CNS-Sparing Histamine H<sub>3</sub> Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal Symptoms
Arianna Carolina Rosa,
Patrizia Nardini,
Silvia Sgambellone,
Maura Gurrieri,
Simona Federica Spampinato,
Alfonso Dell’Accio,
Paul L Chazot,
Ilona Obara,
Wai L Liu,
Alessandro Pini
Affiliations
Arianna Carolina Rosa
Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy
Patrizia Nardini
Department of Clinical and Experimental Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy
Silvia Sgambellone
Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy
Maura Gurrieri
Department of Clinical and Experimental Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy
Simona Federica Spampinato
Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, Italy
Alfonso Dell’Accio
Department of Clinical and Experimental Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy
Paul L Chazot
School of Biological and Biomedical Science, Durham University, Durham DH1 3LE, UK
Ilona Obara
School of Pharmacy and Translational and Clinical Research Institute, King George VI Building, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UK
Wai L Liu
Liu & Co Consulting Limited, Whitstable CT5 3RF, UK
Alessandro Pini
Department of Clinical and Experimental Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy
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 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.
