Regulatory role of phospholipase A2 inhibitor in oxidative stress and inflammation induced by an experimental mouse migraine model

Abstract

Migraine is a complex neurological problem whose primary symptom is headache and is common in the human population. It is well known that neuroinflammation plays a vital role in the pathogenesis of migraine, with adverse effects on the nervous system, including headache disorders such as migraine. The infusion of the nitric oxide donor glyceryl trinitrate (GTN) is often used in experimental models of migraine because it is the best-known model of migraine provocation. N-(p-amyl cinnamoyl) anthranilic acid (ACA) has been shown to inhibit both TRPM2 and phospholipase A2 (PLA2). Recent research has explored potential interventions to mitigate GTN-induced neurotoxicity. One such candidate is ACA, a compound with anti-inflammatory and antioxidant properties. Thirty-six C57BL/6j black mice were divided into the control groups of ACA, GTN, and ACA+GTN. Mice in the ACA were treated intraperitoneally with ACA (25 mg/kg) for three days. Mice in the GTN were treated intraperitoneally with a single dose of GTN (10 mg/kg) for migraine induction. After the experimental stages were completed, the mice in all groups were sacrificed, and brain tissue and erythrocyte samples were taken from the mice. The levels of inflammatory cytokines (TNF α, IL 1β, and IL 6), apoptosis, intracellular ROS, lipid peroxidation, caspase 3-9, and mitochondrial membrane potential increased in the GTN group. However, their levels were decreased in the ACA+GTN group by the injection of ACA. The treatment of ACA regulated the GTN treatment-induced decreases of glutathione levels, glutathione peroxidase activation, and cell viability in the brain and erythrocytes. In conclusion, GTN plays a role in neurotoxicity caused by increased apoptosis and ROS. We observed that ACA modulated the brain and erythrocyte oxidant, antioxidant parameters, and apoptotic processes. The neuro-protective role of ACA treatment may be explained by its modulating activity against increased apoptosis and oxidative stress.

Keywords

• Apoptosis
• Brain
• Glutathione
• Glyceryl trinitrate
• Inflammatory cytokines

References

1. Abushik PA, Niittykoski M, Giniatullina R, Shakirzyanova A, Bart G, Fayuk D, Sibarov DA, Antonov SM. (2014). The role of NMDA and mGluR5 receptors in calcium mobilization and neurotoxicity of homocysteine in trigeminal and cortical neurons and glial cells. J Neurochem 129(2):264–274. https://doi.org/10. 1111/jnc.12615
2. Aguilar-Shea AL, Membrilla Md JA, Diaz-de-Teran J. (2022). Migraine review for general practice. Aten Primaria. Feb;54(2):102208. https://doi.org/10.1016/j.aprim.2021.102208
3. Amin FM, Aristeidou S, Baraldi C, Czapinska-Ciepiela EK, Ariadni DD, Di Lenola D, Fenech C, Kampouris K, Karagiorgis G, Braschinsky M, Linde M; European Headache Federation School of Advanced Studies (EHF-SAS). (2018). The association between migraine and physical exercise. J Headache Pain. 10;19(1):83. https://doi.org/10.1186/s10194-018-0902-y
4. Argun M, Tök L, Uğuz AC, Çelik Ö, Tök ÖY, Naziroğlu M. (2014). Melatonin and amfenac modulate calcium entry, apoptosis, and oxidative stress in ARPE-19 cell culture exposed to blue light irradiation (405 nm). Eye (Lond) 28:752–760. https://doi.org/10.1038/eye.2014.50
5. Ashina M, Hansen JM, Olesen J. (2013). Pearls and pitfalls in human pharmacological models of migraine: 30 years' experience. Cephalalgia. 33(8):540-53. https://doi.org/10.1177/0333102412475234
6. Bruno PP, Carpino F, Carpino G, Zicari A. (2007). An overview on immune system and migraine. Eur Rev Med Pharmacol Sci. 11(4):245-8. PMID: 17876959.
7. Bütün A, Nazıroğlu M, Demirci S, Çelik Ö, Uğuz AC. (2015). Riboflavin and vitamin E increase brain calcium and antioxidants, and microsomal calcium-ATP-ase values in rat headache models induced by glyceryl trinitrate. J Membr Biol. 248(2):205-13. https://doi.org/10.1007/s00232-014-9758-5
8. Cakir M, Duzova H, Tekin S, Taslıdere E, Kaya GB, Cigremis Y, Ozgocer T, Yologlu S. (2017). ACA, an inhibitor phospholipases A2 and transient receptor potential melastatin-2 channels, attenuates okadaic acid induced neurodegeneration in rats. Life Sci. 1;176:10-20. https://doi.org/10.1016/j.lfs.2017.03.022

