Role of Prostaglandins and Calcitonin Gene-Related Peptide in Central Vagal Cholinergic-Dependent Protection against Gastric Injury in Urethane-Anesthetized Rats

Kato, Kimitoshi; Yang, Hong; Taché, Yvette

doi:10.1159/000201352

Cited by 18 publications

(7 citation statements)

References 31 publications

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“…In tests with sensory afferent nerves and neuropeptides in gastroprotection afforded by leptin or CCK-8, rats with capsaicin-induced deactivation of these nerves (series C) or those pretreated with the CGRP antagonist, CGRP 8–37 [25, 26, 33](series D) were used. For the purpose of sensory inactivation, the animals (series C) were pretreated with capsaicin (Sigma Co., St. Louis, Mo., USA) injected s.c. for 3 consecutive days at a respective dose of 25, 50 and 50 mg/kg about 2 weeks before the experiment [26].…”

Section: Methodsmentioning

confidence: 99%

Central Leptin and Cholecystokinin in Gastroprotection against Ethanol-Induced Damage

Brzozowski

Konturek

et al. 2000

Digestion

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Background: Leptin, a product of the ob gene controlling food intake, has recently been detected in the stomach and shown to be released by cholecystokinin (CCK) and to induce gastroprotection against various noxious agents, but it is not known whether centrally applied leptin influences gastric secretion and mucosal integrity. Aims: In this study we compared the effects of leptin and CCK-8 applied intracerebroventricularly (i.c.v.) on gastric secretion and gastric mucosal lesions induced by topical application of 75% ethanol. Methods: Several major series of Wistar rats were used in this study. The effects of leptin or CCK applied i.c.v. on gastric secretion were examined using conscious rats with gastric fistulas. For the studies on gastroprotection the following series of rats were used to determine the effects of: (A) leptin and CCK applied centrally on this protection and the blockade of CCK_A with loxiglumide (30 mg/kg i.p.) and CCK_B receptors with RPR 102681 (30 mg/kg i.p.); (B) cutting of vagal nerves; (C) inactivation of sensory nerves by capsaicin (125 mg/kg s.c.); (D) inhibition of calcitonin gene-related peptide (CGRP) receptors with CGRP_8–37 (100 μg/kg i.p.), and (E) suppression of nitric oxide synthase (NOS) with N^G-nitro-L-arginine methyl ester (L-NAME) (5 mg/kg i.v.) on ethanol-induced gastric lesions in rats with or without the i.c.v. pretreatment with leptin or CCK-8. Rats were anesthetized 1 h after ethanol administration to measure the gastric blood flow (GBF) and then to determine the area of gastric lesions by planimetry. Blood was withdrawn for the measurement of plasma leptin and gastrin levels by radioimmunoassay and gastric biopsy samples were collected for the determination of cNOS and iNOS mRNA by RT-PCR. Results: Leptin and CCK-8 (0.01–5 μg/kg i.c.v.) dose dependently attenuated gastric lesions induced by 75% ethanol; the doses reducing these lesions by 50% (ED₅₀) were 0.8 and 1.2 μg/kg, respectively. The protective effects of leptin and CCK-8 applied i.c.v. were accompanied by a significant rise in plasma leptin level and an increase in GBF. Blockade of CCK_A receptors with loxiglumide abolished the protective and hyperemic effects of CCK but not those of leptin, while RPR 10268, a specific antagonist of CCK_B receptors, counteracted leptin-induced protection and the rise in the GBF but failed to influence those afforded by CCK-8. For comparison, pretreatment with peripheral CCK-8 or leptin (10 μg/kg i.p.) causing a similar rise in the plasma leptin level also significantly reduced gastric lesions induced by 75% ethanol. The protective and hyperemic effects of centrally administered leptin were abolished by vagotomy, producing a fall in plasma leptin levels, and significantly attenuated by sensory denervation with capsaicin, by pretreatment with the CGRP antagonist, CGRP_8–37, or with L-NAME. A strong signal for iNOS mRNA was recorded in the gastric mucosa of leptin- and CCK-8-treated animals, whereas...

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Section: Methodsmentioning

confidence: 99%

Central Leptin and Cholecystokinin in Gastroprotection against Ethanol-Induced Damage

Brzozowski

Konturek

et al. 2000

Digestion

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“…Activation of sensory nerves influences the secretory functions in the stomach and exhibits gastroprotection by increasing gastric mucosal blood flow via the release of CGRP from sensory afferent nerves (Holzer et al, 1991;Kato et al, 1996). Given that NA and its metabolites reverse the symptoms of pellagra (pellagra preventive vitamin PP also known as vitamin B 3 ) and they were reported to exert cytoprotective effects in the neural, vascular, and dermal tissues, we attempted to test the hypothesis that MNA protection involves the activation of afferent sensory nerves leading to the release of CGRP.…”

Section: Downloaded Frommentioning

confidence: 99%

Therapeutic Potential of 1-Methylnicotinamide against Acute Gastric Lesions Induced by Stress: Role of Endogenous Prostacyclin and Sensory Nerves

