RESUMO
We studied potential changes in the subventricular zone (SVZ) stem cell niche of the senescence-accelerated mouse prone-8 (SAM-P8) aging model. Bromodeoxyuridine (BrdU) assays with longtime survival revealed a lower number of label-retaining stem cells in the SAM-P8 SVZ compared with the SAM-Resistant 1 (SAM-R1) control strain. We also found that in SAM-P8 niche signaling is attenuated and the stem cell pool is less responsive to the self-renewal niche factor pigmented epithelium-derived factor (PEDF). Protein analysis demonstrated stable amounts of the PEDF ligand in the SAM-P8 SVZ niche; however, SAM-P8 stem cells present a significant expression decrease of patatin-like phospholipase domain containing 2, a receptor for PEDF (PNPLA2-PEDF) receptor, but not of laminin receptor (LR), a receptor for PEDF (LR-PEDF) receptor. We observed changes in self-renewal related genes (hairy and enhancer of split 1 (Hes1), hairy and enhancer of split 1 (Hes5), Sox2] and report that although these genes are down-regulated in SAM-P8, differentiation genes (Pax6) are up-regulated and neurogenesis is increased. Finally, sheltering mammalian telomere complexes might be also involved given a down-regulation of telomeric repeat binding factor 1 (Terf1) expression was observed in SAM-P8 at young age periods. Differences between these 2 models, SAM-P8 and SAM-R1 controls, have been previously detected at more advanced ages. We now describe alterations in the PEDF signaling pathway and stem cell self-renewal at a very young age, which could be involved in the premature senescence observed in the SAM-P8 model.
Assuntos
Envelhecimento/metabolismo , Envelhecimento/patologia , Proteínas do Olho/metabolismo , Ventrículos Laterais/metabolismo , Ventrículos Laterais/patologia , Fatores de Crescimento Neural/metabolismo , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Serpinas/metabolismo , Envelhecimento/genética , Animais , Bromodesoxiuridina/metabolismo , Contagem de Células , Proteínas do Olho/genética , Camundongos , Modelos Animais , Modelos Neurológicos , Fatores de Crescimento Neural/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/metabolismo , Serpinas/genética , Transdução de Sinais , Nicho de Células-TroncoRESUMO
This study was aimed at investigating the anticonvulsant activity of lipoic acid (LA) against pilocarpine-induced seizures as well as the effects of this metabolic antioxidant on the hippocampal extracellular concentrations of amino acid neurotransmitters glutamate, aspartate, glycine and glutamate and γ-aminobutyric acid (GABA). In vivo microdialysis demonstrated that an intraperitoneal administration of pilocarpine induced a pronounced increment of hippocampal glutamate and aspartate concentrations, whereas no significant change was observed in the levels of glycine or GABA. LA (10, 20 or 30 mg/kg) pretreatment completely blocked pilocarpine-evoked increases in extracellular glutamate and aspartate concentrations. Significant reductions in hippocampal GABA and glycine concentrations were also observed although not as pronounced as those shown by glutamate and aspartate. Based on the finding that LA protected rats against pilocarpine-induced seizures, it could be suggested that the reduction in inhibitory amino acid neurotransmitters levels was comparatively minor and offset by a more pronounced reduction in glutamate and aspartate extracellular concentrations. Therefore, the fact that LA could drastically reduce pilocarpine-induced increases in glutamate and aspartate should account, at least partly, for its anticonvulsant activity observed in pilocarpine-induced seizure in rats.
