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- Ekblad, Eva, et al.
(författare)
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Cocaine- and amphetamine-regulated transcript: distribution and function in rat gastrointestinal tract.
- 2003
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Ingår i: Neurogastroenterology and Motility. - : Wiley. - 1350-1925 .- 1365-2982. ; 15:5, s. 545-557
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Tidskriftsartikel (refereegranskat)abstract
- Cocaine- and amphetamine-regulated transcript (CART) peptide, originally isolated from brain, is also expressed in the peripheral nervous system. The distribution, origin and projections of CART-expressing enteric neurones by immunocytochemistry and in situ hybridization in rat gastrointestinal (GI) tract were studied. Possible motor functions of CART were studied in vitro using longitudinal muscle strips from stomach, ileum and colon. Cocaine- and amphetamine-regulated transcript peptide was found in numerous myenteric neurones throughout the GI tract while CART-expressing submucous neurones were scarce. Cocaine- and amphetamine-regulated transcript was also expressed in the antral gastrin cells. Myenteric CART-expressing neurones in both small and large intestine issued short descending projections. In atrophic ileum, CART mRNA-expressing neurones increased in number while neurones containing CART peptide decreased. In hypertrophied ileum, no change in CART peptide or CART mRNA containing myenteric neurones was detected. Cocaine- and amphetamine-regulated transcript 55-102 (10-9-10-7 mol L-1) did not induce any contractile or relaxatory responses in the muscle strips, neither did it affect responses induced by vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide or neuronal stimulation. In colonic, but not in ileal, strips addition of CART attenuated nitric oxide (NO) donor-induced relaxations. Although CART does not seem to play a pivotal role in classic neurotransmission to the longitudinal muscle, it may serve a modulatory role in NO transmission. It may, moreover, be involved in intestinal adaptation, and an additional hormonal role is also possible.
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| 2. |
- Härndahl, Linda, et al.
(författare)
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Beta-cell-targeted overexpression of phosphodiesterase 3B in mice causes impaired insulin secretion, glucose intolerance, and deranged islet morphology.
- 2004
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Ingår i: The Journal of biological chemistry. - 0021-9258 .- 1083-351X. ; 279:15, s. 15214-22
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Tidskriftsartikel (refereegranskat)abstract
- The second messenger cAMP mediates potentiation of glucose-stimulated insulin release. Use of inhibitors of cAMP-hydrolyzing phosphodiesterase (PDE) 3 and overexpression of PDE3B in vitro have demonstrated a regulatory role for this enzyme in insulin secretion. In this work, the physiological significance of PDE3B-mediated degradation of cAMP for the regulation of insulin secretion in vivo and glucose homeostasis was investigated in transgenic mice overexpressing PDE3B in pancreatic beta-cells. A 2-fold overexpression of PDE3B protein and activity blunted the insulin response to intravenous glucose, resulting in reduced glucose disposal. The effects were "dose"-dependent because mice overexpressing PDE3B 7-fold failed to increase insulin in response to glucose and hence exhibited pronounced glucose intolerance. Also, the insulin secretory response to intravenous glucagon-like peptide 1 was reduced in vivo. Similarly, islets stimulated in vitro exhibited reduced insulin secretory capacity in response to glucose and glucagon-like peptide 1. Perifusion experiments revealed that the reduction specifically affected the first phase of glucose-stimulated insulin secretion. Furthermore, morphological examinations demonstrated deranged islet cytoarchitecture. In conclusion, these results are consistent with an essential role for PDE3B in cAMP-mediated regulation of insulin release and glucose homeostasis.
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| 3. |
- Lundblad, Martin, et al.
(författare)
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Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson's disease.
- 2002
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Ingår i: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 15:1, s. 120-132
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Tidskriftsartikel (refereegranskat)abstract
- In an attempt to define clinically relevant models of akinesia and dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats, we have examined the effects of drugs with high (L-DOPA) vs. low (bromocriptine) dyskinesiogenic potential in Parkinson's disease on three types of motor performance, namely: (i) abnormal involuntary movements (AIMs) (ii) rotational behaviour, and (iii) spontaneous forelimb use (cylinder test). Rats with unilateral 6-OHDA lesions received single daily i.p. injections of L-DOPA or bromocriptine at therapeutic doses. During 3 weeks of treatment, L-DOPA but not bromocriptine induced increasingly severe AIMs affecting the limb, trunk and orofacial region. Rotational behaviour was induced to a much higher extent by bromocriptine than L-DOPA. In the cylinder test, the two drugs initially improved the performance of the parkinsonian limb to a similar extent. However, L-DOPA-treated animals showed declining levels of performance in this test because the drug-induced AIMs interfered with physiological limb use, and gradually replaced all normal motor activities. L-DOPA-induced axial, limb and orolingual AIM scores were significantly reduced by the acute administration of compounds that have antidyskinetic efficacy in parkinsonian patients and/or nonhuman primates (-91%, yohimbine 10 mg/kg; -19%, naloxone 4-8 mg/kg; -37%, 5-methoxy 5-N,N-dimethyl-tryptamine 2 mg/kg; -30%, clozapine 8 mg/kg; -50%, amantadine 40 mg/kg). L-DOPA-induced rotation was, however, not affected. The present results demonstrate that 6-OHDA-lesioned rats do exhibit motor deficits that share essential functional similarities with parkinsonian akinesia or dyskinesia. Such deficits can be quantified using novel and relatively simple testing procedures, whereas rotometry cannot discriminate between dyskinetic and antiakinetic effects of antiparkinsonian treatments.
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| 7. |
- Wierup, Nils, et al.
(författare)
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The ghrelin cell: a novel developmentally regulated islet cell in the human pancreas.
- 2002
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Ingår i: Regulatory Peptides. - 1873-1686. ; 107:1-3, s. 63-69
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), was recently identified in the stomach. Ghrelin is produced in a population of endocrine cells in the gastric mucosa, but expression in intestine, hypothalamus and testis has also been reported. Recent data indicate that ghrelin affects insulin secretion and plays a direct role in metabolic regulation and energy balance. On the basis of these findings, we decided to examine whether ghrelin is expressed in human pancreas. Specimens from fetal to adult human pancreas and stomach were studied by immunocytochemistry, for ghrelin and islet hormones, and in situ hybridisation, for ghrelin mRNA. RESULTS: We identified ghrelin expression in a separate population of islet cells in human fetal, neonatal, and adult pancreas. Pancreatic ghrelin cells were numerous from midgestation to early postnatally (10% of all endocrine cells). The cells were few, but regularly seen in adults as single cells at the islet periphery, in exocrine tissue, in ducts, and in pancreatic ganglia. Ghrelin cells did not express any of the known islet hormones. In fetuses, at midgestation, ghrelin cells in the pancreas clearly outnumbered those in the stomach. CONCLUSIONS: Ghrelin is expressed in a quite prominent endocrine cell population in human fetal pancreas, and ghrelin expression in the pancreas precedes by far that in the stomach. Pancreatic ghrelin cells remain in adult islets at lower numbers. Ghrelin is not co-expressed with any known islet hormone, and the ghrelin cells may therefore constitute a new islet cell type.
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