RESUMO
OBJECTIVES: Post-stroke cognitive impairment (PSCI) interferes with neurorehabilitation in patients with stroke. Epigenetic regulation of the hippocampus has been targeted to ameliorate cognitive function. In particular, the acetylation level of histones is modulated by exercise, a potent therapy for patients with stroke. MATERIALS AND METHODS: We examined the effects of exercise and pharmacological inhibition of histone deacetylase (HDAC) using sodium butyrate (NaB) on cognitive function and epigenetic factors in the hippocampus after intracerebral hemorrhage (ICH) to seek beneficial neuronal conditioning against PSCI. Forty rats were randomly assigned to five groups: sham, control, NaB, exercise, and NaB plus exercise groups (n=8 in each group). Except for those in the sham group, all rats underwent stereotaxic ICH surgery with a microinjection of collagenase solution. Intraperitoneal administration of NaB (300 mg/kg) and treadmill exercise (11 m/min for 30 min) were conducted for approximately 4 weeks starting 3 days post-surgery. RESULTS: ICH reduced cognitive function, as detected by the object location test, accompanied by enhanced activity of HDACs. Although exercise did not modulate HDAC activity or cognitive function, repetitive NaB administration increased HDAC activity and ameliorated cognitive impairment induced by ICH. CONCLUSIONS: This study suggests that pharmacological treatment with an HDAC inhibitor could potentially present an enriched epigenetic platform in the hippocampus and ameliorate PSCI for neurorehabilitation following ICH.
Assuntos
Disfunção Cognitiva , Acidente Vascular Cerebral , Ratos , Animais , Epigênese Genética , Histona Desacetilases/metabolismo , Histona Desacetilases/farmacologia , Hipocampo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Hemorragia Cerebral/complicações , Hemorragia Cerebral/tratamento farmacológicoRESUMO
OBJECTIVE: Pharmacological inhibition of GABAergic synapses could represent a potent neuromodulation strategy to activate hippocampal neurons and increase neurotrophic factor gene expression, thus exerting a beneficial effect on post-stroke cognitive impairment (PSCI). The objective of this study was to assess the effects of low-level inhibition of GABAergic synapses on hippocampal gene expressions related to neuroplasticity using the middle cerebral artery occlusion surgery (MCAO) ischemic stroke rat model. METHODS: The animals were randomly assigned to three experimental groups-(1) a sham operated group (SHAM), (2) a control group (CON), and (3) a bicuculline group (BIC). MCAO was performed in the CON and BIC groups. A non-epileptic dose of bicuculline (0.25 mg/kg) was intraperitoneally administered every day for two weeks, starting three days after surgery, to the rats in the BIC group. The mRNA expression of brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), in relation to neurotrophic intracellular signal, p75, in relation to apoptosis, and synaptophysin (SYP) and PSD-95, synaptic markers, were assessed in the hippocampus ipsilateral to the ischemic site. RESULTS: MCAO increased the gene expression of TrkB. Furthermore, MCAO plus bicuculline administration increased the expression ratio of TrkB to p75 and SYP gene expression. CONCLUSION: Therefore, this study showed that administration of bicuculline after stroke beneficially modulated the expression of crucial genes for neuroplasticity, including BDNF receptors and SYP, in the ipsilateral hippocampus, suggesting that low-level inhibition of GABAergic synapses could lead to beneficial neuromodulation in the hippocampus after stroke.
Assuntos
Bicuculina/farmacologia , Antagonistas de Receptores de GABA-A/farmacologia , Neurônios GABAérgicos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/genética , Inibição Neural/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/genética , Proteína 4 Homóloga a Disks-Large/metabolismo , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/patologia , Regulação da Expressão Gênica , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Infarto da Artéria Cerebral Média/metabolismo , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Ratos Sprague-Dawley , Receptor trkB/genética , Receptor trkB/metabolismo , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/metabolismo , Sinaptofisina/genética , Sinaptofisina/metabolismoRESUMO
Kakeromamide A (1), a new cyclic pentapeptide encompassing a thiazole ring moiety and a ß-amino acid, was isolated from the marine cyanobacterium Moorea bouillonii. Its structure was elucidated by the spectral analysis and the modified Marfey's method. Compound 1 induced differentiation of neural stem cells into astrocytes at the concentration of 10⯵M.
