CNS-Sparing Histamine H<sub>3</sub> Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal Symptoms
Among the histamine receptors, growing evidence points to the histamine H<sub>3</sub> 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 hista...
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MDPI AG
2022-01-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/2/184 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Arianna Carolina Rosa |
| collection | DOAJ |
| description | Among the histamine receptors, growing evidence points to the histamine H<sub>3</sub> 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 H<sub>3</sub> 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 (<i>p</i> < 0.05) and a parallel increase in the excitatory component evaluated as substance P-positive fibres (<i>p</i> < 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. |
| first_indexed | 2024-03-09T22:31:22Z |
| format | Article |
| id | doaj.art-e499ba4ea6514e01847df64e78640c43 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T22:31:22Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-e499ba4ea6514e01847df64e78640c432023-11-23T18:57:50ZengMDPI AGBiomolecules2218-273X2022-01-0112218410.3390/biom12020184CNS-Sparing Histamine H<sub>3</sub> Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal SymptomsArianna Carolina Rosa0Patrizia Nardini1Silvia Sgambellone2Maura Gurrieri3Simona Federica Spampinato4Alfonso Dell’Accio5Paul L Chazot6Ilona Obara7Wai L Liu8Alessandro Pini9Department of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, ItalyDepartment of Clinical and Experimental Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyDepartment of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Pharmacology and Toxicology Section, University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyDepartment of Clinical and Experimental Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyDepartment of Scienza e Tecnologia del Farmaco, University of Turin, Via P. Giuria 9, 10125 Turin, ItalyDepartment of Clinical and Experimental Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, ItalySchool of Biological and Biomedical Science, Durham University, Durham DH1 3LE, UKSchool of Pharmacy and Translational and Clinical Research Institute, King George VI Building, Newcastle University, Newcastle-upon-Tyne NE1 7RU, UKLiu & Co Consulting Limited, Whitstable CT5 3RF, UKDepartment of Clinical and Experimental Medicine, University of Florence, Viale Pieraccini 6, 50139 Florence, ItalyAmong the histamine receptors, growing evidence points to the histamine H<sub>3</sub> 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 H<sub>3</sub> 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 (<i>p</i> < 0.05) and a parallel increase in the excitatory component evaluated as substance P-positive fibres (<i>p</i> < 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.https://www.mdpi.com/2218-273X/12/2/184histaminePF0086087ZPL-868diabetesgastrointestinal neuropathy |
| spellingShingle | 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 CNS-Sparing Histamine H<sub>3</sub> Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal Symptoms Biomolecules histamine PF0086087 ZPL-868 diabetes gastrointestinal neuropathy |
| title | CNS-Sparing Histamine H<sub>3</sub> Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal Symptoms |
| title_full | CNS-Sparing Histamine H<sub>3</sub> Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal Symptoms |
| title_fullStr | CNS-Sparing Histamine H<sub>3</sub> Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal Symptoms |
| title_full_unstemmed | CNS-Sparing Histamine H<sub>3</sub> Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal Symptoms |
| title_short | CNS-Sparing Histamine H<sub>3</sub> Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal Symptoms |
| title_sort | cns sparing histamine h sub 3 sub receptor antagonist as a candidate to prevent the diabetes associated gastrointestinal symptoms |
| topic | histamine PF0086087 ZPL-868 diabetes gastrointestinal neuropathy |
| url | https://www.mdpi.com/2218-273X/12/2/184 |
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