depleted (reduced approximately 20-fold) but by 120 h CRF-41 content had partially recovered and was about 70% of control animals. In adrenalectomized animals, 6-OHDA lesions caused a complete inhibition of the increase in serum ACTH both at 18 h and at 120 h. Pretreatment with 6-OHDA partially attenuated the drastic reduction in ME CRF-41 content following adrenalectomy at 18 h. However, at 120 h, the neurotoxin prevented the recovery of CRF-41 following adrenalectomy. These results suggest that intact norepinephrine innervation to the hypothalamus is necessary for the increased production of ACTH following adrenalectomy and that its interruption interferes with both the adrenalectomy-induced ME CRF-41 reduction and subsequent recovery.
Assuntos
Adrenalectomia , Hormônio Adrenocorticotrópico/sangue , Hormônio Liberador da Corticotropina/metabolismo , Hipotálamo/metabolismo , Eminência Mediana/metabolismo , Norepinefrina/metabolismo , Animais , Hidroxidopaminas , Injeções , Masculino , Neurotoxinas , Oxidopamina , Ratos , Ratos Endogâmicos , Valores de ReferênciaRESUMO
The hypothesis that a functional projection from the locus coeruleus (LC) to the posterior hypothalamus contributes to the development of hypertension in SHR, was tested by measuring norepinephrine (NE) in the posterior hypothalamus by brain dialysis after injections of L-glutamate (L-glu) into LC. L-glu elicited a prolonged elevation of blood pressure in both SHR and WKY. Pressor effects were significantly larger in SHR than in WKY. Extracellular NE in the posterior hypothalamus increased after LC stimulation; NE release was significantly higher in SHR than in WKY. Injections of 6-hydroxydopamine (6-OHDA) into posterior hypothalamus lowered the resting blood pressure and attenuated the pressor responses to L-glu injections into the LC in SHR. These findings suggest that the LC projects functionally to the posterior hypothalamus and that the projection can contribute to the development of hypertension in SHR.
Assuntos
Hipertensão/etiologia , Hipotálamo/metabolismo , Locus Cerúleo/metabolismo , Norepinefrina/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Glutamatos/administração & dosagem , Glutamatos/farmacologia , Ácido Glutâmico , Hidroxidopaminas/administração & dosagem , Hidroxidopaminas/farmacologia , Hipotálamo/fisiologia , Locus Cerúleo/fisiologia , Microinjeções , Oxidopamina , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Experiment 1 investigated the effects of catecholaminergic deafferentation or cell body lesions of the amygdala on fear conditioning to explicit and contextual cues. Bilateral infusions of quinolinic acid mainly damaged neurons within the basolateral region of the amygdala. 6-Hydroxydopamine infusions at the same coordinates resulted in an 86% depletion of noradrenaline and a 63% depletion of dopamine from the amygdala, but had no effect on the concentration of 5-hydroxytryptamine. After recovery from surgery, lesioned rats and controls were exposed to pairings of an auditory (clicker) conditioned stimulus and (foot shock) unconditioned stimulus in a distinctive environment. During testing, rats with both 6-hydroxydopamine and cell body lesions showed severely impaired conditioning to explicit cues, compared with controls, indicated by their reduced suppression of drinking when the conditioned stimulus was introduced into a separate, lick-operant chamber. Neither lesion affected fear conditioning to contextual cues, measured as preference for a "safe" environment over the one in which they were shocked. In Experiment 2, rats received bilateral, ibotenic acid-induced lesions of the hippocampal formation. Lesioned rats and controls were again tested for aversive conditioning to explicit and contextual cues. Rats with cell body lesions of the hippocampus showed normal suppression of drinking in the presence of the conditioned stimulus, but were severely impaired in choosing the safe environment based on contextual cues alone. These results suggest a double dissociation of the effects of amygdala and hippocampal damage on fear conditioning to explicit and contextual cues.