Log in

Riboflavin and Vitamin E Increase Brain Calcium and Antioxidants, and Microsomal Calcium-ATP-ase Values in Rat Headache Models Induced by Glyceryl Trinitrate

  • Published:
The Journal of Membrane Biology Aims and scope Submit manuscript

Abstract

The essential use of riboflavin is the prevention of migraine headaches, although its effect on migraines is considered to be associated with the increased mitochondrial energy metabolism. Oxidative stress is also important in migraine pathophysiology. Vitamin E is a strong antioxidant in nature and its analgesic effect is not completely clear in migraines. The current study aimed to investigate the effects of glyceryl trinitrate (GTN)-sourced exogen nitric oxide (NO), in particular, and also riboflavin and/or vitamin E on involved in the headache model induced via GTN-sourced exogen NO on oxidative stress, total brain calcium levels, and microsomal membrane Ca2+-ATPase levels. GTN infusion is a reliable method to provoke migraine-like headaches in experimental animals and humans. GTN resulted in a significant increase in brain cortex and microsomal lipid peroxidation levels although brain calcium, vitamin A, vitamin C, and vitamin E, and brain microsomal-reduced glutathione (GSH), glutathione peroxidase (GSH-Px), and plasma-membrane Ca2+-ATPase values decreased through GTN. The lipid peroxidation, GSH, vitamin A, β-carotene, vitamin C, and vitamin E, and calcium concentrations, GSH-Px, and the Ca2+-ATPase activities were increased both by riboflavin and vitamin E treatments. Brain calcium and vitamin A concentrations increased through riboflavin only. In conclusion, riboflavin and vitamin E had a protective effect on the GTN-induced brain injury by inhibiting free radical production, regulation of calcium-dependent processes, and supporting the antioxidant redox system. However, the effects of vitamin E on the values seem more important than in riboflavin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

[Ca2+]i :

Intracellular Ca2+

CSD:

Cortical spreading depression

DMSO:

Dimethyl sulfoxide

GSH:

Reduced glutathione

GSH-Px:

Glutathione peroxidase

LP:

Lipid peroxidation

MMCA:

Microsomal membrane Ca2+-ATPase

NO:

Nitric oxide

PMCA:

Plasma-membrane Ca2+-ATPase

ROS:

Reactive oxygen species

VGCC:

Voltage-gated calcium channels

References

  • Akerman S, Williamson DJ, Goadsby PJ (2003) Voltage-dependent calcium channels are involved in neurogenic dural vasodilatation via a presynaptic transmitter release mechanism. Br J Pharmacol 140:558–566

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Amrutkar DV, Ploug KB, Olesen J, Jansen-Olesen I (2011) Role for voltage gated calcium channels in calcitonin gene-related peptide release in the rat trigeminovascular system. Neuroscience 172:510–517

    Article  CAS  PubMed  Google Scholar 

  • Brown GC, Bal-Price A (2003) Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol 27:325–355

    Article  CAS  PubMed  Google Scholar 

  • Burette A, Rockwood JM, Strehler EE, Weinberg RJ (2003) Isoform-specific distribution of the PMCA in the rat brain. J Comp Neurol 467:464–476

    Article  CAS  PubMed  Google Scholar 

  • Calişkan AM, Nazıroğlu M, Uğuz AC, Ovey IS, Sütçü R, Bal R, Calişkan S, Ozcankaya R (2010) Acamprosate modulates alcohol-induced hippocampal NMDA receptors and brain microsomal Ca2+-ATPase but induces oxidative stress in rat. J Membr Biol 237:51–58

    Article  PubMed  Google Scholar 

  • Ceylan BG, Nazıroğlu M, Uğuz AC, Barak C, Erdem B, Yavuz L (2011) Effects of vitamin C and E combination on element and oxidative stress levels in the blood of operative patients under desflurane anesthesia. Biol Trace Elem Res 141(1–3):16–25

    Article  CAS  PubMed  Google Scholar 

  • Colombo B, Saraceno L, Comi G (2014) Riboflavin and migraine: the bridge over troubled mitochondria. Neurol Sci 35(Suppl 1):141–144

