CNS-Sparing Histamine H3 Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal Symptoms

Abstract

Among the histamine receptors, growing evidence points to the histamine H3 receptor as a pharmacological candidate to counteract the autonomic neuropathy associated with diabetes. The study aimed to evaluate the effect of PF00868087 (also known as ZPL-868), a CNS-sparing histamine H3 receptor antagonist, on the autonomic neuropathy of the intestinal tract associated with diabetes. Diabetes was induced in male BALB/c mice by a single high dose of streptozotocin (150 mg/kg). Colorectal specimens from control and diabetic mice, randomized to vehicle or PF0086087 (10, 30, 100 mg/kg/day by oral gavage for 14 days), were processed for morphological and immunohistochemical analysis. A significant overproduction of mucus in the intestinal mucosa of diabetic mice compared to the controls was observed. PF0086087 at the highest dose prevented mucin overproduction. The immunohistochemistry analysis demonstrated that diabetes causes a decrease in the inhibitory component of enteric motility, measured as the percentage of neuronal nitric oxide synthase-positive neurons (p < 0.05) and a parallel increase in the excitatory component evaluated as substance P-positive fibres (p < 0.01). PF0086087 dose-dependently prevented these pathophysiological events. In conclusion, PF0086087 may be an essential tool in preventing nitrergic dysfunction in the myenteric plexus of the distal colon and diabetes-induced gastrointestinal complications.

β3 Adrenoceptor Agonism Prevents Hyperoxia-Induced Colonic Alterations

“…Our study first shows that neonatal hyperoxia significantly alters neuronal chemical coding in the myenteric plexus, increasing both ChAT + neurons and the SP immunoreactivity of nerve fibers while reducing the nNOS + neurons without changing the number of neurons per ganglion. This observation agrees with our previous results from a model of diabetes-induced intestinal injury [25]. In contrast, other models of colonic disorders have shown neuronal loss or different alterations in neuronal subpopulations [36,42,43].…”

“…The decrease in mucin production indicated by the observed reduction in PAS + -relative area is a marker of intestinal damage [24,36] and could be at least partially explained by a loss of goblet cells [24]. This finding is at variance with previous studies, which have reported an overproduction of mucins in rodent models of colonic injury as a reaction to dysmotility [25,37]. However, these animal models were designed to mimic intestinal disorders characterized by chronic inflammation and longlasting treatments, whereas ours exploits a different noxious stimulus applied for a short time to immature animals.…”

“…As shown in Figure 3 (panels D-F), infiltrating mixed leukocytes were present in the colonic mucosa of all the hyperoxia-exposed rats, regardless of the treatment with BRL37344. The effect of hyperoxia on mucin expression was then evaluated by a quantitative analysis of PAS-stained colon sections [25]. As reported in Figure 4, hyperoxia induced a statistically significant loss of the PAS + relative area of goblet cells, suggesting reduced mucin production [24].…”

KSK-74: Dual Histamine H3 and Sigma-2 Receptor Ligand with Anti-Obesity Potential

“…However, a significant improvement in glucose tolerance was observed in experimental animals treated with the tested compounds. We suspected that this may be due to the fact that the experimental animals did not develop full obesity or to the effect of the tested ligands on H 3 R present in pancreatic β cells responsible for insulin secretion and blood glucose regulation [48].…”