Time-of-Day-Dependent Effects of Bromocriptine to Ameliorate Vascular Pathology and Metabolic Syndrome in SHR Rats Held on High Fat Diet.

The treatment of type 2 diabetes patients with bromocriptine-QR, a unique, quick release micronized formulation of bromocriptine, improves glycemic control and reduces adverse cardiovascular events. While the improvement of glycemic control is largely the result of improved postprandial hepatic glucose metabolism and insulin action, the mechanisms underlying the drug's cardioprotective effects are less well defined. Bromocriptine is a sympatholytic dopamine agonist and reduces the elevated sympathetic tone, characteristic of metabolic syndrome and type 2 diabetes, which potentiates elevations of vascular oxidative/nitrosative stress, known to precipitate cardiovascular disease. Therefore, this study investigated the impact of bromocriptine treatment upon biomarkers of vascular oxidative/nitrosative stress (including the pro-oxidative/nitrosative stress enzymes of NADPH oxidase 4, inducible nitric oxide (iNOS), uncoupled endothelial nitric oxide synthase (eNOS), the pro-inflammatory/pro-oxidative marker GTP cyclohydrolase 1 (GTPCH 1), and the pro-vascular health enzyme, soluble guanylate cyclase (sGC) as well as the plasma level of thiobarbituric acid reactive substances (TBARS), a circulating marker of systemic oxidative stress), in hypertensive SHR rats held on a high fat diet to induce metabolic syndrome. Inasmuch as the central nervous system (CNS) dopaminergic activities both regulate and are regulated by CNS circadian pacemaker circuitry, this study also investigated the time-of-day-dependent effects of bromocriptine treatment (10 mg/kg/day at either 13 or 19 h after the onset of light (at the natural waking time or late during the activity period, respectively) among animals held on 14 h daily photoperiods for 16 days upon such vascular biomarkers of vascular redox state, several metabolic syndrome parameters, and mediobasal hypothalamic (MBH) mRNA expression levels of neuropeptides neuropeptide Y (NPY) and agouti-related protein (AgRP) which regulate the peripheral fuel metabolism and of mRNA expression of other MBH glial and neuronal cell genes that support such metabolism regulating neurons in this model system. Such bromocriptine treatment at ZT 13 improved (reduced) biomarkers of vascular oxidative/nitrosative stress including plasma TBARS level, aortic NADPH oxidase 4, iNOS and GTPCH 1 levels, and improved other markers of coupled eNOS function, including increased sGC protein level, relative to controls. However, bromocriptine treatment at ZT 19 produced no improvement in either coupled eNOS function or sGC protein level. Moreover, such ZT 13 bromocriptine treatment reduced several metabolic syndrome parameters including fasting insulin and leptin levels, as well as elevated systolic and diastolic blood pressure, insulin resistance, body fat store levels and liver fat content, however, such effects of ZT 19 bromocriptine treatment were largely absent versus control. Finally, ZT 13 bromocriptine treatment reduced MBH NPY and AgRP mRNA levels and mRNA levels of several MBH glial cell/neuronal genes that code for neuronal support/plasticity proteins (suggesting a shift in neuronal structure/function to a new metabolic control state) while ZT 19 treatment reduced only AgRP, not NPY, and was with very little effect on such MBH glial cell genes expression. These findings indicate that circadian-timed bromocriptine administration at the natural circadian peak of CNS dopaminergic activity (that is diminished in insulin resistant states), but not outside this daily time window when such CNS dopaminergic activity is naturally low, produces widespread improvements in biomarkers of vascular oxidative stress that are associated with the amelioration of metabolic syndrome and reductions in MBH neuropeptides and gene expressions known to facilitate metabolic syndrome. These results of such circadian-timed bromocriptine treatment upon vascular pathology provide potential mechanisms for the observed marked reductions in adverse cardiovascular events with circadian-timed bromocriptine-QR therapy (similarly timed to the onset of daily waking as in this study) of type 2 diabetes subjects and warrant further investigations into related mechanisms and the potential application of such intervention to prediabetes and metabolic syndrome patients as well.

Experimental dopaminergic neuron lesion at the area of the biological clock pacemaker, suprachiasmatic nuclei (SCN) induces metabolic syndrome in rats.