Assuntos
Antineoplásicos/farmacologia , Astrócitos/efeitos dos fármacos , Cianobactérias/química , Oligopeptídeos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Conformação Molecular , Oligopeptídeos/química , Oligopeptídeos/isolamento & purificação , Relação Estrutura-AtividadeRESUMO
Exercise increases the expression of brain-derived neurotrophic factor (BDNF) in the brain and contributes to cognitive and sensorimotor functions. This study aimed to elucidate how repeated exercise modifies BDNF expression elicited by a single bout of exercise in the brain using in vivo bioluminescence imaging (BLI). Bdnf-luciferase (Luc) mice with the firefly luciferase gene inserted at the translation start point of the Bdnf gene were used for BLI to monitor changes in BDNF expression in the brain. The treadmill exercise at a speed of 10 m/s for 60 min was repeated 5 days a week for 4 weeks. BLI in individual subjects was repeated four times: before the exercise intervention, on the first exercise day, and 14 and 28 days after the start of the intervention. Each BLI was performed after a single bout of exercise and monitored for 8 h after exercise. Repetitive BLI showed that the exercise regimen enhanced BDNF expression in the brain, specifically at 4-8 h after a single bout of exercise. Repeated exercise for 2 weeks accelerated the start of enhancement after a single bout of exercise, but not after 4 weeks of repeated exercise. This study showed that repeated exercise modulated the time window of exercise-enhanced BDNF expression, suggesting that repeated exercise could change the sensitivity of gene expression to a single bout of exercise. These findings can be attributed to the advantages of in vivo BLI, which allowed us to precisely measure the time course of BDNF expression after repeated exercise in individual subjects.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Encéfalo , Medições Luminescentes , Condicionamento Físico Animal , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Animais , Condicionamento Físico Animal/fisiologia , Condicionamento Físico Animal/métodos , Encéfalo/metabolismo , Medições Luminescentes/métodos , Masculino , Camundongos , Fatores de Tempo , Camundongos Endogâmicos C57BLRESUMO
Epigenetic regulation is involved in post-stroke neuroplasticity. We investigated the effects of intracerebral hemorrhage (ICH) on histone acetylation and gene expression related to neuronal plasticity in the bilateral sensorimotor cortices, which may affect post-stroke sensorimotor function. Wistar rats were randomly divided into the SHAM and ICH groups. We performed ICH surgery stereotaxically based on the microinjection of a collagenase solution in the ICH group. Foot fault and cylinder tests were performed to evaluate motor functions at 4-time points, including pre-ICH surgery. The amount of acetyl histones and the mRNA expression of neurotrophic factors crucial to neuroplasticity in the bilateral sensorimotor cortices were analyzed approximately 2 weeks after ICH surgery. Sensorimotor functions of the ICH group were inferior to those of the SHAM group during 2 weeks post-ICH. ICH increased the acetylation of histone H3 and H4 over the sham level in the ipsilateral and contralateral cortices. ICH increased the mRNA expression of IGF-1, but decreased the expression of BDNF compared with the sham level in the ipsilateral cortex. The present study suggests that histone acetylation levels are enhanced in bilateral sensorimotor cortices after ICH, presenting an altered epigenetic platform for gene expressions related to neuronal plasticity.
