Abstract
The role of histamine H3 receptors (H3Rs) in the regulation of gastroprotection and production of prostaglandin E2 (PGE2) as well as somatostatin remains contradictory. Therefore, the effects of the H3R antagonist/inverse agonist M39 on in vivo acidified ethanol-induced gastric ulcers and gastric acid secretion in the C57BL/6 mice were assessed. Results showed that acute systemic administration of H3R agonist (R)-α-methylhistamine (RAMH, 100 mg/kg, i.g.) significantly reduced the severity of ulcer index, increased gastric acid output, and increased mucosal PGE2 production without any alteration of somatostatin concentration in gastric juice. However, only acute systemic administration of the H2R agonist dimaprit (DIM, 10 mg/kg, p.o.) significantly decreased the level of somatostatin measured in gastric juice. Moreover, acute systemic administration of M39 (0.3 mg/kg, i.g.) abrogated the RAMH-induced increase of acid output as well as PGE2 production, but not the DIM (10 mg/kg, i.g.)-stimulated acid secretion, indicating that RAMH as well as M39 modulate the gastroprotective effects through interactions with histamine H3Rs. The present findings indicate that agonistic interaction with H3Rs is profoundly involved in the maintenance of gastric mucosal integrity by modulating PGE2 as well as gastric acid secretion, with no apparent role in the regulation of the inhibitory influence of somatostatin.
Highlights
Peptic ulcer is a chronic disease affecting up to 10% of the world’s population, and the formation of peptic ulcers depends on the presence of increased acidic gastric juice and the decreased mucosal defenses (Kuna et al, 2019)
The results observed show that the gastroprotective effect provided by H3 receptors (H3Rs) agonist RAMH was partly reversed when mice were pretreated with M39 as measured on the level of ulcer index, indicating that, in addition to histaminergic pathways through activation of H3Rs, the protective effects might be attributed to mechanisms other than histaminergic neurotransmission
The latter results are in disagreement with previous studies in which modulation of H3Rs resulted in a significant alteration of somatostatin synthesis, demonstrating that the mechanisms responsible for the protective action observed for RAMH and H3R antagonist/ inverse agonist M39 appear to be unrelated to their effects on somatostatin synthesis (Morini et al, 1995a; Morini et al, 1995b; Morini et al, 1997; Morini et al, 2000)
Summary
Peptic ulcer is a chronic disease affecting up to 10% of the world’s population, and the formation of peptic ulcers depends on the presence of increased acidic gastric juice and the decreased mucosal defenses (Kuna et al, 2019). Mounting preclinical experimental evidences related numerous functional and behavioral effects to central H3R-mediation The activation of such cerebral sites appears to stimulate a waking effect in cats (Schwartz et al, 2003; Lin et al, 2008; Lin et al, 2011), modulation of locomotor activity, anticonvulsant, antinociceptive, and procognitive actions in mice and rats (Clapham and Kilpatrick, 1993; Yokoyama et al, 1993; Clapham and Kilpatrick, 1994; Malmberg-Aiello et al, 2003; Sadek et al, 2013; Sadek et al, 2014a; Sadek et al, 2014b; Sadek et al, 2015; Sadek and Stark, 2015; Sadek et al, 2016a; Sadek et al, 2016b; Sadek et al, 2016c). Complexity of histamine H3R biology e.g. many isoforms, constitutive activity, the aforementioned heteromerization with other receptors (dopamine D2, D1, adenosine A2A), and pharmacology make it difficult to realize and evaluate the therapeutic potential of H3R antagonists (Lazewska and Kiec-Kononowicz, 2018)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