    Article  PubMed  Google Scholar 

  • Daiber A, Mader M, Stamm P, Zinßius E, Kröller-Schön S, Oelze M, Münzel T (2013) Oxidative stress and vascular function. Cell Membr Free Radic Res 5:221–231

    Google Scholar 

  • DasEvcimen N, Ulusu NN, Karasu C, Doğru B (2004) Adenosine triphosphatase activity of streptozotocin-induced diabetic rat brain microsomes. Effect of vitamin E. Gen Physiol Biophys 23(3):347–355

    CAS  Google Scholar 

  • Dawson VL (1995) Nitric oxide: role neurotoxicity. Clin Exp Pharmacol Physiol 122:305–308

    Article  Google Scholar 

  • Desai ID (1984) Vitamin E analysis methods for animal tissues. Methods Enzymol 105:138–147

    Article  CAS  PubMed  Google Scholar 

  • Dyatlov VA, Makovetskaıa VV, Leonhardt R, Lawrence DA, Carpenter DO (1998) Vitamin E enhances Ca+2-mediated vulnerability of immature cerebellar granule cells to ischemia. Free Radic Biol Med 25:793–802

    Article  CAS  PubMed  Google Scholar 

  • Eikermann-Haerter K, Ayata C (2010) Cortical spreading depression and migraine. Curr Neurol Neurosci Rep 10:167–173

    Article  PubMed  Google Scholar 

  • Erol I, Alehan F, Aldemir D, Ogus E (2010) Increased vulnerability to oxidative stress in pediatric migraine patients. Pediatr Neurol 43:21–24

    Article  PubMed  Google Scholar 

  • Espino J, Bejarano I, Redondo PC, Rosado JA, Barriga C, Reiter RJ, Pariente JA, Rodríguez AB (2010) Melatonin reduces apoptosis induced by calcium signaling in human leukocytes: evidence for the involvement of mitochondria and Bax activation. J Membr Biol 233:105–118

    Article  CAS  PubMed  Google Scholar 

  • França DS, Souza AL, Almeida KR, Dolabella SS, Martinelli C, Coelho MM (2001) B vitamins induce an antinociceptive effect in the asetic acid and formaldehyde models of nociception in mice. Eur J Pharmacol 421:157–164

    Article  PubMed  Google Scholar 

  • Galagan ME, Mordvintcev PI, Vanin AF (1991) Effect of riboflavin on hypotensive activity of dinitrosyl iron complex with thiosulphate. Eur J Pharmacol 203:325–326

    Article  CAS  PubMed  Google Scholar 

  • Granados-Soto V, Terán-Rosales F, Rocha-González HI, Reyes-García G, Medina-Santillán R, Rodríguez-Silverio J, Flores-Murrieta FJ (2004) Riboflavin reduces hyperalgesia and inflammation but not tactile allodynia in the rat. Eur J Pharmacol 492:35–40

    Article  CAS  PubMed  Google Scholar 

  • Hassan I, Chibber S, Khan AA, Naseem I (2013) Cisplatin-induced neurotoxicity in vivo can be alleviated by riboflavin under photoillumination. Cancer Biother Radiopharm 28:160–168

    Article  CAS  PubMed  Google Scholar 

  • Huang HM, Ou HC, Hsieh SJ (2000) Antioxidants prevent amyloid peptide-induced apoptosis and alteration of calcium homeostasis in cultured cortical neurons. Life Sci 66:1879–1892

    Article  CAS  PubMed  Google Scholar 

  • 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 358:1–11

    Article  CAS  PubMed  Google Scholar 

  • **g J, Aitken PG, Somjen GG (1993) Role of calcium channels in spreading depression in rat hippocampal slices. Brain Res 604:251–259

    Article  CAS  PubMed  Google Scholar 

  • Kovács R, Schuchmann S, Gabriel S, Kann O, Kardos J, Heinemann U (2002) Free radical-mediated cell damage after experimental status epilepticus in hippocampal slice cultures. J Neurophysiol 88:2909–2918