Assuntos
Epigênese Genética , Córtex Sensório-Motor , Ratos , Animais , Histonas/metabolismo , Ratos Wistar , Acetilação , Hemorragia Cerebral/genética , Hemorragia Cerebral/metabolismo , Córtex Sensório-Motor/metabolismo , RNA Mensageiro/metabolismoRESUMO
OBJECTIVES: Physical exercise is known to induce expression of the neuroprotective brain derived neurotrophic factor (BDNF) in the hippocampus. This study examined the effects of physical exercise on hippocampal BDNF expression and the potential benefits for preventing remote secondary hippocampal damage and neurological impairment following intracerebral hemorrhage (ICH). MATERIALS AND METHODS: Wistar rats were randomly assigned to sham-operated, ICH, and ICH followed by exercise (ICH/Ex) groups. The two ICH groups were injected with type IV collagenase into the left basal ganglia, while sham animals were injected with equal-volume saline. The ICH/Ex group rats ran on a treadmill at 11 m/min for 30 min/day from day 3 to 16 post-ICH. All animals were examined for neurological function on day 2 pretreatment and from day 3 to 15 posttreatment, for spontaneous motor activity in the open field on day 15, and for cognitive ability using the object location test on day 16. Animals were then euthanized and bilateral hippocampi collected for gene expression analyses. RESULTS: Experimental ICH induced neurological deficits that were not reversed by exercise. In contrast, ICH did not alter spontaneous activity or object location ability. Expression of BDNF mRNA of the ICH group was significantly downregulated in the ipsilateral hippocampus compared to the SHAM group, but this downregulation was not shown in the ICH/Ex group. The ICH/Ex group showed the downregulation of caspase-3 mRNA expression in the contralateral hippocampus compared to the SHAM group, while neither ICH nor exercise influenced toll-like receptor 4 mRNA expression. CONCLUSIONS: ICH induced the secondary BDNF downregulation in the hippocampus remote from the lesion, whereas physical exercise might partially mitigate the downregulation.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Hemorragia Cerebral , Condicionamento Físico Animal , Animais , Ratos , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hemorragia Cerebral/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Hipocampo/metabolismo , Ratos Wistar , RNA MensageiroRESUMO
Epigenetic regulation is expected to provide an enriched platform for neurorehabilitation of post-stroke patients. Acetylation of specific lysine residues in histones is a potent epigenetic target essential for transcriptional regulation. Exercise modulates histone acetylation and gene expression in neuroplasticity in the brain. This study sought to examine the effect of epigenetic treatment using a histone deacetylase (HDAC) inhibitor, sodium butyrate (NaB), and exercise on epigenetic markers in the bilateral motor cortex after intracerebral hemorrhage (ICH) to identify a more enriched neuronal condition for neurorehabilitation. Forty-one male Wistar rats were randomly divided into five groups: sham (n = 8), control (n = 9), NaB, exercise (n = 8), and NaB and exercise (n = 8). Intraperitoneal administration of an HDAC inhibitor (300 mg/kg NaB) and treadmill exercise (11 m/min for 30 min) was conducted five days a week for approximately-four weeks. ICH specifically decreased the acetylation level of histone H4 in the ipsilateral cortex, and HDAC inhibition with NaB increased the acetylation level of histone H4 over the sham level, accompanied by an improvement in motor function as assessed by the cylinder test. Exercise increased the acetylation levels of histones (H3 and H4) in the bilateral cortex. Synergistic effects of exercise and NaB were not observed during histone acetylation. Pharmacological treatment with a HDAC inhibitor and exercise can provide an enriched epigenetic platform for neurorehabilitation in an individual manner.
Assuntos
Histonas , Córtex Motor , Ratos , Animais , Masculino , Histonas/metabolismo , Epigênese Genética , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Córtex Motor/metabolismo , Ratos Wistar , Hemorragia Cerebral/tratamento farmacológico , AcetilaçãoRESUMO
Physical exercise increases brain-derived neurotrophic factor (BDNF) expression in the brain. However, the absence of non-invasive and repetitive monitoring of BDNF expression in the brains of living animals has limited the understanding of how BDNF expression changes after exercise. This study aimed to elucidate the temporal dynamics of BDNF expression in the brain after a single bout of exercise, using in vivo bioluminescence imaging. This study included Bdnf-Luc mice with a firefly Luciferase gene inserted at the translation start site of the mouse Bdnf gene. BDNF expression was evaluated based on the luminescence signal of the luciferase substrate administered to mice. Bioluminescence imaging was performed at 0, 1, 3, 6, 12, and 24 h after treadmill exercise (15 m/min for 1 h). Compared to the sedentary condition of each mouse, the luminescence signal increased by approximately 60 % between 1 and 3 h after exercise. The luminescence signal remained slightly increased by approximately 20 % even 6-24 h after exercise. This study is the first to demonstrate exercise-enhanced BDNF expression in the brains of living animals. These results provide evidence that a single bout of exercise transiently increases BDNF expression in the brain within a limited time window.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Condicionamento Físico Animal , Camundongos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Encéfalo/metabolismo , Genes ReporterRESUMO
The present study aimed to examine the synergistic effects of exercise and pharmacological inhibition of the α5 subunit-containing gamma-aminobutyric acid (GABA)A receptors (α5GABAAR) on motor function recovery after intracerebral hemorrhage (ICH). Wistar rats were divided into five groups (n = 8 per group): SHAM, ICH, ICH + exercise (ICH + EX), ICH + L-655,708 (ICH + L6), and ICH + L-655,708 and exercise (ICH + L6EX) groups. ICH was induced by microinjection of a collagenase solution. The ICH + EX and ICH + L6EX groups exercised on a treadmill (12 m/min for 30 min/day). L-655,708 (0.5 mg/kg), a negative allosteric modulator of α5GABAAR, was administered intraperitoneally to the ICH + L6 and ICH + L6EX groups. Each intervention was initiated 1 week after the ICH surgery and was performed for 3 weeks, followed by tissue collection, including the motor cortex and spinal cord. At 4 weeks after ICH, significant motor recovery was found in the ICH + L6EX group compared to the ICH group. L-655,708 administration increased brain-derived neurotrophic factor (BDNF) expression in the cortex. Regarding neuroplastic changes in the spinal cord, rats in the ICH + L6EX group showed a significant increase in several neuroplastic markers: 1) BDNF, 2) growth-associated protein 43 as an axonal sprouting marker, 3) synaptophysin as a synaptic marker, and 4) Nogo-A as an axonal growth inhibitor. This study is the first to demonstrate that combined treatment with exercise and α5GABAAR inhibitor effectively promoted motor function recovery after ICH. Regarding the underlying mechanism of post-ICH recovery with the combined treatment, the present study highlights the importance of both growth and inhibitory modification of axonal sprouting in the spinal cord.
