RESUMEN
AIM: To investigate the metabolite changes caused by simvastatin or fenofibrate intervention in diet-induced hyperlipidemia rats using a GC-MS-based metabolomic profiling approach. METHODS: SD rats were fed with high-lipid diet for 4 weeks to induce hyperlipidemia, then the rats were fed with normal diet, and orally administered with simvastatin (10 mg·kg(-1)·d(-1)) or fenofibrate (150 mg·kg(-1)·d(-1)) for 2 weeks. Blood samples were collected once a week, and potential biomarkers were examined using commercial assay kits and a metabolomic approach. The metabolomics data were analyzed using a multivariate statistical technique and a principal component analysis (PCA). RESULTS: Oral administration of simvastatin or fenofibrate significantly decreased the plasma levels of total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol and increased the plasma level of high-density lipoprotein (HDL) cholesterol in the hyperlipidemia rats. Plasma samples were scattered in the PCA scores plots in response to the diet and to the drugs administered. The main metabolites changed in the hyperlipidemia rats were cholesterol, creatinine, linoleic acid, ß-hydroxybutyric acid, tyrosine, isoleucine and ornithine. The plasma level of creatinine was significantly lower in the simvastatin-treated rats than in the fenofibrate-treated rats. The plasma tyrosine concentration was declined following intake of high-lipid diet, which was reversed by fenobrate, but not by simvastatin. CONCLUSION: A series of potential biomarkers including tyrosine, creatinine, linoleic acid, ß-hydroxybutyric acid and ornithine have been identified by metabolomic profiling, which may be used to identify the metabolic changes during hyperlipidemia progression.
Asunto(s)
Dieta Alta en Grasa/efectos adversos , Fenofibrato/farmacología , Hiperlipidemias/tratamiento farmacológico , Metaboloma/efectos de los fármacos , Simvastatina/farmacología , Ácido 3-Hidroxibutírico/sangre , Animales , Biomarcadores/sangre , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Creatinina/sangre , Hiperlipidemias/sangre , Isoleucina/sangre , Ácido Linoleico/sangre , Masculino , Metabolómica/métodos , Ornitina/sangre , Ratas , Ratas Sprague-Dawley , Tirosina/sangreRESUMEN
This study was aimed to investigate the protective effect of Liu Wei Dihuang (LWDH) against D-galactose (D-gal)-induced brain injury in rats and the existence of sex-dependent differences in LWDH protection. Sixty-four rats evenly composed of males and females were randomly assigned into 4 groups (n = 8): normal saline (NS) + NS (N + N), NS + LWDH (N + L), D-gal + NS (D + N) and D-gal + LWDH (D + L) groups. Rats in D + N and D + L groups received daily injection of D-gal (100 mg/kg, s.c.) for six weeks to establish the aging model, while rats in N + N and N + L groups were injected with the same volume of NS. From the third week, rats in N + L and D + L groups were orally administered with a decoction of LWDH for subsequent six weeks. Rats in N + N and D + N groups were orally administered just with the same volume of NS simultaneously. Morris water maze test was employed to evaluate the ability of learning and memory of the rats in all the groups. Acetylcholine (ACh) content, activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in visual cortex were assayed. Hematoxylin and eosin (HE) staining were used to observe the morphologic injury in hippocampus and visual cortex, and immunohistochemistry was performed to evaluate ChAT and AChE expression levels in the visual cortex. The results showed that the rats in D + N groups exhibited a longer escape latency to platform, lower swimming speed, less percent of target quadrant search time and platform crossings, compared with N + N groups, suggesting the establishment of aging model, while LWDH improved these indexes in D-gal-treated rats. Compared with D + N groups, LWDH increased ACh content and ChAT activity, and decreased AChE activity in visual cortex. Remarkable loss of neurons was found in hippocampus and visual cortex of aging rats, and the injury was significantly attenuated by LWDH. Immunohistochemistry showed D-gal-induced decreases of ChAT and AChE expressions were restored by LWDH. Furthermore, under the neural protection of LWDH, the improvement on platform crossings in male aging rats was better than that in female ones, while in ChAT expression and neuron density in visual cortex, female aging rats obtained more amelioration. These results suggest LWDH can markedly reverse the D-gal-induced cognitive impairments and neuronal damage in both hippocampus and visual cortex, which are achieved at least partly through restoring cholinergic system in central nervous system. Moreover, there is some sex difference in protective effects of LWDH against D-gal-induced impairment.