Thyrotropin-releasing hormone (TRH) acts centrally to exert pleiotropic actions independently from its endocrine function, including antinociceptive effects against somatic pain in rodents. Whether exogenous or endogenous activation of TRH signaling in the brain modulates visceral pain is unknown. Adult male Sprague-Dawley rats received an intracerebroventricular (ICV) injection of the stable TRH analog, RX-77368 (10, 30 and 100 ng/rat) or saline (5 µl) or were semi-restrained and exposed to cold (4°C) for 45 min. The visceromotor response (VMR) to graded phasic colorectal distensions (CRD) was monitored using non-invasive intracolonic pressure manometry. Naloxone (1 mg/kg) was injected subcutaneously 10 min before ICV RX-77368 or saline. Fecal pellet output was monitored for 1 h after ICV injection. RX-77368 ICV (10, 30 and 100 ng/rat) reduced significantly the VMR by 56.7%, 67.1% and 81.1% at 40 mmHg and by 30.3%, 58.9% and 87.4% at 60 mmHg respectively vs ICV saline. Naloxone reduced RX-77368 (30 and 100 ng, ICV) analgesic response by 51% and 28% at 40 mmHg and by 30% and 33% at 60 mmHg respectively, but had no effect per se. The visceral analgesia was mimicked by the acute exposure to cold. At the doses of 30 and 100 ng, ICV RX-77368 induced defecation within 30 min. These data established the antinociceptive action of RX-77368 injected ICV in a model of visceral pain induced by colonic distension through recruitment of both opioid and non-opioid dependent mechanisms.

01 Oct 2017·American Journal of Physiology-Gastrointestinal and Liver PhysiologyQ3 · MEDICINE

Abdominal surgery induced gastric ileus and activation of M1-like macrophages in the gastric myenteric plexus: prevention by central vagal activation in rats

Q3 · MEDICINE

Article

Author: Yuan, Pu-Qing ; Taché, Yvette

Inflammation plays a role in abdominal surgery (AS)-induced intestinal ileus that is alleviated by electrical vagal stimulation. Intracisternal injection of RX-77368, the stable thyrotropin-releasing hormone agonist, activates dorsal motor nucleus neurons and gastric vagal efferent discharges. We investigated the gastric inflammation induced by AS and the modulation by intracisternal RX-77368 in rats. RX-77368 (50 ng/rat) or saline was injected followed, 1 h later, by laparotomy and small intestinal/cecal manipulation. The sham group had anesthesia alone. After 6 h, gastric emptying (GE) and the inflammation in gastric corpus were determined. AS inhibited GE by 72% vs. control and doubled the number of M1-like macrophage immunoreactive for major histocompatibility complex class II (MHCII; M1 marker) but not for cluster of differentiation 206 (CD206; M2 marker) (MHCII+/CD206−) while there was no change in M2-like macrophages (MHCII−/CD206+). AS increased mRNA levels of interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) by 1.7- and 1.5-fold, respectively, in the gastric submucosa plus muscle layers and the infiltration of neutrophils labeled by myeloperoxidase by 9.5-fold in the muscularis externa. RX-77368 inhibited AS-related gastric changes while not altering these parameters in the sham group. There was a significant negative correlation between GE and IL-1β ( r = −0.46), TNF-α ( r = −0.44), M1 macrophage ( r = −0.82), and neutrophils ( r = −0.91). The M2-like macrophages and IL-10 expression were unchanged by AS with intracisternal saline or RX-77368. These data indicate that AS activates gastric M1 macrophages and increases proinflammatory cytokines expression, which are prevented by central vagal activation and may contribute to the correlated dampening of postoperative gastric ileus. NEW & NOTEWORTHY MHCII+/CD206− (M1) and MHCII−/CD206+ (M2) constitute two distinct populations of macrophages that are in close apposition to the cholinergic neurons in the rat gastric myenteric plexus (MP). Abdominal surgery (6 h) activates M1 macrophage leading to inflammation in the gastric MP correlated with the delayed gastric emptying, which was abolished by central vagal stimulation via intracisternal injection of RX-77368. Vagal stimulation linked with the cephalic phase may have potential beneficial effects to curtail postoperative gastric ileus.

01 Feb 2012·Hypertension ResearchQ3 · MEDICINE

Role of brainstem thyrotropin-releasing hormone-triggered sympathetic overactivation in cardiovascular mortality in type 2 diabetic Goto–Kakizaki rats

Q3 · MEDICINE

Article

Author: David W Adelson ; Yan Ao ; Michael D Nyby ; Janake Wijesuriya ; Victoria Smutko ; Michael L Tuck ; Vay Liang W Go ; Ai Chen ; Hong Yang

Sympathetic hyperactivity has an important role in cardiovascular mortality in patients with type 2 diabetes (T2D). Thyrotropin-releasing hormone (TRH)-containing fibers innervate autonomic motor and premotor nuclei of the brainstem and spinal cord that regulate cardiovascular functions. We compared cardiovascular responses to application of TRH-analog in the brainstem of Wistar and T2D Goto-Kakizaki (GK) rats. GK rats exhibited basal systolic hypertension (152±2 mm Hg) and had a significantly potentiated, dose-related hypertensive response to intracisternal (i.c.) injection of the TRH-analog RX77368 (10-60 ng). In GK rats only, i.c. RX77368 (30-60 ng) markedly increased heart rate (HR; +88 b.p.m.) and induced acute cardiac mortality (100%), concurrent with extreme hyperglycemia (>26 mmol l(-1)), increased plasma H(2)O(2) and 8-isoprostane, and enhanced heart expression of NADPH oxidase 4 and vascular cell adhesion molecule-1 mRNAs. GK rats also had elevated basal plasma epinephrine, higher adrenal gene expression of tyrosine hydroxylase and dopamine β-hydroxylase (DβH), and greater plasma catecholamine and adrenal DβH responses to i.c. TRH-analog, compared with Wistar rats. In GK rats, hexamethonium blocked i.c. RX77368-induced hypertensive and tachycardic responses, and reduced mortality by 86%, whereas phentolamine abolished the hypertensive response but enhanced tachycardia (+160 b.p.m.), and reduced mortality by 50%. The angiotensin II type 1 receptor antagonist irbesartan prevented i.c. RX77368-induced increases in blood pressure, HR and mortality. In conclusion, sympathetic overactivation triggered by brainstem TRH contributes to the mechanism of cardiovascular morbidity and mortality in T2D, which involves heightened cardiac inflammation and peripheral oxidative stress responses to sympathetic drive, and a mediating role of the renin-angiotensin system.

100 Deals associated with Thymoliberin

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Indication	Highest Phase	Country/Location	Organization	Date
Motor Neuron Disease	Phase 3	SE	Ferring Pharmaceuticals SA	-
Amyotrophic Lateral Sclerosis	Phase 2	GB	Reckitt & Colman Plc	-
Depressive Disorder, Major	Phase 2	-	Ferring BV	-
Learning Disabilities	Phase 2	GB	Reckitt Benckiser Group Plc	-
Peptic Ulcer	Phase 2	-	Ferring BV	-

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