    Article  PubMed  Google Scholar 

  • Kumar VS, Gopalakrishnan A, Naziroğlu M, Rajanikant GK (2014) Calcium ion: the key player in cerebral ischemia. Curr Med Chem 21:2065–2075

    Article  PubMed  Google Scholar 

  • Lawrence RA, Burk RF (1976) Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 71:952–958

    Article  CAS  PubMed  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the folin- phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • Markley HG (2012) CoEnzyme Q10 and riboflavin: the mitochondrial connection. Headache 52(Suppl 2):81–87

    Article  PubMed  Google Scholar 

  • Nazıroğlu M (2007) New molecular mechanisms on the activation of TRPM2 channels by oxidative stress and ADP-ribose. Neurochem Res 32:1990–2001

    Article  PubMed  Google Scholar 

  • Nazıroğlu M, Lückhoff A (2008) Effects of antioxidants on calcium influx through TRPM2 channels in transfected cells activated by hydrogen peroxide. J Neurol Sci 270:152–158

    Article  PubMed  Google Scholar 

  • Nazıroğlu M, Özgül C (2013) Vitamin E modulates oxidative stress and protein kinase C activator (PMA)-induced TRPM2 channel gate in dorsal root ganglion of rats. J Bioenerg Biomembr 45:541–549

    Article  PubMed  Google Scholar 

  • Nazıroğlu M, Yürekli VA (2013) Effects of antiepileptic drugs on antioxidant and oxidant molecular pathways: focus on trace elements. Cell Mol Neurobiol 33:589–599

    Article  PubMed  Google Scholar 

  • Nazıroğlu M, Karaoğlu A, Aksoy AO (2004) Selenium and high dose vitamin E administration protects cisplatin-induced oxidative damage to renal, liver and lens tissues in rats. Toxicology 195:221–230

    Article  PubMed  Google Scholar 

  • Nazıroğlu M, Kutluhan S, Yilmaz M (2008) Selenium and topiramate modulates brain microsomal oxidative stress values, Ca2+-ATPase activity, and EEG records in pentylentetrazol-induced seizures in rats. J Membr Biol 225:39–49

    Article  PubMed  Google Scholar 

  • Nazıroğlu M, Uğuz AC, Koçak A, Bal R (2009) Acetaminophen at different doses protects brain microsomal Ca2+-ATPase and the antioxidant redox system in rats. J Membr Biol 231:57–64

    Article  PubMed  Google Scholar 

  • Nazıroğlu M, Özgül C, Çiğ B, Doğan S, Uğuz AC (2011) Glutathione modulates Ca(2+) influx and oxidative toxicity through TRPM2 channel in rat dorsal root ganglion neurons. J Membr Biol 242:109–118

    Article  PubMed  Google Scholar 

  • Nazıroğlu M, Senol N, Ghazizadeh V, Yürüker V (2014) Neuroprotection Induced by N-acetylcysteine and selenium against traumaticb injury-induced apoptosis and calcium entry in hippocampus of rat. Cell Mol Neurobiol 34:895–903

    Article  PubMed  Google Scholar 

  • Özkaya D, Nazıroğlu M, Armağan A, Demirel A, Köroglu BK, Çolakoğlu N, Kükner A, Sönmez TT (2011) Dietary vitamin C and E modulates oxidative stress induced-kidney and lens injury in diabetic aged male rats through modulating glucose homeostasis and antioxidant systems. Cell Biochem Funct 29:287–293

    Article  PubMed  Google Scholar 

  • Paredes SD, Reiter RJ (2010) Melatonin: hel** cells cope with oxidative disaster. Cell Membr Free Radic Res 2:99–111

    Google Scholar 

  • Placer ZA, Cushman L, Johnson BC (1966) Estimation of products of lipid peroxidation (malonyl dialdehyde) in biological fluids. Anal Biochem 16:359–364

    Article  CAS  PubMed  Google Scholar 

  • Ramachandran R, Bhatt DK, Ploug KB, Olesen J, Jansen-Olesen I, Hay-Schmidt A, Gupta S (2012) A naturalistic glyceryl trinitrate infusion migraine model in the rat. Cephalalgia 32:73–84