Assuntos
Hemorragia Cerebral , Antagonistas de Receptores de GABA-A/farmacologia , Imidazóis/farmacologia , Condicionamento Físico Animal/métodos , Recuperação de Função Fisiológica/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Ratos , Ratos Wistar , Receptores de GABA-A , Recuperação de Função Fisiológica/efeitos dos fármacos , Medula Espinal/efeitos dos fármacosRESUMO
Intracerebral hemorrhage (ICH) is a subtype of stroke that causes major motor impairments. Brain-derived neurotrophic factor (BDNF) is known to have important roles in neuroplasticity and beneficially contributes to stroke recovery. This study aimed to characterize BDNF expression in the motor cortex after ICH and investigate the relationship between cortical BDNF expression and behavioral outcomes using an ICH rat model. Wistar rats were divided into two groups: a SHAM group (n = 7) and an ICH group (n = 8). ICH was induced by the injection of collagenase into the left striatum near the internal capsule. For behavioral assessments, the cylinder test and open field test were performed before surgery and 3 days, 1 week, 2 weeks, and 4 weeks after surgery. Following the behavioral assessments at 4 weeks, BDNF expression in the ipsilateral and contralateral motor cortex was assayed using RT-PCR and ELISA methods. There was no significant difference in either cortical BDNF mRNA or protein expression levels between the SHAM and ICH groups. However, the asymmetry index of BDNF mRNA expression between the ipsilateral and contralateral hemispheres shifted to the ipsilateral hemisphere after ICH. Furthermore, the ipsilateral cortical BDNF mRNA expression level positively correlated with motor function in the affected forelimb after ICH. This study describes for the first time that cortical BDNF mRNA expression is related to post-ICH motor impairment. These results highlight the importance of assessing the interhemispheric laterality of BDNF expression and could help develop novel treatment strategies for BDNF-dependent recovery after ICH.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Atividade Motora/genética , Córtex Motor/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/fisiologia , Hemorragia Cerebral/metabolismo , Modelos Animais de Doenças , Terapia por Exercício/métodos , Membro Anterior/metabolismo , Lateralidade Funcional/fisiologia , Expressão Gênica/genética , Regulação da Expressão Gênica/genética , Masculino , Atividade Motora/fisiologia , Córtex Motor/fisiologia , Plasticidade Neuronal , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Recuperação de Função Fisiológica , Transcriptoma/genéticaRESUMO
Transcranial static magnetic field stimulation (tSMS) has inhibitory neuromodulatory effects on the human brain. Most of the studies on static magnetic fields have been performed in vitro. To further understand the biological mechanisms of tSMS, we investigated the effects of in vivo tSMS on motor behavior in normal awake rats. The skull of a male Wistar rat was exposed and a polyethylene tube was attached to the skull using dental cement at the center of the motor cortex (nâ¯=â¯7) or the other cortex (nâ¯=â¯6). By attaching a cylindrical NdFeB neodymium magnet into the tube, in vivo tSMS (REAL) was performed. For SHAM, we applied a similar size non-magnetic stainless-steel cylinder. All rats received twice each SHAM and REAL stimulation every two days using a crossover design, and motor function was measured during the stimulation. Activity level and asymmetry of forelimb use were not affected, but less accurate movements in the horizontal ladder test were found in REAL stimulation of the motor cortex. This study shows that in vivo tSMS has inhibitory neuromodulatory effects on motor behavior depending on the stimulated region on the rat cortex.
