RESUMO
Ascorbic acid is essential for normal brain development and homeostasis. However, the effect of ascorbic acid on adult brain aging has not been determined. Long-term treatment with high levels of D-galactose (D-gal) induces brain aging by accumulated oxidative stress. In the present study, mice were subcutaneously administered with D-gal (150 mg/kg/day) for 10 weeks; from the seventh week, ascorbic acid (150 mg/kg/day) was orally co-administered for four weeks. Although D-gal administration alone reduced hippocampal neurogenesis and cognitive functions, co-treatment of ascorbic acid with D-gal effectively prevented D-gal-induced reduced hippocampal neurogenesis through improved cellular proliferation, neuronal differentiation, and neuronal maturation. Long-term D-gal treatment also reduced expression levels of synaptic plasticity-related markers, i.e., synaptophysin and phosphorylated Ca2+/calmodulin-dependent protein kinase II, while ascorbic acid prevented the reduction in the hippocampus. Furthermore, ascorbic acid ameliorated D-gal-induced downregulation of superoxide dismutase 1 and 2, sirtuin1, caveolin-1, and brain-derived neurotrophic factor and upregulation of interleukin 1 beta and tumor necrosis factor alpha in the hippocampus. Ascorbic acid-mediated hippocampal restoration from D-gal-induced impairment was associated with an enhanced hippocampus-dependent memory function. Therefore, ascorbic acid ameliorates D-gal-induced impairments through anti-oxidative and anti-inflammatory effects, and it could be an effective dietary supplement against adult brain aging.
Assuntos
Envelhecimento , Ácido Ascórbico/farmacologia , Encéfalo/efeitos dos fármacos , Galactose/efeitos adversos , Memória/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Plasticidade Neuronal , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Caveolina 1/metabolismo , Hipocampo/patologia , Interleucina-1beta/metabolismo , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Transtornos da Memória/prevenção & controle , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Sirtuína 1/metabolismo , Sinaptofisina/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Ginseng has been used to improve brain function and increase longevity. However, little is known about the ingredients of ginseng and molecular mechanisms of its anti-brain aging effects. Gintonin is a novel exogenous ginseng-derived lysophosphatidic acid (LPA) receptor ligand; LPA and LPA1 receptors are involved in adult hippocampal neurogenesis. D-galactose (D-gal) is used to induce brain -aging in animal models because long-term treatment with D-gal facilitates hippocampal aging in experimental adult animals by decreasing hippocampal neurogenesis and inducing learning and memory dysfunction. OBJECTIVE: To investigate the protective effects of gintonin on D-gal-induced hippocampal senescence, impairment of long-term potentiation (LTP), and memory dysfunction. METHODS: Brain hippocampal aging was induced by D-gal administration (150 mg/kg/day, s.c.; 10 weeks). From the 7th week, gintonin (50 or 100 mg/kg/day, per os) was co-administered with D-gal for 4 weeks. We performed histological analyses, LTP measurements, and object location test. RESULTS: Co-administration of gintonin ameliorated D-gal-induced reductions in hippocampal Ki67-immunoreactive proliferating cells, doublecortin-immunoreactive neuroblasts, 5-bromo-2'-deoxyuridine-incorporating NeuN-immunoreactive mature neurons, and LPA1 receptor expression. Co-administration of gintonin in D-gal-treated mice increased the expression of phosphorylated cyclic adenosine monophosphate response element binding protein in the hippocampal dentate gyrus. In addition, co-administration of gintonin in D-gal-treated mice enhanced LTP and restored the cognitive functions compared with those in mice treated with D-gal only. CONCLUSION: These results show that gintonin administration restores D-gal-induced memory deficits by enhancing hippocampal LPA1 receptor expression, LTP, and neurogenesis. Finally, the present study shows that gintonin exerts anti-brain aging effects that are responsible for alleviating brain aging-related dysfunction.
Assuntos
Senescência Celular , Galactose/metabolismo , Hipocampo , Potenciação de Longa Duração/efeitos dos fármacos , Transtornos da Memória , Extratos Vegetais/farmacologia , Animais , Senescência Celular/efeitos dos fármacos , Senescência Celular/fisiologia , Modelos Animais de Doenças , Glicoproteínas/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Lisofosfolipídeos/farmacologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Receptores de Ácidos Lisofosfatídicos/metabolismo , Resultado do TratamentoRESUMO
OBJECTIVES: In patients with schizophrenia, γ-band (30-70 Hz) auditory steady-state electroencephalogram responses (ASSR) are reduced in power and phase locking. Here, we examined whether γ-ASSR deficits are also present in a mouse model of schizophrenia, whose behavioural changes have shown schizophrenia-like endophenotypes. METHODS: Electroencephalogram in frontal cortex and local field potential in primary auditory cortex were recorded in phospholipase C ß1 (PLC-ß1) null mice during auditory binaural click trains at different rates (20-50 Hz), and compared with wild-type littermates. RESULTS: In mutant mice, the ASSR power was reduced at all tested rates. The phase locking in frontal cortex was reduced in the ß band (20 Hz) but not in the γ band, whereas the phase locking in auditory cortex was reduced in the γ band. The cortico-cortical connectivity between frontal and auditory cortex was significantly reduced in mutant mice. CONCLUSIONS: The tested mouse model of schizophrenia showed impaired electrophysiological responses to auditory steady state stimulation, suggesting that it could be useful for preclinical studies of schizophrenia".