    Article  PubMed  Google Scholar 

  • Ramachandran R, Bhatt DK, Ploug KB, Hay-Schmidt A, Jansen-Olesen I, Gupta S, Olesen J (2014) Nitric oxide synthase, calcitonin gene-related peptide and NK-1 receptor mechanisms are involved in GTN-induced neuronal activation. Cephalalgia 34:136–147

    Article  PubMed  Google Scholar 

  • Reuter U, Chiarugi A, Bolay H, Moskowitz MA (2002) Nuclear factor-κ B as a molecular target for migraine therapy. Ann Neurol 51:507–516

    Article  CAS  PubMed  Google Scholar 

  • Sanches SC, Ramalho LN, Mendes-Braz M, Terra VA, Cecchini R, Augusto MJ, Ramalho FS (2014) Riboflavin (vitamin B-2) reduces hepatocellular injury following liver ischaemia and reperfusion in mice. Food Chem Toxicol 67:65–71

    Article  CAS  PubMed  Google Scholar 

  • Sedlak J, Lindsay RHC (1968) Estimation of total, protein bound and non-protein sulfhydryl groups in tissue with Ellmann’ s reagent. Anal Biochem 25:192–205

    Article  CAS  PubMed  Google Scholar 

  • Shatillo A, Koroleva K, Giniatullina R, Naumenko N, Slastnikova AA, Aliev RR, Bart G, Atalay M, Gu C, Khazipov R, Davletov B, Grohn O, Giniatullin R (2013) Cortical spreading depression induces oxidative stress in the trigeminal nociceptive system. Neuroscience 253:341–349

    Article  CAS  PubMed  Google Scholar 

  • Siler-Marsiglio KI, Pan Q, Paiva M, Madorsky I, Khurana NC, Heaton MB (2005) Mitochondrially targeted vitamin E and vitamin E mitigate ethanol-mediated effects on cerebellar granule cell antioxidant defense systems. Brain Res 1052(2):202–211

    Article  CAS  PubMed  Google Scholar 

  • Suzuki J, Katoh N (1990) A simple and cheap method for measuring vitamin A in cattle using only a spectrophotometer. Jpn J Vet Sci 52:1282–1284

    Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Chambers G, Cottrell JE, Kass IS (2001) Differential fall in ATP accounts for effects of temperature on hypoxic damage in rat hippocampal slices. J Neurophysiol 83:3462–3471

    Google Scholar 

  • **e Y, Zhong C, Zeng M, Guan L, Luo L (2013) Effect of hexavalent chromium on electron leakage of respiratory chain in mitochondria isolated from rat liver. Cell Physiol Biochem 31(2–3):473–485

    Article  CAS  PubMed  Google Scholar 

  • Yan J, Dussor G (2014) Ion channels and migraine. Headache 54:619–639

    Article  PubMed Central  PubMed  Google Scholar 

  • Yilmaz N, Aydin O, Yegin A, Tiltak A, Eren E (2011) Increased levels of total oxidant status and decreased activity of arylesterase in migraineurs. Clin Biochem 44:832–837

    Article  CAS  PubMed  Google Scholar 

  • Yürekli VA, Nazıroğlu M (2013) Selenium and topiramate attenuates blood oxidative toxicity in patients with epilepsy: a clinical pilot study. Biol Trace Elem Res 152:180–186

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The study was partially supported by the Scientific Research Project Unit of Suleyman Demirel University (BAP-1595-TU-07).

Conflict interest

None of the authors have any conflicts to disclose. All authors approved the final manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mustafa Nazıroğlu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bütün, A., Nazıroğlu, M., Demirci, S. et al. Riboflavin and Vitamin E Increase Brain Calcium and Antioxidants, and Microsomal Calcium-ATP-ase Values in Rat Headache Models Induced by Glyceryl Trinitrate. J Membrane Biol 248, 205–213 (2015). https://doi.org/10.1007/s00232-014-9758-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00232-014-9758-5

Keywords

Navigation