Assuntos
Atividade Motora/efeitos da radiação , Córtex Motor/efeitos da radiação , Reabilitação do Acidente Vascular Cerebral/métodos , Estimulação Magnética Transcraniana/métodos , Animais , Potencial Evocado Motor/fisiologia , Potencial Evocado Motor/efeitos da radiação , Estudos de Viabilidade , Humanos , Masculino , Modelos Animais , Atividade Motora/fisiologia , Córtex Motor/fisiopatologia , RatosRESUMO
The objective of this study was to examine the effect of epigenetic treatment using an histone deacetylases (HDAC) inhibitor in addition to aerobic exercise on the epigenetic markers and neurotrophic gene expressions in the motor cortex, to find a more enriched brain pre-conditioning for motor learning in neurorehabilitation. ICR mice were divided into four groups based on two factors: HDAC inhibition and exercise. Intraperitoneal administration of an HDAC inhibitor (1.2 g/kg sodium butyrate, NaB) and treadmill exercise (approximately at 10 m/min for 60 min) were conducted five days a week for four weeks. NaB administration inhibited total HDAC activity and enhanced acetylation level of histones specifically in histone H4, accompanying the increase of transcription levels of immediate-early genes (IEGs) (c-fos and Arc) and neurotrophins (BDNF and NT-4) crucial for neuroplasticity in the motor cortex. However, exercise enhanced HDAC activity and acetylation level of histone H4 and H3 without the modification of transcription levels. In addition, there were no synergic effects between HDAC inhibition and the exercise regime on the gene expressions. This study showed that HDAC inhibition could present more enriched condition for neuroplasticity to the motor cortex. However, exercise-induced neurotrophic gene expressions could depend on exercise regimen based on the intensity, the term etc. Therefore, this study has a novelty suggesting that pharmacological HDAC inhibition could be an alternative potent approach to present a neuronal platform with enriched neuroplasticity for motor learning and motor recovery, however, an appropriate exercise regimen is expected in this approach.
Assuntos
Ácido Butírico/farmacologia , Plasticidade Neuronal/genética , Condicionamento Físico Animal/fisiologia , Acetilação/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ácido Butírico/metabolismo , Cognição/fisiologia , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Feminino , Expressão Gênica/genética , Expressão Gênica/fisiologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Hipocampo/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Córtex Motor/metabolismo , Córtex Motor/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/metabolismoRESUMO
Gamma-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system (CNS). This study examined the effect of specific inhibition of α5 subunit-containing GABAA receptors (α5GABAAR) on the behavioral profile and neuronal activity of the CNS using a compound called L-655,708, which is a selective negative allosteric modulator of α5GABAAR. L-655,708 administration significantly increased locomotor activity without anxiety-related behavior. Furthermore, L-655,708 administration significantly increased c-Fos mRNA expression (a neuronal activity marker) in motor area of the cerebral cortex, whereas it hardly altered c-Fos mRNA expression in the sensory cortex, hippocampus, and spinal cord. This study revealed for the first time that alteration of neuronal activity with specific inhibition of α5GABAAR differs depending on each CNS region. α5GABAAR could be a potential target for modulating CNS excitability and behavioral activity.
