Targeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis
| Autor: | Betül Gökcek, Güralp O. Ceyhan, Mert Erkan, Matthias Maak, Kalliope N. Diakopoulos, Michael Schemann, Helmut Friess, Achim Krüger, Sarah Klauss, Bahar E. Ucurum, Steffen Teller, Ihsan Ekin Demir, Elke Tieftrunk, Dorukhan H. Bahceci, Timo Kehl, Carmen Mota Reyes, Dominique G. Carty, Hana Algül, Ömer Cemil Saricaoglu, Tobias Heinrich, Maria Lazarou, Marina Lesina |
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| Přispěvatelé: | Bahçeci, Dorukhan H., Gökçek, Betül, Uçurum, Bahar E., Erkan, Murat Mert (ORCID 0000-0002-2753-0234 & YÖK ID 214689), Demir, İhsan Ekin, Heinrich, Tobias, Carty, Dominique G., Sarıcaoğlu, Ömer Cemil, Klauss, Sarah, Teller, Steffen, Kehl, Timo, Reyes, Carmen Mota, Tieftrunk, Elke, Lazarou, Maria, Maak, Matthias, Diakopoulos, Kalliope N., Lesina, Marina, Schemann, Michael, Krueger, Achim, Algül, Hana, Friess, Helmut, Ceyhan, Güralp O., School of Medicine, Department of General Surgery, Acibadem University Dspace |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Research paper Pancreatic disease Nitric Oxide Synthase Type I Pharmacology Mice 0302 clinical medicine Molecular Targeted Therapy Nitrergic Enzyme Inhibitors Genetically engineered mice General Medicine Middle Aged Immunohistochemistry ddc 030220 oncology & carcinogenesis Neuropathic pain Knockout mouse Female Atg5 Chronic pancreatitis Neurology of the digestive tract Adult Medicine General and internal medicine Pancreatic Extracts Pain nNOS Mice Transgenic General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Pancreatitis Chronic Pancreatic cancer Genetic model medicine Animals Humans business.industry Brain-Derived Neurotrophic Factor medicine.disease Pancreatic Neoplasms Disease Models Animal 030104 developmental biology nervous system Research and experimental medicine Neuralgia Pancreatitis business Biomarkers Ex vivo |
| Zdroj: | EBioMedicine |
| ISSN: | 2352-3964 |
| DOI: | 10.1016/j.ebiom.2019.07.055 |
| Popis: | Background: pain due to pancreatic cancer/PCa or chronic pancreatitis/CP, is notoriously resistant to the strongest pain medications. Here, we aimed at deciphering the specific molecular mediators of pain at surgical-stage pancreatic disease and to discover novel translational targets. Methods: we performed a systematic, quantitative analysis of the neurotransmitter/neuroenzmye profile within intrapancreatic nerves of CP and PCa patients. Ex vivo neuronal cultures treated with human pancreatic extracts, conditional genetically engineered knockout mouse models of PCa and CP, and the cerulein-induced CP model were employed to explore the therapeutic potential of the identified targets. Findings: we identified a unique enrichment of neuronal nitric-oxide-synthase (nNOS) in the pancreatic nerves of CP patients with increasing pain severity. Employment of ex vivo neuronal cultures treated with pancreatic tissue extracts of CP patients, and brain-derived-neurotrophic-factor-deficient (BDNF+/−) mice revealed neuronal enrichment of nNOS to be a consequence of BDNF loss in the progressively destroyed pancreatic tissue. Mechanistically, nNOS upregulation in sensory neurons was induced by tryptase secreted from perineural mast cells. In a head-to-head comparison of several genetically induced, painless mouse models of PCa (KPC, KC mice) or CP (Ptf1a-Cre;Atg5fl/fl) against the hypersecretion/cerulein-induced, painful CP mouse model, we show that a similar nNOS enrichment is present in the painful cerulein-CP model, but absent in painless genetic models. Consequently, mice afflicted with painful cerulein-induced CP could be significantly relieved upon treatment with the specific nNOS inhibitor NPLA. Interpretation: we propose nNOS inhibition as a novel strategy to treat the unbearable pain in CP. Fund: Deutsche Forschungsgemeinschaft/DFG (DE2428/3-1 and 3-2). Deutsche Forschungsgemeinschaft (DFG) |
| Databáze: | OpenAIRE |
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