Effects of a single dose of amisulpride on functional brain changes during reward- and motivation-related processing using task-based fMRI in healthy subjects and patients with major depressive disorder - study protocol for a randomized clinical trial.

Background: Anhedonia and other deficits in reward- and motivation-related processing in psychiatric patients, including patients with major depressive disorder (MDD), represent a high unmet medical need. Neurobiologically, these deficits in MDD patients are mainly associated with low dopamine function in a frontostriatal network. In this study, alterations in brain activation changes during reward processing and at rest in MDD patients compared with healthy subjects are explored and the effects of a single low dose of the dopamine D2 receptor antagonist amisulpride are investigated.

The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling.

Uncertainty exists as to whether the glucose-dependent insulinotropic polypeptide receptor (GIPR) should be activated or inhibited for the treatment of obesity. Gipr was recently demonstrated in hypothalamic feeding centers, but the physiological relevance of CNS Gipr remains unknown. Here we show that HFD-fed CNS-Gipr KO mice and humanized (h)GIPR knockin mice with CNS-hGIPR deletion show decreased body weight and improved glucose metabolism.

Differences in kidney-specific DPP-4 inhibition by linagliptin and sitagliptin.

The two dipeptidyl peptidase (DPP)-4 inhibitors, linagliptin and sitagliptin, were shown to exert different binding kinetics in vitro. Twenty-four hours after oral dosing particularly in vivo inhibition of renal-specific DPP-4 activity was more sustained in Sprague Dawley rats after exposure to linagliptin than it was after sitagliptin.

Discovery and translation of a target engagement marker for AMP-activated protein kinase (AMPK).

Background: Activation of the AMP-activated protein kinase (AMPK) is an attractive approach for the treatment of type 2 diabetes. AMPK activation reduces glucose levels in animal models of type 2 diabetes by increasing glucose uptake in skeletal muscles and reducing hepatic glucose production. Furthermore, AMPK activation ameliorates hepatic steatosis in animal models.

A high-throughput, image-based screen to identify kinases involved in brown adipocyte development.

Brown adipose tissue (BAT) is responsible for thermogenesis that is not associated with shivering through the process of converting chemical energy into heat through uncoupling protein 1 (UCP1) in the mitochondria. Thus, expanding or activating BAT could be a potential tool against obesity. To analyze the effect of kinase signaling on brown adipocyte formation, a process that describes the acquisition of the ability to dissipate energy as heat, we performed lentiviral-mediated short hairpin knockdown or used pharmacological inhibitors in a high-content and high-throughput in vitro image-based screen.

Short- and Longterm Glycemic Control of Streptozotocin-Induced Diabetic Rats Using Different Insulin Preparations.

The chemical induction of diabetes with STZ has gained popularity because of the relative ease of rendering normal animals diabetic. Insulin substitution is required in STZ-rats in long-term studies to avoid ketoacidosis and consequently loss of animals. Aim of the present studies was to test different insulin preparations and different ways of administration in their ability to reduce blood glucose in STZ-induced diabetic rats.

Characterization of Micro-RNA Changes during the Progression of Type 2 Diabetes in Zucker Diabetic Fatty Rats.

The aim of the present pilot study was the identification of micro-RNA changes over time during the development and progression of type 2 diabetes (T2D) in Zucker diabetic fatty rats (ZDF rats). T2D is a complex metabolic disorder that is characterized, inter alia, by progressive failure of pancreatic β cells to produce insulin, but also by functional or morphological modifications of others organ, such as liver, adipose tissue and the cardiovascular system. Micro-RNAs are a novel class of biomarkers that have the potential to represent biomarkers of disease progression.

Gene delivery to adipose tissue using transcriptionally targeted rAAV8 vectors.

In recent years, the increasing prevalence of obesity and obesity-related co-morbidities fostered intensive research in the field of adipose tissue biology. To further unravel molecular mechanisms of adipose tissue function, genetic tools enabling functional studies in vitro and in vivo are essential. While the use of transgenic animals is well established, attempts using viral and non-viral vectors to genetically modify adipocytes in vivo are rare.

Potent cholesteryl ester transfer protein inhibitors of reduced lipophilicity: 1,1'-spiro-substituted hexahydrofuroquinoline derivatives.