Assuntos
Ansiedade/induzido quimicamente , Córtex Cerebral/efeitos dos fármacos , Córtex Motor/patologia , Neurônios/metabolismo , Receptores de GABA-A/química , Animais , Comportamento , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Imidazóis/química , Locomoção/efeitos dos fármacos , Masculino , Córtex Motor/efeitos dos fármacos , Movimento , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Medula Espinal/efeitos dos fármacosRESUMO
Exercise is recognized to increase the expression of neurotrophic genes in the hippocampus and prevent cognitive impairment. Histone deacetylase (HDAC) inhibitor acetylate histones and enhance gene transcription in epigenetic regulation. HDAC inhibitors are expected to be an efficacious pharmacological treatment for cognitive function. This study aimed to examine the effect of HDAC inhibitors and exercise on epigenetic markers and neurotrophic gene expression in the hippocampus to find a more enriched brain conditioning for cognitive function based on the synergic effects of pharmacological treatment and behavioral therapy. Thirteen-week-old male mice were divided into four groups. Intraperitoneal administration of an HDAC inhibitor (1.2 g/kg sodium butyrate, NaB) and treadmill exercise (approximately 10 m/min for 60 min) were performed 5 days a week for 4 weeks. NaB administration increased the expression of an immediate-early gene, a neurotrophin, and a neurotrophin receptor in the hippocampus. These results indicate that HDAC inhibition could present an enriched platform for neuronal plasticity in the hippocampus and cognitive function. The novel object recognition test showed that NaB administration increased the score. Notably, the step-through passive avoidance test showed improved learning and memory in the presence of exercise and exercise, indicating that the mice acquired fear memory, specifically in the presence of NaB administration plus exercise. This study found that repetitive administration of HDAC inhibitors improved cognitive function and HDAC inhibitor administration plus exercise has a synergic effect on learning and memory, accompanying the enhancement of crucial gene transcriptions for neuronal plasticity in the hippocampus.
Assuntos
Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Histona Desacetilases/efeitos dos fármacos , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ácido Butírico/farmacologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Masculino , Camundongos , Condicionamento Físico Animal/fisiologiaRESUMO
Preconditioning exercise prior to stroke exerts neuroprotection, which is an endogenous strategy that leads the brain cells to express several intrinsic factors and inhibits their apoptosis. However, it is unclear how long these benefits last after exercise cessation. The aim of this study was to investigate the effects of detraining on preconditioning exercise-induced neuroprotective potential after stroke. Rats were trained using a treadmill for aerobic exercise 5 days each week for 3 weeks, and their neuroprotective effects were examined until 3 weeks after exercise cessation. Stroke was induced by 60 min of left middle cerebral artery occlusion at 3 days, 1, 2, and 3 weeks after exercise cessation. Infarct volume, neurological deficits, sensorimotor function, expression levels of brain-derived neurotrophic factor (BDNF), hypoxia-induced factor-1α (HIF-1α), glial fibrillary acidic protein (GFAP), and P2X7 receptors, and apoptosis activity were examined using immunohistochemical and western blot analyses. Preconditioning exercise significantly reduced infarct volume and ameliorated sensorimotor function after stroke, and its beneficial effects were observed until 2 weeks after exercise cessation. The expression level of BDNF in the ischemic brain was significantly upregulated at 3 days after exercise cessation; however, the expression levels of HIF-1α, GFAP, and P2X7 receptor were significantly increased until 2 weeks after exercise cessation; thereby, significant anti-apoptotic effects were lost at 3 weeks of detraining. Our findings suggest that preconditioning exercise-induced neuroprotective potential may be lost shortly after exercise cessation. Neuroprotection through intrinsic protective factors, such as BDNF and HIF-1α, may provide different neuroprotective mechanisms in a time-dependent manner during detraining.
Assuntos
AVC Isquêmico , Animais , Fator Neurotrófico Derivado do Encéfalo , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média , Neuroproteção , Ratos , Ratos Sprague-DawleyRESUMO
The objective of this study was to examine the interactive effects of exercise and low-level inhibition of GABAA receptors on the recovery of motor function and BDNF expression in the primary motor cortex (M1) of a stroke rat model. Male Sprague-Dawley rats were divided into five groups: sham (SHAM), control (CON), exercise (EX), bicuculline (BIC), and bicuculline plus exercise (BICEX) groups. All rats, except those in the SHAM group, underwent middle cerebral artery occlusion (MCAO) surgery to induce an ischemic stroke. GABAA receptor antagonist, bicuculline (0.25â¯mg/kg, i.p.), was administered to the BIC and BICEX groups. The EX and BICEX groups exercised on a treadmill (11â¯m/min for 30â¯min). Each intervention started 3â¯days after the MCAO surgery and was carried out every day for 2â¯weeks. Following the intervention, bilateral M1 BDNF mRNA and protein expression levels were assessed using qRT-PCR and ELISA. Marginal recovery was found in the EX and BIC groups, whereas motor function recovery was enhanced with exercise in the presence of BIC administration specifically in the BICEX group. Furthermore, BDNF protein level in the ipsilateral M1 was significantly higher in the BICEX group than in other groups. This study indicated that exercise combined with low-level inhibition of GABAA receptors after stroke could facilitate the recovery of motor function accompanied by BDNF upregulation in the ipsilateral M1. Therefore, this study provides a novel insight of pharmacological neuromodulation into stroke rehabilitation.