9. Çakır M, Tekin S, Taşlıdere A, Çakan P, Düzova H, Gül CC. (2019). Protective effect of N-(p-amylcinnamoyl) anthranilic acid, phospholipase A2 enzyme inhibitor, and transient receptor potential melastatin-2 channel blocker against renal ischemia-reperfusion injury. J Cell Biochem. 120(3):3822-3832. https://doi.org/10.1002/jcb.27664
10. Fila M, Jablkowska A, Pawlowska E, Blasiak J. (2023). DNA Damage and Repair in Migraine: Oxidative Stress and Beyond. Neuroscientist. 29(3):277-286. https://doi.org/10.1177/10738584221090836
11. Filippone A, Scuderi SA, Basilotta R, Lanza M, Casili G, Bova V, Paterniti I, Esposito E. (2022). BAY-117082-driven NLRP3 inflammasome inhibition resolves nitro-glycerine (NTG) neuronal damage in in vivo model of migraine. Biomed Pharmacother. 156:113851. https://doi.org/10.1016/j.biopha.2022.113851
12. Gao J, Cheng Z, Jiang S, Wills M, Wehbe A, Rajah GB, Geng X, Ding Y. (2022). Arterial Glyceryl Trinitrate in Acute Ischemic Stroke after Thrombectomy for Neuroprotection (AGAIN): Rationale, design and protocol for a prospective randomized controlled trial. BMC Geriatr. 17;22(1):804. https://doi.org/10.1186/s12877-022-03506-5
13. Greco R., Demartini C., Zanaboni A.M., Redavide E., Pampalone S., Toldi J., Fülöp F., Blandini F., Nappi G., Sandrini G. (2017). Effects of kynurenic acid analogue 1 (KYNA-A1) in nitroglycerin-induced hyperalgesia: Targets and anti-migraine mechanisms. Cephalalgia. 37:1272–1284. https://doi.org/10.1177/0333102416678000
14. Gross EC, Putananickal N, Orsini AL, Vogt DR, Sandor PS, Schoenen J, Fischer D. (2021). Mitochondrial function and oxidative stress markers in higher-frequency episodic migraine. Sci Rep. 25;11(1):4543. https://doi.org/10.1038/s41598-021-84102-2
15. Harteneck C, Frenzel H, Kraft R. (2007). N-(p-amylcinnamoyl)anthranilic acid (ACA): a phospholipase A(2) inhibitor and TRP channel blocker. Cardiovasc Drug Rev. 25(1):61-75. https://doi.org/10.1111/j.1527-3466.2007.00005.x
16. Hou M, Tang Q, Xue Q, Zhang X, Liu Y, Yang S, Chen L, Xu X. (2017). Pharmacodynamic action and mechanism of Du Liang soft capsule, a traditional Chinese medicine capsule, on treating nitroglycerin-induced migraine. J Ethnopharmacol. 4;195:231-237. https://doi.org/10.1016/j.jep
17. Ishii M, Iizuka R, Kiuchi Y, Mori Y, Shimizu S. (2011). Neuroprotection by lomerizine, a prophylactic drug for migraine, against hydrogen peroxide-induced hippocampal neurotoxicity. Mol Cell Biochem 358(1 2):1–11. https://doi.org/10.1007/s11010-011-0913-3
18. Islam MT. (2017). Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. Neurol Res. 39(1):73-82. https://doi.org/10.1080/01616412.2016.1251711
19. Joshi DC, Bakowska JC. (2011). Determination of mitochondrial membrane potential and reactive oxygen species in live rat cortical neurons. J Vis Exp 23(51):2704. https://doi.org/10.3791/2704
20. Kayan M, Nazıroğlu M, Ovey IS, Aykur M, Uğuz AC, Yürekli VA. (2012). Non-ionic contrast media induces oxidative stress and apoptosis through Ca²⁺ influx in human neutrophils. J Membr Biol. 245(12):833-40. https://doi.org/10.1007/s00232-012-9491-x
21. Keil VC, Funke F, Zeug A, Schild D, Müller M. (2011). Ratiometric high-resolution imaging of JC-1 fluorescence reveals the subcellular heterogeneity of astrocytic mitochondria. Pflugers Arch 462:693–708. https://doi.org/10.1007/s00424-011-1012-8