A series of 1,1'-spiro-substituted hexahydrofuroquinoline derivatives exhibiting potent cholesteryl ester transfer protein (CETP) inhibition at reduced lipophilicity was identified. A focused structure-activity relationship (SAR) exploration led to the potent and comparatively polar CETP inhibitor 26 showing robust high density lipoprotein-cholesterol (HDL-C) elevation and low density lipoprotein-cholesterol (LDL-C) reduction in transgenic hCETP/hApoB-100 mice. Compound 26 was also shown to positively differentiate from highly lipophilic CETP inhibitors in its complete elimination from fat tissue in hCETP transgenic mice as evident within 21 days after cessation of treatment.

An antibody against the C-terminal domain of PCSK9 lowers LDL cholesterol levels in vivo.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with autosomal dominant hypercholesterolemia, a state of elevated levels of LDL (low-density lipoprotein) cholesterol. Autosomal dominant hypercholesterolemia can result in severe implications such as stroke and coronary heart disease. The inhibition of PCSK9 function by therapeutic antibodies that block interaction of PCSK9 with the epidermal growth factor-like repeat A domain of LDL receptor (LDLR) was shown to successfully lower LDL cholesterol levels in clinical studies.

Identification of a potential biomarker for FABP4 inhibition: the power of lipidomics in preclinical drug testing.

The fatty acid binding protein 4 (FABP4) belongs to the family of lipid chaperones that control intracellular fluxes and compartmentalization of their respective ligands (e.g., fatty acids).

Evidence for a predominant intrinsic sympathetic control of cerebral blood flow alterations in an animal model of cerebral arteriovenous malformation.

In terms of neurogenic cerebral blood flow (CBF) control, the activity of the sympathetic nervous system (SNS) has a regulating effect. The impact of a manipulation of both the peripheral (via the perivascular sympathetic net) and central components (via the intracortical noradrenergic terminals originating from the locus coeruleus) on CBF-and especially on hyperperfusion syndromes-is unclear. To test the specific patterns following such alterations, cortical oxygen saturation (rSO2), regional CBF (rCBF), and cortical interstitial norepinephrine (NE) concentrations were measured.

Norepinephrine and cerebral blood flow regulation in patients with arteriovenous malformations.

Objective: To test the hypothesis that the sympathetic nervous system plays a role in cerebral blood flow regulation in patients with arteriovenous malformations (AVM).

Methods: Cortical interstitial norepinephrine was measured by means of microdialysis, regional cerebral blood flow was measured by a thermal diffusion technique, and regional oxygen saturation (SO2) was measured by microspectrophotometry in 12 patients harboring cerebral AVMs (AVM group) and in 15 patients with deep-seated nonvascular lesions (control group) before and after resection. Measurements were compared according to groups and times of measurements.

Arterial blood pressure and renal sodium excretion in dopamine D3 receptor knockout mice.

Alterations in the dopaminergic system may contribute to the development of hypertension. Recently, it has been reported that pentobarbital-anesthetized mice with deficient dopamine D(3) receptors showed renin-dependent elevation in blood pressure. In a series of experiments, we evaluated the contribution of the dopamine D(3) receptor to the renal sodium excretion and arterial blood pressure behavior in conscious as well as anesthetized dopamine D(3) receptor knockout (-/-) mice.

Effect of L-dopa decarboxylase inhibitor benserazide on renal function in streptozotocin-diabetic rats.

Background/aims: Benserazide (BZD), an inhibitor of the dopamine synthesis, abolished the increase in glomerular filtration rate (GFR) following the infusion of a mixed amino acid solution. These results reveal endogenous dopamine as a mediator in the renal response to amino acids. The aim of the present study was to evaluate whether dopamine is also involved in the regulation of glomerular hyperfiltration during the early state of diabetes mellitus (DM).

Absence of amino acid-induced glomerular hyperfiltration in dopamine D3 receptor knockout mice.

Pharmacological inhibition of receptors of the dopamine D2-like family has been shown to abolish the glomerular hyperfiltration in response to amino acids. To further discriminate between the receptor subtypes within the D2-like family, we investigated the effects of amino acid infusion on renal function in dopamine D3 receptor knockout (-/-) mice. In clearance experiments pentobarbital-anesthetized D3 receptor (-/-) and wild-type (+/+) mice were infused with Ringer solution at baseline, followed by a continuous infusion of mixed amino acids (10%).

