RESUMO
Maternal lead exposure is associated with poor outcomes in fetal brain development such as cognitive dysfunction. Here, we aimed to reveal the effect and mechanism of omega-3 fatty acids in ameliorating maternal lead exposure-induced cognitive impairment in mouse offspring. The activity levels of locomotor and anxiety, memory and learning capacity, spatial working memory, and cognitive behavioral function were determined using the open field test, Morris water maze, Y-maze, and nest-building test, respectively. The protein levels of brain-derived neurotrophic factor (BDNF), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were measured using enzyme-linked immunosorbent assay or Western blot. The mRNA levels of BDNF, tyrosine kinase B (TrkB) and cyclic AMP response element binding protein (CREB) were measured by real-time qPCR. Malondialdehyde (MDA) and anti-oxidants, including SOD, GSH and CAT, were measured using bioassay kits. We found that supplementing omega-3 significantly improved cognitive behavioral function in offspring after prenatal lead exposure. The protein and mRNA levels of BDNF, TrkB and CREB in the prenatal lead exposure group were significantly upregulated by omega-3 supplementation. The MDA level in the prenatal lead exposure group was markedly elevated compared with the control group, which was significantly reduced by omega-3. Omega-3 restored anti-oxidants SOD, GSH and CAT to control levels after prenatal lead exposure. Omega-3 significantly upregulated Nrf2 nuclear expression and HO-1 expression after prenatal lead exposure. Overall, omega-3 supplementation significantly elevated the BDNF/TrkB/CREB pathway and restores anti-oxidants by upregulating the Nrf2/HO-1, thereby improving cognitive function in offspring after prenatal lead exposure.
Assuntos
Disfunção Cognitiva , Ácidos Graxos Ômega-3 , Chumbo , Efeitos Tardios da Exposição Pré-Natal , Animais , Antioxidantes/farmacologia , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/induzido quimicamente , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Suplementos Nutricionais , Ácidos Graxos Ômega-3/uso terapêutico , Feminino , Hipocampo/metabolismo , Chumbo/toxicidade , Aprendizagem em Labirinto , Camundongos , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , RNA Mensageiro/metabolismo , Receptor trkB/genética , Receptor trkB/metabolismo , Receptor trkB/farmacologia , Transdução de Sinais , Superóxido Dismutase/metabolismoRESUMO
BACKGROUND: High rates of co-morbidity have been reported in patients with diabetes mellitus with depression (DD). Danggui Buxue Decoction (DBD), a Traditional Chinese Medicine formula composed of Angelica and Astragalus, has been historically used for the treatment of diabetes. PURPOSE: This study aimed to investigated whether DBD and its main active component, ferulic acid (FA) from Angelica, could ameliorate depression-like behavior in DD and the underlying mechanisms. METHODS: Goto-Kakizaki (GK) rats were administered DBD (4 or 8 g/kg) by oral gavage during a 4-week period of chronic unpredictable mild stress. After 4 weeks, blood glucose, glycated serum protein, serum insulin, oral glucose tolerance and depression-like behavior were examined, along with brain-derived neurotrophic factor (BDNF)-related signaling pathway proteins and the ultrastructure of hippocampal tissues. UPLC-QTOF-MS was adopted to detect the absorption of FA in the serum and hippocampus. Rat primary hippocampal cells were cultured in a DD model. Protein and mRNA levels of genes involved in BDNF-related signaling and neuroplasticity were analyzed. RESULTS: DBD effectively improved glucose tolerance in DD rats and relieved depression-like behavior. Upregulation of cAMP response element binding protein (CREB), BDNF, and tropomyosin receptor kinase B (TrkB) and improvement of the hippocampal neuron ultrastructure supported the antidepressant-Like effects of DBD on the hippocampal neurons. In addition, DBD enhanced the protein and mRNA levels of components of the CREB/BDNF/TrkB pathway in rat primary hippocampal cells induced by elevated glycemia and cortisol. Interestingly, FA, the main component of DBD absorbed in the blood and hippocampus, showed similar effects as DBD on primary hippocampal cells. CONCLUSION: This study suggests that the TCM formula DBD effectively serves as a potential therapeutic agent for prevention of DD through regulatory effects on the CREB/BDNF/TrkB pathway to protect and remodel hippocampal neurons. Moreover, FA contributes significantly to the treatment effects of DBD.