Assuntos
Isquemia Encefálica , AVC Isquêmico , Condicionamento Físico Animal , Acidente Vascular Cerebral , Animais , Isquemia Encefálica/terapia , Modelos Animais de Doenças , Humanos , Infarto da Artéria Cerebral Média/terapia , Masculino , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
It is widely accepted that daily exercise improves the dynamic standing balance of elderly persons. In the current study, 77 community-dwelling Japanese elderly persons (aged 71.1 +/- 0.5 years) participated in a daily exercise program to assess its effect on their dynamic standing balance. The daily exercise consisted of walking, stretching, muscle strengthening, and balance exercises. The program ran for 31 months and the dynamic standing balance was assessed at the start of the program and again at 3, 7, 12, 19, 24, and 31 months. In most of the tests of dynamic standing balance, the measured values improved drastically in the first 7 months; thereafter, they either reached a plateau or continued to improve more slowly. These findings can contribute to the future planning of community-based exercise programs; in particular, the length of the program and the timing of changes to the exercise load.
Assuntos
Acidentes por Quedas , Terapia por Exercício , Equilíbrio Postural , Características de Residência , Fatores Etários , Idoso , Envelhecimento , Análise de Variância , Feminino , Indicadores Básicos de Saúde , Inquéritos Epidemiológicos , Humanos , Japão , Masculino , Fatores de Risco , Fatores de TempoRESUMO
Exercise is a primary therapeutic regimen in physical therapy to rehabilitate the motor function of patients with central nervous system (CNS) disorders such as cerebrovascular accident (CVA). Furthermore, exercise positively contributes to cognitive function related to neuroplasticity and neuroprotection in the hippocampus. Neurotrophins play a crucial role in neuroplasticity, neurogenesis, and neuroprotection in the CNS. Exercise enhances the expression of neurotrophins in the brain. Thus, novel regimens for kinesiotherapy in CNS disorders to further enhance exercise-induced expression are expected. In this review, we described three novel regimens for kinesiotherapy in CNS disorders based on the interaction between exercise and pharmacological treatment with the idea of "inhibition of inhibition" in the CNS.
RESUMO
Exercise increases the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus and beneficially contributes to cognitive function and is accompanied by epigenetic changes. Specifically, the activity levels of histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate histone acetylation and modulate gene transcription. The objective of the present study was to assess the effect of an exercise regimen over a long period on the expression of BDNF, tropomyosin receptor kinase B (TrkB) and p75, and the activity of HATs and HDACs in the degenerative hippocampus. We used senescence-accelerated mice (SAM), and specifically, 3-month-old SAM resistant 1 (SAMR1) and SAM prone 8 (SAMP8) strains. Mice were distributed into four groups based on accelerated senescence and exercise status. Mice in the exercise groups exercised on a treadmill for 45 min a day, 3 days a week, for 6 months. Exercise significantly increased BDNF expression and decreased the expression of p75 in both SAMR1 and SAMP8. In addition, aging decreased HAT activity, whereas exercise decreased HDAC activity and increased the activity ratio of HAT to HDAC (HAT/HDAC). Therefore, the present study revealed that despite accelerated senescence, exercise up-regulated the expression of BDNF along with decreased the expression of p75, a receptor involved in apoptotic signaling. Furthermore, exercise increased HAT/HDAC, which might beneficially contribute to the transcriptional regulation for degenerative changes in the hippocampus.
Assuntos
Envelhecimento/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Epigênese Genética/fisiologia , Hipocampo/metabolismo , Condicionamento Físico Animal/fisiologia , Animais , Cognição/fisiologia , Regulação da Expressão Gênica , Histona Acetiltransferases/metabolismo , Histona Desacetilases/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Proteínas Tirosina Quinases/metabolismo , Receptor de Fator de Crescimento Neural/metabolismoRESUMO
Evaluation of antiangiogenic activity of marine sponge derived azumamides by the in vitro vascular organization model using mouse induced pluripotent stem (iPS) cells was carried out. Azumamide E (5) strongly inhibited in vitro angiogenesis from iPS cells at 1.9microM while azumamide A (1) showed only weak inhibition at 19microM. These results were well correlated with HDAC inhibitory activity of these compounds, revealing the prospect of azumamides as the probe molecules useful for stem cell chemical biology.