22. Kursun O, Yemisci M, van den Maagdenberg AMJM, Karatas H. (2021). Migraine and neuroinflammation: the inflammasome perspective. J Headache Pain. 10;22(1):55. https://doi.org/10.1186/s10194-021-01271-1 Lama A, Pirozzi C, Severi I, Morgese MG, Senzacqua M, Annunziata C, Comella F, Del Piano F, Schiavone S, Petrosino S, Mollica MP, Diano S, Trabace L, Calignano A, Giordano A, Mattace Raso G, Meli R. (2022). Palmitoylethanolamide dampens neuroinflammation and anxiety-like behavior in obese mice. Brain Behav Immun. 102:110-123. https://doi.org/10.1016/j.bbi.2022.02.008
23. Lee M, Cho T, Jantaratnotai N, Wang YT, McGeer E, McGeer PL. (2010). Depletion of GSH in glial cells induces neurotoxicity: relevance to aging and degenerative neurological diseases. FASEB J 24(7):2533–2545. https://doi.org/10.1096/f.09-149997
24. Li X, Jiang LH. (2019). A critical role of the transient receptor potential melastatin 2 channel in a positive feedback mechanism for reactive oxygen species-induced delayed cell death. J Cell Physiol 234(4):3647–3660. https://doi.org/10.1002/jcp.27134
25. Maniskas ME, Roberts JM, Trueman R, Learoyd AE, Gorman A, Fraser JF, Bix GJ. (2018). Intra-arterial nitroglycerin as directed acute treatment in experimental ischemic stroke. J Neurointerv Surg. 10(1):29–33. https://doi.org/10.1136/neurintsurg-2016-012793
26. Marone IM, De Logu F, Nassini R, De Carvalho GM, Benemei S, Ferreira J, Jain P. (2018). TRPA1/NOX in the soma of trigeminal ganglion neurons mediates migraine-related pain of glyceryl trinitrate in mice. Brain 141(8):2312–2328. https://doi.org/10.1093/brain/awy177
27. Nazıroğlu M. (2012). Molecular role of catalase on oxidative stress-induced Ca(2+) signaling and TRP cation channel activation in nervous system. J Recept Signal Transduct Res. 32(3):134-141. https://doi.org/10.3109/10799893.2012.672994
28. Nazıroğlu M, Çelik Ö, Uğuz AC, Bütün A. (2015). Protective efects of ribofavin and selenium on brain microsomal Ca2+- ATPase and oxidative damage caused by glyceryl trinitrate in a rat headache model. Biol Trace Elem Res 164(1):72–79. https://doi.org/10.1007/s12011-014-0199-x
29. Norden D.M., Trojanowski P.J., Villanueva E., Navarro E., Godbout J.P. (2016). Sequential activation of microglia and astrocyte cytokine expression precedes increased Iba-1 or GFAP immunoreactivity following systemic immune challenge. Glia. 64:300–316. https://doi.org/10.1002/glia.22930
30. Owen RN, Semanchik PL, Latham CM, Brennan KM, White-Springer SH. (2022). Elevated dietary selenium rescues mitochondrial capacity impairment induced by decreased vitamin E intake in young exercising horses. J Anim Sci. 1;100(8):skac172. https://doi.org/10.1093/jas/skac172
31. Özgül C, Nazıroğlu M. (2012). TRPM2 channel protective properties of N-acetylcysteine on cytosolic glutathione depletion dependent oxidative stress and Ca2+ infux in rat dorsal root ganglion. Physiol Behav 106(2):122–128. https://doi.org/10.1016/j. physbeh.2012.01.014
32. Park HJ, Kwak M, Baek SH. (2020). Neuroprotective efects of Dendropanax morbifera leaves on glutamate-induced oxidative cell death in HT22 mouse hippocampal neuronal cells. J Ethnopharmacol 251:112518. https://doi.org/10.1016/j.jep.201
33. Perini F, D'Andrea G, Galloni E, Pignatelli F, Billo G, Alba S, Bussone G, Toso V. (2005). Plasma cytokine levels in migraineurs and controls. Headache. 45(7):926–931. https://doi.org/10.1111/j.1526-4610.2005.05135.x
34. Reuter U., Bolay H., Jansen-Olesen I., Chiarugi A., Sanchez del Rio M., Letourneau R., Theoharides T.C., Waeber C., Moskowitz M.A. (2001). Delayed inflammation in rat meninges: Implications for migraine pathophysiology. Brain. 124:2490–2502. https://doi.org/10.1093/brain/124.12.2490
35. Su XT, Wang L, Ma SM, Cao Y, Yang NN, Lin LL, Fisher M, Yang JW, Liu CZ. (2020). Mechanisms of Acupuncture in the Regulation of Oxidative Stress in Treating Ischemic Stroke. Oxid Med Cell Longev. 24;2020:7875396. https://doi.org/10.1155/2020/7875396
