The Effects of Atorvastatin on the Migraine Pathophysiology in Nitroglycerin Induced Migraine in Ovariectomized Rats

Year 2019, Volume: 78 Issue: 1, 11 - 22, 31.05.2019

Ahmet Can Hicyilmaz Kadriye Akgun-dar

Abstract

ABSTRACT

Objective: Migraine is one of the common primary headaches which affects the majority of the population. However, in spite of increasing information on migraine pathophysiology and various researches, the underlying mechanisms of migraine attacks still not completely understood. Statins have antioxidant, anti-inflammatory neuroprotective effects and they might be a useful drug for curing neurodegenerative disorders. There are several studies suggesting nitric oxide (NO) causes migraine attacks in migraine pathogenesis. We aimed to investigate the effects of atorvastatin (AT) which is a member of the statin family, on migraine pathophysiology in ovariectomized female rats in which migraine was stimulated using nitroglycerine (NTG). Materials and Methods: In the study, ovariectomized adult Sprague Dawley female rats were divided into 4 groups; control, NTG, AT, NTG+AT. We examined immunohistochemically inducible nitric oxide (iNOS), endothelial nitric oxide (eNOS), neuronal nitric oxide (nNOS), matrix metalloproteinase-2 (MMP-2), β-catenin expression on brain sections and biochemically c-fos, calcitonin gene-related peptide (CGRP), β-catenin, calcium-binding protein B (S100B), NO, total antioxidant capacity (TAS) and total oxidant capacity (TOS) levels. Results: Our results showed that AT was immunohistochemically increasing eNOS and nNOS levels, and reducing iNOS. In brain homogenates AT was reducing S100B, CGRP, c-fos, total Nitrite-Nitrate, β-catenin but increasing TAS and TOS. There was no change in MMP-2. Also, our findings showed that AT could inhibit astroglial activity with its anti-inflammatory effect and showed a protective effect towards blood-brain barrier and reduced the risk of possible neurodegenerative diseases in rats with migraine. Conclusion: Our findings showed that AT could inhibit astroglial activity with its anti-inflammatory effect and showed a protective effect towards blood-brain barrier and reduced the risk of possible neurodegenerative diseases in rats with migraine. Our results will provide a significant contribution to studies in this field. 

Keywords

Migraine, nitroglycerin, atorvastatin, ovariectomized, rat

Supporting Institution

Istanbul University Scientific Research Projects Coordination Unit

Project Number

50185

Thanks

We thanks to Facultad Ciencias Exactas Naturales, Universidad Nacional Catamarca (FACEN-UNCA) and Instituto Biodiversidad Neotropical (IBN-UNT) by facilities and other assistances. For the loan of specimens we thank to J. Andreoli Bize (FACEN).

