Effect Of α-lipoic Acid On Inflammation And The Level Of BDNF In Hippocampus From Obese Rats Induced By Ovariectomy And A High-fat Diet

ObjectiveObesity, which is a state characterized with chronic inflammation, not only increases the risks of insulin resistance, metabolic syndrome and cardiovascular disease, but also contribute to cognitive decline. It had been confirmed that a-lipoic acid(a-LA) had the ability of ameliorating lipid abnormalities and improving insulin sensitivity in obese rats, which were induced by consumption of a high-fat diet, through antioxdative and anti-inflammation effects. Moreover, a-LA has been shown an anti-inflammatory and neruroprotective function on Alzheimer’s disease. In present study, an animal model to mimick the postmenopausal and hyperlipidemic situation was induced by the association of ovariectomy with a high-fat diet, and then to explore the effects of ovariectomy plus high-fat diet on insulin resistance in serum, inflammatory reaction and the level of BDNF in hippocampus, and to investigate the effects of a-LA on their expressions.Materials and Methods1. Animals Forty female Wistar rats (three-month old) were randomly divided into four groups (n=10per group):sham-operation with normal diet (SHAM+ND); sham-operation with high-fat diet (SHAM+HFD); ovariectomy with high-fat diet (OVX+HFD); ovariectomy plus high-fat diet treated with a-LA (OVX+HFD+a-LA). Except for SHAM groups, others were underwent bilateral ovariectomy, and then rats were dosed with a-LA solution(200mg-kg-1·d-1) or sodium carboxymethyl cellulose solution by gavage once daily for12weeks, and body weights of rats were measured once a week.2. Blood and hippocampus sample preparation After12weeks, blood was collected from femoral artery. Blood samples were centrifuged at3000rpm at4℃for15min, serum was separated and stored at-80℃until assayed; Rats in each group (n=8-10in each group) were terminated by decapitation and the brains were rapidly removed, then the bilateral hippocampi were dissected on the ice and immediately stored in liquid nitrogen.3. Methods of measurement The serum concentrations of17β-estradiol (E2) were detected by lodine[125Ⅰ] Estradiol Radioimmunoassay Kit according to the manufacturer’s protocol; The serum total cholesterol (TC), triglycerides (TG) were determined by enzymatic colorimetric methods, high-density lipoprotein cholesterol(HDL-C) and high-density lipoprotein cholesterol(LDL-C) were determined by direct methods; Serum leptin, adiponectin and insulin concentrations were measured by enzyme-linked immunosorbent assay kits for rats; BDNF, TNF-a and IL-6mRNA in hippocampal tissues were detected by RT-PCR; The levels of TNF-a, IL-6and Aβ1-42protein in hippocampal tissue homogenates were quantified by ELISA; The level of BDNF protein was measured by Western blotting analysis and ELISA respectively.Results1. As compared with SHAM+ND group and SHAM+HFD group respectively, the association of ovariectomy with high-fat diet could highly increase the rats body weight and the levels of TC and leptin in serum, and significantly reduce the content of E2and adiponectin in serum, as well as increase the level of HOMA-IR(P<0.05or P＜0.01); α-lipoic acid could significantly neutralize the increase of the body weight in ovariectomized rats fed with the high-fat diet, and decrease the contents of serum TC and LDL-C as well as the level of serum leptin and insulin in ovariectomized rats with a high-fat diet, also significantly increase the levels of serum adiponectin and HDL-C as compared with OVX+HFD group(P<0.05or P＜0.01).2. As compared with SHAM+ND group and SHAM+HFD group respectively, the expression of BDNF mRNA and BDNF protein were markedly reduced in hippocampal tissue of ovariectomized rats with high-fat diet, and the expression of IL-6and TNF-a mRNA and protein were significantly increased as well as the levels of Aβ1-42protein(P<0.05or P＜0.01); After the administration of a-lipoic acid, the expression of BDNF protein and BDNF mRNA in hippocampus was up-regulated, IL-6and TNF-a protein and mRNA as well as the levels of Aβ1-42protein were decreased as compared with OVX+HFD group(P<0.05or P<0.01).Conclusion1. The association of ovariectomy with high-fat diet could significantly reduce the concentration of E2, increase the rats body weight, lead to hyperlipidemia and insulin resistance, increase the content of serum leptin, decrease the level of adiponectin, exaggerate neuroinflammatory reaction and the deposition of Aβ1-42in hippocampus, and decrease the expression of BDNF in hippocampal tissues as well.2. α-lipoic acid could significantly improve lipid metabolism, enhance insulin sensitivity and decrease the content of serum leptin, increase the level of adiponectin, reverse central inflammatory reaction and high-regulate the expression of BDNF as well as attenuate the accumulation of Aβ1-42in hippocampus of obese rats induced by ovariectomy and a high-fat diet, improve the nerve protective effect of BDNF.SignificanceOur study adopted the association of ovariectomy and high-fat diet to induced the situation of estrogen absence and hyperlipidemic, and explore the effects of a-lipoic acid on metabolic indices and cognition-related factors of postmenopausal obese rats. Our results indicated that a-lipoic acid can improve the nerve protective effect of BDNF on postmenopausal obese rats through anti-inflammatory effect, which provided the scientific basis of a-lipoic acid to prevent the development of cognitive defect for obese postmenopausal women.