36. Sun, G.Y., Shelat, P.B., Jensen, M.B. (2010). Phospholipases A2 and Inflammatory Responses in the Central Nervous System. Neuromol Med 12, 133–148. https://doi.org/10.1007/s12017-009-8092-z
37. Togha M, Razeghi Jahromi S, Ghorbani Z, Ghaemi A, Rafee P. (2019). An investigation of oxidant/antioxidant balance in patients with migraine: a case-control study. BMC Neurol 19(1):323. https://doi.org/10.1186/s12883-019-1555-4
38. Tripathi GM, Kalita J, Misra UK. (2018). A study of oxidative stress in migraine with special reference to prophylactic therapy. Int J Neurosci. 128(4):318-324. https://doi.org/10.1080/00207454.2017.1374959 Ureshino RP, Erustes AG, Bassani TB, Wachilewski P, Guarache GC, Nascimento AC, Costa AJ, Smaili SS, Pereira GJDS. (2019). The Interplay between Ca(2+) signaling pathways and neurodegeneration. Int J Mol Sci. 20(23): pii: E6004. https://doi.org/10.3390/ijms20236004
39. Vurucu S, Karaoglu A, Paksu MS, Yesilyurt O, Oz O, Unay B, Akin R. (2013). Relationship between oxidative stress and chronic daily headache in children. Hum Exp Toxicol 32:113–119 https://doi.org/10.1177/0960327112459204
40. Wang F., He Q., Ren Z., Li F., Chen W., Lin X., Zhang H., Tai G. (2015). Association of serum levels of intercellular adhesion molecule-1 and interleukin-6 with migraine. Neurol. Sci. 36:535–540. https://doi.org/10.1007/s10072-014-2010-3
41. Wang Y, Shan Z, Zhang L, Fan S, Zhou Y, Hu L, Wang Y, Li W, Xiao Z. (2022). P2X7R/NLRP3 signaling pathway-mediated pyroptosis and neuroinflammation contributed to cognitive impairment in a mouse model of migraine. J Headache Pain. 2;23(1):75. https://doi.org/10.1186/s10194-022-01442-8
42. Yamanaka G, Suzuki S, Morishita N, Takeshita M, Kanou K, Takamatsu T, Suzuki S, Morichi S, Watanabe Y, Ishida Y, Go S, Oana S, Kashiwagi Y, Kawashima H. (2021). Role of Neuroinflammation and Blood-Brain Barrier Permutability on Migraine. Int J Mol Sci. 19;22(16):8929. https://doi.org/10.3390/ijms22168929
43. Yazğan, B. & Yazğan, Y. (2022). Potent antioxidant alpha lipoic acid reduces STZ-induced oxidative stress and apoptosis levels in the erythrocytes and brain cells of diabetic rats. Journal of Cellular Neuroscience and Oxidative Stress , 14 (2) , 1085-1094 . https://doi.org/10.37212/jcnos.1245152
44. Yazğan, B., Yazğan, Y. & Nazıroğlu, M. (2023). Alpha-lipoic acid modulates the diabetes mellitus-mediated neuropathic pain via inhibition of the TRPV1 channel, apoptosis, and oxidative stress in rats. J Bioenerg Biomembr 55, 179–193. https://doi.org/10.1007/s10863-023-09971-w
45. Yazğan, Y., Nazıroğlu, M. (2021). Involvement of TRPM2 in the Neurobiology of Experimental Migraine: Focus on Oxidative Stress and Apoptosis. Mol Neurobiol 58, 5581–5601. https://doi.org/10.1007/s12035-021-02503-w
46. Yıldızhan K, Nazıroğlu M. (2020). Glutathione depletion and parkinsonian neurotoxin MPP+-induced TRPM2 channel activation play central roles in oxidative cytotoxicity and inflammation in microglia. Mol Neurobiol 57(8):3508–3525. https://doi.org/10.1007/s12035-020-01974-7
47. Yücel M., Kotan D., Gurol Çiftçi G., Çiftçi I.H., Cikriklar H.I. (2016). Serum levels of endocan, claudin-5 and cytokines in migraine. Eur. Rev. Med. Pharmacol. Sci. 20:930–936. PMID: 27010153.
48. Zhang B, Wang PP, Hu KL, Li LN, Yu X, Lu Y, Chang HS. (2019). Antidepressant-Like Effect and Mechanism of Action of Honokiol on the Mouse Lipopolysaccharide (LPS) Depression Model. Molecules. 28;24(11):2035. https://doi.org/10.3390/molecules24112035