Brzozowski

Konturek²,

Chłopicki³

et al. 2008

J Pharmacol Exp Ther

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1-Methylnicotinamide (MNA) is one of the major derivatives of nicotinamide, which was recently shown to exhibit antithrombotic and antiinflammatory actions. However, it is not yet known whether MNA affects gastric mucosal defense. The effects of exogenous MNA were studied on gastric secretion and gastric lesions induced in rats by 3.5 h of water immersion and water restraint stress (WRS) or in rats administered 75% ethanol. MNA [6.25-100 mg/kg intragastrically (i.g.)] led to a dose-dependent rise in the plasma MNA level, inhibited gastric acid secretion, and attenuated these gastric lesions induced by WRS or ethanol. The gastroprotective effect of MNA was accompanied by an increase in the gastric mucosal blood flow and plasma calcitonin gene-related peptide (CGRP) levels, the preservation of prostacyclin (PGI 2 ) generation (measured as 6-keto-PGF1␣), and an overexpression of mRNAs for cyclooxygenase (COX)-2 and CGRP in the gastric mucosa. R-3-(4-Fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid (RO 324479), which is the selective antagonist of IP/PGI 2 receptors, reversed the effects of MNA on gastric lesions and GBF. MNA-induced gastroprotection was attenuated by suppression of COX-1 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; SC-560] and COX-2 [4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one; rofecoxib] activity, capsaicin denervation, and by the pretreatment with CGRP 8-37 or capsazepine. Addition of exogenous PGI 2 or CGRP restored the MNA-induced gastroprotection in rats treated with COX-1 and COX-2 inhibitors or in those with capsaicin denervation. WRS enhanced MDA content while decreasing superoxide dismutase (SOD) activity in the gastric mucosa, but pretreatment with MNA reversed these changes. MNA exerts potent gastroprotection against WRS damage via mechanisms involving cooperative action of PGI 2 and CGRP in preservation of microvascular flow, antioxidizing enzyme SOD activity, and reduction in lipid peroxidation.Nicotinamide (NA) is a precursor for the coenzyme ␤-nicotinamide adenine dinucleotide (NAD ϩ ), which serves as an essential nutrient for cellular growth, and it participates in the regulation of multiple cellular functions, including apoptosis and response to injury (Mukherjee et al., 1997;Maiese and Chong, 2003). Indeed, NA has been reported to exert several physiological and pharmacological effects, including the prevention of ATP depletion, inhibition of poly(ADPribose) polymerase, prevention of apoptosis, and suppression of lipid peroxidation (Klaidman et al., 1996(Klaidman et al., , 2003. NA also possesses anti-inflammatory properties (Ogata et al., 2002;Ungerstedt et al., 2003) and exhibits angiogenic activity by promoting the growth of capillaries (Morris et al., 1989). Article, publication date, and citation information can be found at

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“…Activation of the TRH 1 receptor in the DMN induces a vagal cholinergic dependent increase of transmitters in the gastric mucosa including prostaglandin E 2 (PGE 2 ) [63] and nitric oxide (NO) [64,65], which contribute to the gastric protection as the NO synthase inhibitor, N G -nitro-L-arginine methyl ester (L-NAME) and the non selective cylcooxygenase (COX)-l and COX-2 inhibitor, indomethacin, unlike the more selective COX-2 inhibitor, nabumetone, negated the protective effect of intracisternal TRH or TRH analog [45,47–50,54,58]. In addition, TRH injected intracisternally at low doses stimulates gastric splanchnic afferents as demonstrated by electrophysiological recording [66] and activates the local effector function of capsaicin-sensitive splanchnic afferent pathways containing CGRP [46,58].…”

Section: Brainstem Trh and Vagal Muscarinic Gastric Protectionmentioning

confidence: 99%

Brainstem Neuropeptides and Vagal Protection of the Gastric Mucosal Against Injury: Role of Prostaglandins, Nitric Oxide and Calcitonin-Gene Related Peptide in Capsaicin Afferents

Taché¹

2012

CMC

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Earlier experimental studies indicated that the integrity of vagal pathway was required to confer gastric protection against damaging agents. Several peptides located in the brainstem initially identified to influence vagal outflow to the stomach, as assessed by electrophysiological approach or by vagal dependent alterations of gastric secretory and motor function, were investigated for their influence in the vagal regulation of the resistance of the gastric mucosa to injury. Thyrotropin releasing hormone (TRH), or its stable TRH analog, RX-77368, injected at low doses into the cisterna magna or the dorsal motor nucleus (DMN) was the first peptide reported to protect the gastric mucosa against ethanol injury through stimulation of vagal cholinergic pathways, inducing the release of gastric prostaglandins/ nitric oxide (NO) and the recruitment of efferent function of capsaicin sensitive afferent fibers containing calcitonin-gene related peptide (CGRP). Activation of endogenous TRH-TRH1 receptor signaling located in the brainstem plays a role in adaptive gastric protection against damaging agents. Since then, an expanding number of peptides, namely peptide YY, CGRP, adrenomedullin, amylin, glugacon-like peptide, opioid peptides acting on μ, δ1 or δ2 receptors, nocicpetin, nocistatin, ghrelin, leptin and TLQP-21, a peptide derived from VGF prohormone, have been reported to act in the brainstem to afford gastric protection against ethanol injury largely through similar peripheral effectors mechanisms than TRH. Therefore gastric prostaglandins and CGRP/NO pathways represent a common final mechanism through which brain peptides confer vagally mediated gastroprotection against injury. A better understanding of brain circuitries through which these peptides are released will provide new strategies to recruit integrated and multifaceted gastroprotective mechanisms.

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Role of Prostaglandins and Calcitonin Gene-Related Peptide in Central Vagal Cholinergic-Dependent Protection against Gastric Injury in Urethane-Anesthetized Rats

Cited by 18 publications

References 31 publications

Central Leptin and Cholecystokinin in Gastroprotection against Ethanol-Induced Damage

Central Leptin and Cholecystokinin in Gastroprotection against Ethanol-Induced Damage

Therapeutic Potential of 1-Methylnicotinamide against Acute Gastric Lesions Induced by Stress: Role of Endogenous Prostacyclin and Sensory Nerves

Brainstem Neuropeptides and Vagal Protection of the Gastric Mucosal Against Injury: Role of Prostaglandins, Nitric Oxide and Calcitonin-Gene Related Peptide in Capsaicin Afferents

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