References

• 1. Erdener SE, Dalkara T. Modelling headache and migraine and its pharmacological manipulation. Br J Pharmacol 2014; 171(20): 4575-94.
• 2. Fischer M, Wille G, Klien S, Shanib H, Holle D, Gaul C, et al. Brainderived neurotrophic factor in primary headaches. J Headache Pain 2012; 13(6): 469-75.
• 3. Somerville BW. Estrogen-withdrawal migraine. I. Duration of exposure required and attempted prophylaxis by premenstrual estrogen administration. Neurology 1975; 25(3): 239–44.
• 4. Multon S, Pardutz A, Mosen J, Hua MT, Defays C, Honda S, et al. Lack of estrogen increases pain in the trigeminal formalin model: a behavioural and immunocytochemical study of transgenic ArKO mice. Pain 2005; 114(1-2): 257-65.
• 5. Scharfman HE, MacLusky NJ. Estrogen-growth factor interactions and their contributions to neurological disorders. Headache 2008; 48 Suppl 2: S77-89.
• 6. Merki-Feld GS, Imthurn B, Langner R, Seifert B, Gantenbein AR. Positive effects of the progestin desogestrel 75 μg on migraine frequency and use of acute medication are sustained over a treatment period of 180 days. J Headache Pain 2015; 16: 522.
• 7. Goldstein LB. Statins and ischemic stroke severity: cytoprotection. Current Atherosclerosis Reports 2009; 11(4): 296-300.
• 8. Hasanein P, Shahidi S. Effects of combined treatment with vitamins C and E on passive avoidance learning and memory in diabetic rats. Neurobiology of Learning and Memory 2010; 93(4): 472-8.
• 9. Üzüm G, Akgün-Dar K, Aksu A. The effects of atorvastatin on the development of Pentylenetetrazole induced kindling, related learning and memory impairments. Epilepsy & Behavior 2010; 19 (3): 284-289.
• 10. Akgün-Dar K, Kapucu A, Acar S, Üzüm G. Evaluation of Antiepileptogenic Effect of Atorvastatin on Development of Pentylenetetrazole Induced Kindling in Rats: The Responsibility of Inducible Nitric Oxide Synthase and Metalloproteinase 2. Turkiye Klinikleri J Med Sci 2013; 33: 995-1006.
• 11. Bahçekapılı N, Akgün-Dar K, Albeniz I, Kapucu A, Kandil A, Yağız O, et al. Erythropoietin pretreatment suppresses seizures and prevents the increase in inflammatory mediators during pentylenetetrazole induced generalized seizures. Int J Neurosci 2014; 124(10): 762-70.
• 12. Yin Z, Fang Y, Ren L, Wang X, Zhang A, Lin J, et al. Atorvastatin attenuates NF-kappaB activation in trigeminal nucleus caudalis in a rat model of migraine. Neurosci Lett 2009; 465(1): 61-5.
• 13. Sarrouilhe D, Dejean C, Mesnil M. Involvement of gap junction channels in the pathophysiology of migraine with aura. Front Physiol 2014; 5: 78.
• 14. Sicuteri F, Del Bene E, Poggioni M, Bonazzi A. Unmasking latent dysnociception in healthy subjects. Headache 1987; 27(4): 180-5.
• 15. Olesen J, Iversen HK, Thomsen LL. Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain. Neuroreport 1993; 4(8): 1027-30.
• 16. Pardutz A, Krizbai I, Multon S, Vecsei L, Schoenen J. Systemic nitroglycerin increases nNOS levels in rat trigeminal nucleus caudalis. Neuroreport 2000; 11(14): 3071-5.
• 17. Marcus DA. Interrelationships of neurochemicals, estrogen, and recurring headache. Pain 1995; 62(2): 129-39.
• 18. Silberstein SD, Merriam GR. Physiology of the menstrual cycle. Cephalalgia 2000; 20(3): 148-54.
• 19. Tassorelli C, Joseph SA. Systemic nitroglycerin induces Fos immunoreactivity in brainstem and forebrain structures of the rat. Brain Res 1995; 682(1-2): 167-81.
• 20. Garry MG, Walton LP, Davis MA. Capsaicin-evoked release of immunoreactive calcitonin gene-related peptide from the spinal cord is mediated by nitric oxide but not by cyclic GMP. Brain Res 2000; 861(2): 208-19.
• 21. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990; 28(2): 183-7.
• 22. Greco R, Tassorelli C, Mangione AS, Smeraldi A, Allena M, Sandrini G, et al. Effect of sex and estrogens on neuronal activation in an animal model of migraine. Headache 2013; 53(2): 288-96.
• 23. Arakaki X, Galbraith G, Pikov V, Fonteh AN, Harrington MG. Altered brainstem auditory evoked potentials in a rat central sensitization model are similiar to those in migraine. Brain Res 2014; 1563: 110-21.
