V. Andresen

Anti-ghrelin Spiegelmer NOX-B11 inhibits neurostimulatory and orexigenic effects of peripheral ghrelin in rats

Background and aims: Ghrelin, the natural ligand of the growth hormone secretagogue receptor 1a, is the most powerful peripherally active orexigenic agent known. In rodents, ghrelin administration stimulates growth hormone release, food intake, and adiposity. Because of these effects, blocking of ghrelin has been widely discussed as a potential treatment for obesity. Spiegelmer NOX-B11 is a synthetic l-oligonucleotide, which was previously shown to bind ghrelin. We examined the effects of NOX-B11 on ghrelin induced neuronal activation and food intake in non-fasted rats. Methods: Animals received various doses of NOX-B11, inactive control Spiegelmer, or vehicle intravenously. Ghrelin or vehicle was administered intraperitoneally 12 hours later and food intake was measured over four hours. Neuronal activation was assessed as c-Fos-like immunoreactivity in the arcuate nucleus. Results: Treatment with NOX-B11 30 nmol suppressed ghrelin induced c-Fos-like immunoreactivity in the arcuate nucleus and blocked the ghrelin induced increase in food intake within the first half hour after ghrelin injection (mean 1.13 (SEM 0.59) g/kg body weight; 4.94 (0.63) g/kg body weight versus 0.58 (0.58) g/kg body weight; p<0.0001). Treatment with NOX-B11 1 nmol or control Spiegelmer had no effect whereas treatment with NOX-B11 10 nmol showed an intermediate effect on ghrelin induced food intake. Conclusions: Spiegelmer NOX-B11 suppresses ghrelin induced food intake and c-Fos induction in the arcuate nucleus in rats. The use of an anti-ghrelin Spiegelmer could be an innovative new approach to inhibit the biological action of circulating ghrelin. This may be of particular relevance to conditions associated with elevated plasma ghrelin, such as the Prader-Willi syndrome.

Brain activation responses to subliminal or supraliminal rectal stimuli and to auditory stimuli in irritable bowel syndrome

Abstract  Visceral hypersensitivity in irritable bowel syndrome (IBS) has been associated with altered cerebral activations in response to visceral stimuli. It is unclear whether these processing alterations are specific for visceral sensation. In this study we aimed to determine by functional magnetic resonance imaging (fMRI) whether cerebral processing of supraliminal and subliminal rectal stimuli and of auditory stimuli is altered in IBS. In eight IBS patients and eight healthy controls, fMRI activations were recorded during auditory and rectal stimulation. Intensities of rectal balloon distension were adapted to the individual threshold of first perception (IPT): subliminal (IPT −10 mmHg), liminal (IPT), or supraliminal (IPT +10 mmHg). IBS patients relative to controls responded with lower activations of the prefrontal cortex (PFC) and anterior cingulate cortex (ACC) to both subliminal and supraliminal stimulation and with higher activation of the hippocampus (HC) to supraliminal stimulation. In IBS patients, not in controls, ACC and HC were also activated by auditory stimulation. In IBS patients, decreased ACC and PFC activation with subliminal and supraliminal rectal stimuli and increased HC activation with supraliminal stimuli suggest disturbances of the associative and emotional processing of visceral sensation. Hyperreactivity to auditory stimuli suggests that altered sensory processing in IBS may not be restricted to visceral sensation.

Reassessing the benefits and risks of alosetron: what is its place in the treatment of irritable bowel syndrome?

Functional gastrointestinal disorders such as the irritable bowel syndrome (IBS) cause substantial morbidity and a high amount of healthcare utilisation. However, no direct mortality can be attributed to functional disorders. Hence, drug treatment of IBS must not only be highly efficient to relieve clinical symptoms but also very safe for the long-term use in humans with such chronic disorders. Alosetron is a potent and highly selective serotonin 5-HT3 receptor antagonist that in large randomised controlled clinical trials has been shown to be clinically efficient in female patients with diarrhoea-predominant IBS. The efficacy data along with a low number of serious adverse effects in the preclinical and clinical trials suggested a favourable benefit/risk profile that led to US FDA approval of alosetron in early 2000. However, postmarketing experience has proven that several serious adverse effects, including death, occurred in the treated patient population, which resulted (for a time) in the withdrawal of alosetron from the US market by the producer (GlaxoSmithKline). In the meantime, both public pressure and the proposal of a careful postmarketing surveillance have led the FDA to re-approve alosetron to the US drug market under severe restrictions. These restrictions aim to ensure a safer use of the drug with a more favourable safety profile. Under these restrictions, however, it is not very likely that alosetron will become a major treatment option for many patients, but presumably the continued use of this first selective serotonin antagonist will open an avenue for the development of similar drugs with more favourable benefit/risk profiles in the near future.