Sándor Farkas1, Kata Bölcskei2, Adrienn Markovics3, Anita Varga4, Ágnes Kis-Varga5, Viktória Kormos6, Balázs Gaszner7, Csilla Horváth8, Bernadett Tuka9, János Tajti10, Zsuzsanna Helyes11. 1. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Szigeti u. 12, H-7624 Pécs, Hungary; Research Division, Gedeon Richter Plc., H-1103 Budapest, Gyömrői út 19-21, Hungary. Electronic address: farkass1@gmail.com. 2. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Szigeti u. 12, H-7624 Pécs, Hungary; János Szentágothai Research Centre, University of Pécs, Ifjúság út 20, H-7624 Pécs, Hungary. Electronic address: kata.bolcskei@aok.pte.hu. 3. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Szigeti u. 12, H-7624 Pécs, Hungary; János Szentágothai Research Centre, University of Pécs, Ifjúság út 20, H-7624 Pécs, Hungary. Electronic address: adri.markovics@gmail.com. 4. Laboratory of Neuropharmacology, Pharmacological and Drug Safety Research, Gedeon Richter Plc., H-1103 Budapest, Gyömrői út 19-21, Hungary. Electronic address: anivarga@richter.hu. 5. Laboratory of Neuropharmacology, Pharmacological and Drug Safety Research, Gedeon Richter Plc., H-1103 Budapest, Gyömrői út 19-21, Hungary. Electronic address: i.kisvarga@richter.hu. 6. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Szigeti u. 12, H-7624 Pécs, Hungary. Electronic address: viktoria.kormos@gmail.com. 7. Department of Anatomy, Faculty of Medicine, University of Pécs, Szigeti u. 12, H-7624 Pécs, Hungary. Electronic address: balazs.b.gaszner@aok.pte.hu. 8. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Szigeti u. 12, H-7624 Pécs, Hungary; Laboratory of Neuropharmacology, Pharmacological and Drug Safety Research, Gedeon Richter Plc., H-1103 Budapest, Gyömrői út 19-21, Hungary. Electronic address: horvathcsiti@gmail.com. 9. Neurology Department, University of Szeged, Faculty of Medicine, H-6725 Szeged, Semmelweis u. 6, Hungary; MTA-SZTE Neuroscience Research Group, H-6725 Szeged, Semmelweis u. 6, Hungary. Electronic address: tukabernadett@googlemail.com. 10. Neurology Department, University of Szeged, Faculty of Medicine, H-6725 Szeged, Semmelweis u. 6, Hungary. Electronic address: tajti.janos@med.u-szeged.hu. 11. Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Szigeti u. 12, H-7624 Pécs, Hungary; János Szentágothai Research Centre, University of Pécs, Ifjúság út 20, H-7624 Pécs, Hungary; MTA-PTE NAP B Chronic Pain Research Group, Faculty of Medicine, University of Pécs, Szigeti u. 12, H-7624 Pécs, Hungary. Electronic address: zsuzsanna.helyes@aok.pte.hu.
Abstract
INTRODUCTION: Majority of the work for establishing nitroglycerin (NTG)-induced migraine models in animals was done in rats, though recently some studies in mice were also reported. Different special formulations of NTG were investigated in various studies; however, NTG treated groups were often compared to simple saline treated control groups. The aim of the present studies was to critically assess the utility of a panel of potential outcome measures in mice by revisiting previous findings and investigating endpoints that have not been tested in mice yet. METHODS: We investigated two NTG formulations, Nitrolingual and Nitro Pohl, at an intraperitoneal dose of 10mg/kg, in comparison with relevant vehicle controls, and evaluated the following outcome measures: light aversive behaviour, cranial blood perfusion by laser Doppler imaging, number of c-Fos- and neuronal nitrogen monoxide synthase (nNOS)-immunoreactive neurons in the trigeminal nucleus caudalis (TNC) and trigeminal ganglia, thermal hyperalgesia and tactile allodynia of the hind paw and orofacial pain hypersensitivity. RESULTS: We could not confirm previous reports of significant NTG-induced changes in light aversion and cranial blood perfusion of mice but we observed considerable effects elicited by the vehicle of Nitrolingual. In contrast, the vehicle of Nitro Pohl was apparently inert. Increased c-Fos expression in the TNC, thermal hyperalgesia, tactile allodynia and orofacial hypersensitivity were apparently good endpoints in mice that were increased by NTG-administration. The NTG-induced increase in c-Fos expression was prevented by topiramate but not by sumatriptan treatment. However, the NTG-induced orofacial hypersensitivity was dose dependently attenuated by sumatriptan. DISCUSSION: Our results pointed to utilisable NTG formulations and outcome measures for NTG-induced migraine models in mice. Pending further cross-validation with positive and negative control drugs in these mouse models and in the human NTG models of migraine, these tests might be valuable translational research tools for development of new anti-migraine drugs.
INTRODUCTION: Majority of the work for establishing nitroglycerin (NTG)-induced migraine models in animals was done in rats, though recently some studies in mice were also reported. Different special formulations of NTG were investigated in various studies; however, NTG treated groups were often compared to simple saline treated control groups. The aim of the present studies was to critically assess the utility of a panel of potential outcome measures in mice by revisiting previous findings and investigating endpoints that have not been tested in mice yet. METHODS: We investigated two NTG formulations, Nitrolingual and Nitro Pohl, at an intraperitoneal dose of 10mg/kg, in comparison with relevant vehicle controls, and evaluated the following outcome measures: light aversive behaviour, cranial blood perfusion by laser Doppler imaging, number of c-Fos- and neuronal nitrogen monoxide synthase (nNOS)-immunoreactive neurons in the trigeminal nucleus caudalis (TNC) and trigeminal ganglia, thermal hyperalgesia and tactile allodynia of the hind paw and orofacial painhypersensitivity. RESULTS: We could not confirm previous reports of significant NTG-induced changes in light aversion and cranial blood perfusion of mice but we observed considerable effects elicited by the vehicle of Nitrolingual. In contrast, the vehicle of Nitro Pohl was apparently inert. Increased c-Fos expression in the TNC, thermal hyperalgesia, tactile allodynia and orofacial hypersensitivity were apparently good endpoints in mice that were increased by NTG-administration. The NTG-induced increase in c-Fos expression was prevented by topiramate but not by sumatriptan treatment. However, the NTG-induced orofacial hypersensitivity was dose dependently attenuated by sumatriptan. DISCUSSION: Our results pointed to utilisable NTG formulations and outcome measures for NTG-induced migraine models in mice. Pending further cross-validation with positive and negative control drugs in these mouse models and in the humanNTG models of migraine, these tests might be valuable translational research tools for development of new anti-migraine drugs.
Authors: Timea Aczél; Angéla Kecskés; József Kun; Kálmán Szenthe; Ferenc Bánáti; Susan Szathmary; Róbert Herczeg; Péter Urbán; Attila Gyenesei; Balázs Gaszner; Zsuzsanna Helyes; Kata Bölcskei Journal: Int J Mol Sci Date: 2020-04-22 Impact factor: 5.923
Authors: Hui Shu; Sufang Liu; Yuanyuan Tang; Brian L Schmidt; John C Dolan; Larry L Bellinger; Phillip R Kramer; Steven D Bender; Feng Tao Journal: Int J Mol Sci Date: 2020-06-05 Impact factor: 5.923