• 24. Mrak E, Guidobono F, Moro G, Fraschini G, Rubinacci A, Villa I. Calcitonin gene-related peptide (CGRP) inhibits apoptosis in human osteoblasts by β-catenin stabilization. J Cell Physiol 2010; 225(3): 701-8.
• 25. Prévotat L, Filomenko R, Solary E, Jeannin JF, Bettaieb A. Nitric oxide-induced down-regulation of beta-catenin in colon cancer cells by a proteasome-independent specific pathway. Gastroenterology 2006; 131(4): 1142-52.
• 26. Wang Z, Xu L, Zhu X, Cui W, Sun Y, Nishijo H, et al. Demethylation of specific Wnt/β-catenin pathway genes and its upregulation in rat brain induced by prenatal valproate exposure. Anat Rec (Hoboken) 2010; 293(11): 1947-53.
• 27. Wang PH, Zhao LX, Wan JY, Zhang L, Mao XN, Long FY, et al. Pharmacological characterization of a novel gastrodin derivative as a potential anti-migraine agent. Fitoterapia 2016; Mar; 109: 52-7.
• 28. Offenhauser N, Zinck T, Hoffmann J, Schiemann K, Schuh-Hofer S, Rohde W, et al. CGRP release and c-fos expression within trigeminal nucleus caudalis of the rat following glyceryltrinitrate infusion. Cephalalgia 2005; 25(3): 225-36.
• 29. Tassorelli R, Greco P, Morazzoni A, Riva G, Sandrini G, Nappi G. Parthenolide is the component of tanacetum parthenium that inhibits nitroglycerin-induced Fos activation: studies in an animal model of migraine. Cephalalgia 2005; 25(8): 612-21.
• 30. Knyihár-Csillik E, Toldi J, Mihály A, Krisztin-Péva B, Chadaide Z, Németh H, et al. Kynurenine in combination with probenecid mitigates the stimulation-induced increase of c-fos immunoreactivity of the rat caudal trigeminal nucleus in an experimental migraine model. J Neural Transm (Vienna) 2007; 114(4): 417-21.
• 31. Zhu X, Han Y, Xiong W, Liu W, Lu S, Li J, et al. Effects of heating coagulation of middle meningeal artery on plasma CGRP level and c-fos expression in migraine rat triggered by nitroglycerin. Neurol Sci 2011; 32(4): 589-94.
• 32. Teepker M, Munk K, Mylius V, Haag A, Möller JC, Oertel WH, et al. Serum concentrations of s100b and NSE in migraine. Headache 2009; 49(2): 245-52.
• 33. Yilmaz N, Karaali K, Ozdem S, Turkay M, Unal A, Dora B. Elevated S100B and neuron specific enolase levels in patients with migraine-without aura: evidence for neurodegeneration? Cell Mol Neurobiol 2011; 31(4): 579-85.
• 34. Steinacker P, Weidehaas K, Cepek L, Feneberg E, Kretzschmar HA, Otto M. Influence of the blood-CSF-barrier function on S100B in neurodegenerative diseases. Acta Neurol Scand 2013; 128(4): 249-56.
• 35. Eren Y, Dirik E, Neşelioğlu S, Erel Ö. Oxidative stress and decreased thiol level in patients with migraine: cross-sectional study. Acta Neurol Belg 2015; 115(4): 643-9.
• 36. Yilmaz N, Aydin O, Yegin A, Tiltak A, Eren E. Increased levels of total oxidant status and decreased activity of arylesterase in migraineurs. Clin Biochem 2011; 44(10-11): 832-7.
• 37. Alp R, Selek S, Alp SI, Taşkin A, Koçyiğit A. Oxidative and antioxidative balance in patients of migraine. Eur Rev Med Pharmacol Sci 2010; 14(10): 877-82.
• 38. Fernandez-Patron C, Stewart KG, Zhang Y, Koivunen E, Radomski MW, Davidge ST. Vascular matrix metalloproteinase-2-dependent cleavage of calcitonin gene-related peptide promotes vasoconstriction. Circ Res 2000; 87(8): 670-6.
• 39. Wang Q, Yan J, Chen X, Li J, Yang Y, Weng J, et al. Statins: multiple neuroprotective mechanisms in neurodegenerative diseases. Exp Neurol 2011; 230(1): 27-34.
• 40. Eroğlu F, Eroğlu HE. Ratlarda Analjezi ve Anestezi, Küçük Deney Hayvanlarından Rat. In: Yücel O. (ed.), JCAM, Matris Tanıtım Baskı Hizmetleri Hilal Mahallesi (Yıldız) 4. Cadde, 701. Sokak, No: 20/A 06550 Çankaya, Ankara, Türkiye, 2012; ISBN: 978-605-87501-2-8, 52-59.
• 41. Jagatic J, Weiskopf R. A fluorescent method for staining mast cells. Arch Pathol 1966; 82(5): 430-3.
• 42. Erel O. A novel automated method to measure total antioxidant response against potent free radical reactions. Clin Biochem 2004; 37(2): 112-9.
• 43. Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005 38(12): 1103-11.