Effect of dopamine D3 receptor blockade on renal function and glomerular size in diabetic rats.

Dopamine D2-like receptors, including D2, D3, and D4 receptors, are involved in the regulation of glomerular hyperfiltration due to diabetes mellitus. These hemodynamic alterations represent a risk factor for the later development of diabetic nephropathy. The aim of the present study was to determine whether the D3 receptor subtype modulates the diabetes-induced increase in glomerular filtration rate (GFR) in rats.

Blood glucose profiles in diabetic rodents using different insulin preparations.

The aim of the present study was to evaluate several long-acting insulin preparations for their ability to normalize the blood glucose profile of rats and mice with streptozocin-induced diabetes mellitus. The single injection of a long-acting zinc insulin (CAS 8049-62-5) suspension or insulin glargine (CAS 160337-95-1) in both species induced a steep to moderate fall in blood glucose concentration. Blood glucose was then normalized for 2-3 h, until 3 h after insulin injection blood glucose concentration tended towards levels before insulin application.

Subapical localization of the dopamine D3 receptor in proximal tubules of the rat kidney.

The dopamine D3 receptor (D3R), intensively studied in neuroscience, also plays an important role in the regulation of renal and cardiovascular function. In contrast to functional findings, less information is available on its localization in the kidney. Neither RT-PCR studies nor radioligand binding assays are suitable to selectively determine the distribution of renal D3R at the level of cellular or even subcellular structures.

Characterisation of cerivastatin as a P-glycoprotein substrate: studies in P-glycoprotein-expressing cell monolayers and mdr1a/b knock-out mice.

The aim of this study was to characterise the role of the efflux transporter P-glycoprotein in the disposition of cerivastatin. We investigated directional transport characteristics of [14C]cerivastatin across cell monolayers expressing P-glycoprotein (Caco-2 and L-MDR1) and disposition of cerivastatin in mice with disrupted mdr1a and mdr1b genes. The mice were given orally 1 mg/kg cerivastatin and plasma and tissue samples for analysis of cerivastatin were obtained 10, 20, or 30 min after drug administration.

Chronic renal denervation prevents glomerular hyperfiltration in diabetic rats.

Background: The increase in glomerular filtration rate (GFR) induced by amino acid infusion is attenuated in rats with chronic renal denervation. The aim of the present study was to investigate whether renal denervation abrogates glomerular hyperfiltration occurring in the early state of diabetes mellitus.

Methods: Sprague-Dawley rats were subjected to bilateral renal denervation before induction of diabetes mellitus (DM) by streptozotocin.

Dopamine D3 receptor mRNA and renal response to D3 receptor activation in spontaneously hypertensive rats.

Defective dopamine receptors may be involved in the development of hypertension. Recently, it has been shown that gene expression and function of the renal dopamine D3 receptor is impaired in salt-sensitive Dahl rats, a model of salt-dependent hypertension. Here, the functional response to D3 receptor activation was investigated in spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto rats (WKY).

Role of the renin-angiotensin system in the compensation of quinpirole-induced blood pressure decrease.

The dopamine D(2)-like receptor agonist quinpirole has been reported to lower blood pressure. This effect appears to be mediated via activation of presynaptic D(2)-like receptors inhibiting the stimulated neural norepinephrine release. The aim of the present study was to investigate the role of renal nerves and the renin-angiotensin system (RAS) in the blood pressure lowering effect of quinpirole.

Tissue levels of S-adenosylhomocysteine in the rat kidney: effects of ischemia and homocysteine.

Most S-adenosylmethionine (AdoMet)-dependent methyltransferases are regulated in vivo by the AdoMet/S-adenosylhomocysteine (AdoHcy) ratio, also termed as "methylation potential." Since adenosine inhibits in vitro AdoHcy hydrolysis and since adenosine tissue levels increase during hypoxia, it can be predicted that AdoHcy levels may increase in the rat kidney in parallel of those of adenosine. Therefore, the present investigation was performed to assess changes of renal AdoHcy and AdoMet tissue contents during ischemia and after administration of adenosine and homocysteine or both in the ischemic rat kidney.