BACKGROUND: The daily peak in dopaminergic neuronal activity at the area of the biological clock (hypothalamic suprachiasmatic nuclei [SCN]) is diminished in obese/insulin resistant vs lean/insulin sensitive animals. The impact of targeted lesioning of dopamine (DA) neurons specifically at the area surrounding (and that communicate with) the SCN (but not within the SCN itself) upon glucose metabolism, adipose and liver lipid gene expression, and cardiovascular biology in normal laboratory animals has not been investigated and was the focus of this study. METHODS: Female Sprague-Dawley rats received either DA neuron neurotoxic lesion by bilateral intra-cannula injection of 6-hydroxydopamine (2-4 µg/side) or vehicle treatment at the area surrounding the SCN at 20 min post protriptyline ip injection (20 mg/kg) to protect against damage to noradrenergic and serotonergic neurons. RESULTS: At 16 weeks post-lesion relative to vehicle treatment, peri-SCN area DA neuron lesioning increased weight gain (34.8%, P < 0.005), parametrial and retroperitoneal fat weight (45% and 90% respectively, P < 0.05), fasting plasma insulin, leptin and norepinephrine levels (180%, 71%, and 40% respectively, P < 0.05), glucose tolerance test area under the curve (AUC) insulin (112.5%, P < 0.05), and insulin resistance (44%-Matsuda Index, P < 0.05) without altering food consumption during the test period. Such lesion also induced the expression of several lipid synthesis genes in adipose and liver and the adipose lipolytic gene, hormone sensitive lipase in adipose (P < 0.05 for all). Liver monocyte chemoattractant protein 1 (a proinflammatory protein associated with metabolic syndrome) gene expression was also significantly elevated in peri-SCN area dopaminergic lesioned rats. Peri-SCN area dopaminergic neuron lesioned rats were also hypertensive (systolic BP rose from 157 ± 5 to 175 ± 5 mmHg, P < 0.01; diastolic BP rose from 109 ± 4 to 120 ± 3 mmHg, P < 0.05 and heart rate increase from 368 ± 12 to 406 ± 12 BPM, P < 0.05) and had elevated plasma norepinephrine levels (40% increased, P < 0.05) relative to controls. CONCLUSIONS: These findings indicate that reduced dopaminergic neuronal activity in neurons at the area of and communicating with the SCN contributes significantly to increased sympathetic tone and the development of metabolic syndrome, without effect on feeding.

Erratum: Neuroendocrine and metabolic components of dopamine agonist amelioration of metabolic syndrome in SHR rats.

[This corrects the article DOI: 10.1186/1758-5996-6-104.].

Extraction, identification and antioxidant activity of proanthocyanidins from Larix gmelinii Bark.

This study was intended to extract and identify the proanthocyanidins from Larix gmelinii bark. Different extraction methods and degreasing methods were investigated. The content of proanthocyanidins, antioxidant activities and FT-IR analysis were used to evaluate and identify these extracts. The ultrasonic-assisted extracts displayed a higher content of proanthocyanidins and antioxidant activity than supercritical carbon dioxide extracts. The defatted extracts displayed a higher content of proanthocyanidins and antioxidant activity than un-defatted extracts. DPPH radical-scavenging capacity of extracts (29.88 µg mL(- 1)) was higher than VC (36.04 µg mL(- 1)), and the inhibition effect of lipid peroxidation of extracts (15%) was higher than VC (13%) and VE (11%). The FT-IR analysis revealed that the main phenolic compounds were almost the same as proanthocyanidin standards.

Neuroendocrine and metabolic components of dopamine agonist amelioration of metabolic syndrome in SHR rats.

BACKGROUND: The hypertensive, pro-inflammatory, obese state is strongly coupled to peripheral and hepatic insulin resistance (in composite termed metabolic syndrome [MS]). Hepatic pro-inflammatory pathways have been demonstrated to initiate or exacerbate hepatic insulin resistance and contribute to fatty liver, a correlate of MS. Previous studies in seasonally obese animals have implicated an important role for circadian phase-dependent increases in hypothalamic dopaminergic tone in the maintenance of the lean, insulin sensitive condition. However, mechanisms driving this dopaminergic effect have not been fully delineated and the impact of such dopaminergic function upon the above mentioned parameters of MS, particularly upon key intra-hepatic regulators of liver inflammation and lipid and glucose metabolism have never been investigated. OBJECTIVE: This study therefore investigated the effects of timed daily administration of bromocriptine, a potent dopamine D2 receptor agonist, on a) ventromedial hypothalamic catecholamine activity, b) MS and c) hepatic protein levels of key regulators of liver inflammation and glucose and lipid metabolism in a non-seasonal model of MS - the hypertensive, obese SHR rat. METHODS: Sixteen week old SHR rats maintained on 14 hour daily photoperiods were treated daily for 16 days with bromocriptine (10 mg/kg, i.p.) or vehicle at 1 hour before light offset and, subsequent to blood pressure recordings on day 14, were then utilized for in vivo microdialysis of ventromedial hypothalamic catecholamine activity or sacrificed for the analyses of MS factors and regulators of hepatic metabolism. Normal Wistar rats served as wild-type controls for hypothalamic activity, body fat levels, and insulin sensitivity. RESULTS: Bromocriptine treatment significantly reduced ventromedial hypothalamic norepinephrine and serotonin levels to the normal range and systolic and diastolic blood pressures, retroperitoneal body fat level, plasma insulin and glucose levels and HOMA-IR relative to vehicle treated SHR controls. Such treatment also reduced plasma levels of C-reactive protein, leptin, and norepinephrine and increased that of plasma adiponectin significantly relative to SHR controls. Finally, bromocriptine treatment significantly reduced hepatic levels of several pro-inflammatory pathway proteins and of the master transcriptional activators of lipogenesis, gluconeogenesis, and free fatty acid oxidation versus control SHR rats. CONCLUSION: These findings indicate that in SHR rats, timed daily dopamine agonist treatment improves hypothalamic and neuroendocrine pathologies associated with MS and such neuroendocrine events are coupled to a transformation of liver metabolism potentiating a reduction of elevated lipogenic and gluconeogenic capacity. This liver effect may be driven in part by concurrent reductions in hyperinsulinemia and sympathetic tone as well as by reductions in intra-hepatic inflammation.