Assuntos
Aminoácidos Excitatórios/líquido cefalorraquidiano , Hipocampo/metabolismo , Pilocarpina/farmacologia , Convulsões/metabolismo , Ácido Tióctico/farmacologia , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Ácido Aspártico/líquido cefalorraquidiano , Diálise/métodos , Ácido Glutâmico/líquido cefalorraquidiano , Glicina/líquido cefalorraquidiano , Hipocampo/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/mortalidade , Convulsões/fisiopatologia , Convulsões/prevenção & controle , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/metabolismo , Estado Epiléptico/mortalidade , Estado Epiléptico/fisiopatologia , Estado Epiléptico/prevenção & controle , Análise de Sobrevida , Ácido Tióctico/uso terapêutico , Ácido gama-Aminobutírico/líquido cefalorraquidianoRESUMO
UNLABELLED: In this study, we investigated the effects of lipoic acid (LA) in the hippocampus oxidative stress caused by pilocarpine-induced seizures in adult rats. Wistar rats were treated with 0.9% saline (i.p., control group), LA (10mg/kg, i.p., LA group), ubiquinone [20mg/kg, i.p., ubiquinone (UQ) group], pilocarpine (400mg/kg, i.p., P400 group), and the association of LA (10mg/kg, i.p.) plus pilocarpine (400mg/kg, i.p.) or UQ (20mg/kg, i.p.) plus pilocarpine (400mg/kg, i.p.), 30min before of administration of P400 (LA plus P400 group and UQ plus P400 group, respectively). After the treatments, all groups were observed for 1h. The enzyme activities (δ-aminolevulinic dehydratase (δ-ALA-D), Mg(2+) -ATPase, and Na(+) , K(+) -ATPase) were measured using spectrophotometric methods, and the results compared to values obtained from saline and pilocarpine-treated animals. Protective effects of LA and UQ were also evaluated on the same parameters. We reported here for the first time that Na(+) , K(+) -ATPase and δ-ALA-D activities inhibition and Mg(2+) -ATPase stimulation in the pilocarpine model are probably attributed to the oxidative stress caused by seizures in the rat hippocampus. The addition of the antioxidants LA and UQ may reverses the previously mentioned Na(+) , K(+) -ATPase and δ-ALA-D inhibitions and Mg(2+) -ATPase stimulation. CONCLUSIONS: The oxidative stress plays an important signaling role in pilocarpine-induced seizures, and antioxidant drugs might be considered as therapeutical tools in this pathology.
Assuntos
Antioxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Convulsões/tratamento farmacológico , Animais , Antioxidantes/metabolismo , ATPase de Ca(2+) e Mg(2+)/efeitos dos fármacos , ATPase de Ca(2+) e Mg(2+)/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Pilocarpina/toxicidade , Sintase do Porfobilinogênio/efeitos dos fármacos , Sintase do Porfobilinogênio/metabolismo , Ratos , Ratos Wistar , ATPase Trocadora de Sódio-Potássio/efeitos dos fármacos , ATPase Trocadora de Sódio-Potássio/metabolismo , Ácido Tióctico/farmacologia , Ubiquinona/farmacologiaRESUMO
The purposes of the present study were to verify monoamines (dopamine (DA), norepinephrine (NE), serotonin (5-HT)), and their metabolites (3,4-hydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA)) contents in rat hippocampus after lipoic acid (LA) administration. Wistar rats were treated with 0.9% saline (i.p., control group) and LA (10, 20 or 30 mg/kg, i.p., LA10, LA20 and LA30 groups, respectively). After the treatments all groups were observed for 24 h. The NE and DA levels were increased only in 20 mg/kg dose of LA in rat hippocampus. Serotonin content and in their metabolite 5-HIAA levels was decreased in same dose of LA. On the other hand, in DOPAC and HVA levels did not show any significant change. The alterations in hippocampal monoamines can be suggested as a possible of brain mechanism of action from this antioxidant. The outcome of the study may have therapeutic implications in the treatment of neurodegenerative diseases.
Assuntos
Antioxidantes/farmacologia , Monoaminas Biogênicas/metabolismo , Hipocampo/efeitos dos fármacos , Ácido Tióctico/farmacologia , Animais , Hipocampo/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
The purposes of the present study were to verify monoamines (dopamine (DA), norepinephrine (NE), serotonin (5-HT)), and their metabolites (3,4-hydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA)) contents in rat hippocampus after lipoic acid (LA) administration. Wistar rats were treated with 0.9 percent saline (i.p., control group) and LA (10, 20 or 30 mg/kg, i.p., LA10, LA20 and LA30 groups, respectively). After the treatments all groups were observed for 24 h. The NE and DA levels were increased only in 20 mg/kg dose of LA in rat hippocampus. Serotonin content and in their metabolite 5-HIAA levels was decreased in same dose of LA. On the other hand, in DOPAC and HVA levels did not show any significant change. The alterations in hippocampal monoamines can be suggested as a possible of brain mechanism of action from this antioxidant. The outcome of the study may have therapeutic implications in the treatment of neurodegenerative diseases.