• 44. Özyiğit F. Nöropatik Farelerde Oluşan Mekanik Allodini Ve Hiperaljezi Üzerine Minosiklin’in Tek Başına Ve Morfin İle Birlikte Kullanıldığındaki Etkisi. T.C. Trakya Üniversitesi Tıp Fakültesi Farmakoloji Ana Bilim Dalı, Yüksek Lisans Tezi, 2007.
• 45. Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 2011; 12(10): 570-84.
• 46. Greco R, Tassorelli C, Cappelletti D, Sandrini G, Nappi G. Activation of the transcription factor NF-kappaB in the nucleus trigeminalis caudalis in an animal model of migraine. Neurotoxicology 2005; 26(5): 795-800.
• 47. Pardutz A, Szatmári E, Vecsei L, Schoenen J. Nitroglycerin-induced nNOS increase in rat trigeminal nucleus caudalis is inhibited by systemic administration of lysine acetylsalicylate but not of sumatriptan. Cephalalgia 2004; 24(6): 439-45
• 48. Suwattanasophon C, Phansuwan-Pujito P, Srikiatkhachorn A. 5-HT(1B/1D) serotonin receptor agonist attenuates nitroglycerinevoked nitric oxide synthase expression in trigeminal pathway. Cephalalgia 2003; 23(8): 825-32.
• 49. Pardutz A, Krizbai I, Multon S, Vecsei L, Schoenen J. Systemic nitroglycerin increases nNOS levels in rat trigeminal nucleus caudalis. Neuroreport 2000; 11(14): 3071-5.
• 50. Varga H, Pardutz A, Vamos E, Plangar I, Egyud E, Tajti J, et al. Cox2 inhibitor attenuates NO-induced nNOS in rat caudal trigeminal nucleus. Headache 2007; 47(9): 1319-25.
• 51. Pardutz A, Hoyk Z, Varga H, Vecsei L, Schoenen J. Oestrogenmodulated increase of calmodulin-dependent protein kinase II (CamKII) in rat spinal trigeminal nucleus after systemic nitroglycerin. Cephalalgia 2007; 27(1): 46-53.
• 52. Yin Z, Fang Y, Ren L, Wang X, Zhang A, Lin J, Li X. Atorvastatin attenuates NF-kappaB activation in trigeminal nucleus caudalis in a rat model of migraine. Neurosci Lett 2009; 465(1): 61-5.
• 53. Pradhan AA, Smith ML, McGuire B, Tarash I, Evans CJ, Charles A. Characterization of a novel model of chronic migraine. Pain 2014; 155(2): 269-74.
• 54. Iversen HK, Olesen J, Tfelt-hansen P. Intravenous nitroglycerin as an experimental-model of vascular headache basic characteristics. Pain 1989; 38(1): 17-24.
• 55. Olesen J, Thomsen LL, Iversen H. Nitric oxide is a key molecule in migraine and other vascular headaches. Trends Pharmacol Sci 1994; 15(5): 149-53.
• 56. Capuano A, De Corato A, Lisi L, Tringali G, Navarra P, Dello Russo C. Proinflammatory-activated trigeminal satellite cells promote neuronal sensitization: relevance for migraine pathology. Mol Pain 2009; 5: 43.
• 57. Villalón CM, Olesen J. The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs. Pharmacol Ther 2009; 124(3): 309-23.
• 58. Kuzawińska O, Lis K, Cudna A, Bałkowiec-Iskra E. Gender differences in the neurochemical response of trigeminal ganglion neurons to peripheral inflammation in mice. Acta Neurobiol Exp (Wars) 2014; 74(2): 227-32.
• 59. Ward TN. Migraine diagnosis and pathophysiology. Continuum (Minneap Minn) 2012; 18(4): 753-63.
• 60. Sarrouilhe D, Dejean C, Mesnil M. Involvement of gap junction channels in the pathophysiology of migraine with aura. Front Physiol 2014; 5: 78.
• 61. Ji Y, Murphy AZ, Traub RJ. Estrogen modulates the visceromotor reflex and responses of spinal dorsal horn neurons to colorectal stimulation in the rat. J Neurosci 2003; 23(9): 3908-15.
• 62. Sachs M, Pape HC, Speckmann EJ, Gorji A. The effect of estrogen and progesterone on spreading depression in rat neocortical tissues. Neurobiol Dis 2007; 25(1): 27-34.
• 63. Peroni RN, Orliac ML, Abramoff T, Ribeiro ML, Franchi AM, AdlerGraschinsky E. Participation of CGRP and prostanoids in the sexlinked differences of vascular anandamide effects in mesenteric beds of Sprague-Dawley rats. Eur J Pharmacol 2007; 557(1): 49-57.
• 64. Wrobel Goldberg S, Silberstein SD. Targeting CGRP: A New Era for Migraine Treatment. CNS Drugs 2015; 29(6): 443-52.
• 65. Messlinger K, Lennerz JK, Eberhardt M, Fischer MJ. CGRP and NO in the trigeminal system: mechanisms and role in headache generation. Headache 2012; 52(9): 1411-27.
• 66. Mitsikostas DD, Sanchez del Rio M. Receptor systems mediating cfos expression within trigeminal nucleus caudalis in animal models of migraine. Brain Res Brain Res Rev 2001; 35(1): 20-35.
• 67. Greco R, Tassorelli C, Cappelletti D, Sandrini G, Nappi G. Activation of the transcription factor NF-kappaB in the nucleus trigeminalis caudalis in an animal model of migraine. Neurotoxicology 2005; 26(5): 795-800.
• 68. Zhang X, Kainz V, Zhao J, Strassman AM, Levy D. Vascular extracellular signal-regulated kinase mediates migraine-related sensitization of meningeal nociceptors. Ann Neurol 2013; 73(6): 741-50.
• 69. Chenn A, Walsh CA. Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in beta-catenin overexpressing transgenic mice. Cereb Cortex 2003; 13(6): 599-606.
• 70. Yang J, Zhang X, Wu Y, Zhao B, Liu X, Pan Y, et al. Wnt/β-catenin signaling mediates the seizure-facilitating effect of postischemic reactive astrocytes after pentylenetetrazole-kindling. Glia 2016; 64(6):1083-91.
• 71. Siva A, Murat H. editors, Baş Ağrısı Epidemiyolojisi, İ.Ü. Cerrahpaşa Tıp Fakültesi Sürekli Tıp Eğitimi Etkinlikleri. Baş, Boyun, Bel Ağrıları. Siva A 2002; 30, 9-14.
• 72. Sarrouilhe D, Dejean C, Mesnil M. Involvement of gap junction channels in the pathophysiology of migraine with aura. Front Physiol 2014; 5: 78.
• 73. Banach M, Piskorska B, Czuczwar SJ, Borowicz KK. Nitric oxide, epileptic seizures, and action of antiepileptic drugs. CNS Neurol Disord Drug Targets 2011; 10(7): 808-19.
• 74. Reiss AB, Wirkowski E. Statins in neurological disorders: mechanisms and therapeutic value. ScientificWorldJournal 2009; 9: 1242-59.
• 75. Kampoli AM, Tousoulis D, Tentolouris C, Stefanadis C. Novel agents targeting nitric oxide. Curr Vasc Pharmacol 2012; 10(1): 61-76.
• 76. Banach M, Czuczwar SJ, Borowicz KK. Statins - are they anticonvulsant? Pharmacol Rep 2014; 66(4): 521-8.
• 77. Schmidt HH, Walter U. NO at work. Cell 1994; 78(6): 919-25.
• 78. Rikitake Y, Liao JK. Rho GTPases, statins, and nitric oxide. Circ Res 2005; 97(12): 1232-5.
• 79. Sarrouilhe D, Dejean C, Mesnil M. Involvement of gap junction channels in the pathophysiology of migraine with aura. Front Physiol 2014; 5: 78.
• 80. Yin Z, Fang Y, Ren L, Wang X, Zhang A, Lin J, et al. Atorvastatin attenuates NF-kappaB activation in trigeminal nucleus caudalis in a rat model of migraine. Neurosci Lett 2009; 465(1): 61-5.
• 81. Brandes JL. The influence on migraine: A systematic review. JAMA 2006; 295(15): 1824-30.
• 82. Bereiter DA, Cioffi JL, Bereiter DF. Oestrogen receptorimmunoreactive neurons in the trigeminal sensory system of male and cycling female rats. Arch Oral Biol 2005; 50(11): 971-9.
• 83. Marcus DA. Estrogen and tension-type headache. Curr Pain Headache Rep 2001; 5(5): 449-53.
• 84. Shimomura T, Murakami F, Kotani K, Ikawa S, Kono S. Platelet nitric oxide metabolites in migraine. Cephalalgia 1999; 19(4): 218-22.
• 85. D’Amico D, Ferraris A, Leone M, Catania A, Carlin A, Grazzi I, et al. Increased plasma nitrites in migraine and cluster headache patients in interictal period: basal hyperactivity of L-arginine NO patway? Cephalalgia 2002; 22(1): 33-6.
• 86. Stirparo G, Zicari A, Favilla M, Lipari M, Martelletti M. Linked activation of nitric oxide synthase and cyclooxygenase in peripheral monocytes of asymptomatic mi graine without aura patients. Cephalalgia 2000; 20(2): 100-6.
• 87. Gruber HJ, Bernecker C, Lechner A, Weiss S, Wallner-Blazek M, Meinitzer A, et al. Increased nitric oxide stress is associated with migraine. Cephalalgia 2010; 30(4): 486-92.
• 88. Lucchesi C, Baldacci F, Cafalli M, Chico L, Lo Gerfo A, Bonuccelli U, et al. Evidences of reduced antioxidant activity in patients with chronic migraine and medication-overuse headache. Headache 2015; 55(7): 984-91.
• 89. Berk M, Dean O, Drexhage H, McNeil JJ, Moylan S, O’Neil A, et al. Aspirin: A review of its neurobiological properties and therapeutic potential for mental illness. BMC Med 2013; 11: 74.
• 90. Edvinsson L, Warfvinge K. Recognizing the role of CGRP and CGRP receptors in migraine and its treatment. Cephalalgia 2017; 0(0) 1–8 (333102417736900).