O objetivo do presente estudo foi verificar a concentração das monoaminas (dopamina (DA), norepinefrina (NA), serotonina (5-HT)), e seus metabólitos (ácido 3,4-hidroxifenil (DOPAC), ácido homovanílico (HVA) e 5 ácido hydroxiindolacético (5-HIAA)) no hipocampo de ratos após administração do ácido lipóico (AL). Ratos Wistar foram tratados com solução salina 0,9 por cento (i.p., grupo controle) e AL (10, 20 ou 30 mg/kg, i.p., AL10, AL20 e AL30 grupos, respectivamente). Após os tratamentos todos os grupos foram observados durante 24 h. O conteúdo de DA no hipocampo de ratos foi aumentado apenas com AL na dose de 20 mg/kg dose. A concentração de serotonina e do seu metabólito 5-HIAA também foi diminuída com esta dose de AL. Por outro lado, os níveis de DOPAC e de HVA não mostrram nenhuma mudança significativa. As alterações na concentração das monoaminas hipocampais podem ser sugeridas como um possível mecanismo de ação cerebral deste antioxidante. O resultado do estudo pode ter implicações terapêuticas no tratamento de doenças neurodegenerativas.
Assuntos
Animais , Masculino , Ratos , Antioxidantes/farmacologia , Monoaminas Biogênicas/metabolismo , Hipocampo/efeitos dos fármacos , Ácido Tióctico/farmacologia , Hipocampo/metabolismo , Ratos WistarRESUMO
In the present study we investigated the effects of lipoic acid (LA) on delta-aminolevulinic dehydratase (delta-ALA-D) and Na(+), K(+)-ATPase activities in rat brain after seizures induction by pilocarpine. Wistar rats were treated with 0.9% saline (i.p., control group), lipoic acid (10mg/kg, i.p., LA group), pilocarpine (400mg/kg, i.p., pilocarpine group), or the combination of LA (10mg/kg, i.p.) with pilocarpine (400mg/kg, i.p.), 30 min before administration of LA (LA plus pilocarpine group). After the treatments all groups were observed for 1h. The enzyme activities (delta-ALA-D and Na(+), K(+)-ATPase) were measured using spectrophotometric methods, and the results were compared with that obtained from saline and pilocarpine-treated animals. Neuroprotective effects of LA against seizures were evaluated based on those enzyme activities. The pilocarpine group showed a reduction in delta-ALA-D and Na(+), K(+)-ATPase activities after seizures. In turn, LA plus pilocarpine abolished the appearance of seizures and reversed the decreased in delta-ALA-D and Na(+), K(+)-ATPase activities produced by seizures, when compared to the pilocarpine seizing group. The results from the present study demonstrate that preadministration of LA abolished seizure episodes induced by pilocarpine in rat, probably by increasing delta-ALA-D and Na(+), K(+)-ATPase activities in rat brain during seizures.
Assuntos
Encéfalo/efeitos dos fármacos , Pilocarpina/efeitos adversos , Sintase do Porfobilinogênio/metabolismo , Convulsões/prevenção & controle , ATPase Trocadora de Sódio-Potássio/metabolismo , Ácido Tióctico/administração & dosagem , Animais , Encéfalo/enzimologia , Masculino , Ratos , Ratos Wistar , Convulsões/induzido quimicamenteRESUMO
Using the epilepsy model obtained by systemic administration of pilocarpine in rats in the present study we investigated the changes caused by seizures on content and species of gangliosides and phospholipids, as well as on cholesterol concentration, glutathione reduced contents, Na(+), K(+)-ATPase activity and lipid peroxidation levels in rat hippocampus. Wistar rats received pilocarpine hydrochloride (400mg/kg, i.p., pilocarpine group), and other group received 0.9% saline (i.p., control group). Results showed that seizures significantly decreased the total content of lipids and glutathione reduced concentration in rat hippocampus. We also observed that seizures significantly reduced the absolute quantity of the major brain gangliosides (GM1, GD1a, GD1b and GT1b) and phospholipids (sphingomyelin, phosphatidylcholine and phosphatidylethanolamine). Our data also showed a decreased Na(+), K(+)-ATPase activity and an increased TBARS levels in hippocampus of seized rats. If confirmed in human beings, these data could suggest that the alteration in lipid composition, Na(+), K(+)-ATPase activity, glutathione reduced content and TBARS levels caused by seizures might contribute to the neurophysiopathology of seizures observed in epileptic patients.