Skip to main content
Top
Published in: The Journal of Headache and Pain 1/2015

Open Access 01-12-2016 | Research article

Valproate ameliorates nitroglycerin-induced migraine in trigeminal nucleus caudalis in rats through inhibition of NF-кB

Authors: Yuanchao Li, Qin Zhang, Dandan Qi, Li Zhang, Lian Yi, Qianqian Li, Zhongling Zhang

Published in: The Journal of Headache and Pain | Issue 1/2015

Login to get access

Abstract

Background

As a complex nervous system disease, migraine causes severe healthy and social issues worldwide. Valproate (VPA) is a widely used treatment agent against seizures and bipolar disorder, and its function to alleviate damage due to migraine has also been verified in clinical investigations. However, the mechanism underlying the protective effect of VPA against migraine remains poorly revealed. In the current study, the major purpose was to uncover the mechanism which drove VPA to antagonize migraine.

Methods

Nitroglycerin (NTG) was employed to induce a migraine model in rats and the migraine animals were exposed to treatment of VPA of different doses. Thereafter, the levels of indicators related to oxidative stress were measured and used to evaluate the anti-oxidant potential of VPA. The expression of calcitonin gene-related peptide (CGRP) and c-Fos was also quantified with ELISA and immunohistochemistry, respectively. Western blotting and electrophoretic mobility shift assays (EMSA) were conducted to explore the effect of VPA treatment on NF-кB pathway.

Results

NTG induced the activation of oxidative stress and led to migraine in model animals, but pre-treatment with VPA attenuated the damage due to migraine attack in brain tissues. The level of lipid peroxidation was significantly reduced while the prodcution of anti-oxidant factors was restored. Furthermore, expressions of CGRP and c-Fos, which represented the neuronal activation, were also down-regulated by VPA. The results of western blotting and EMSA demonstrated that the above mentioned effect of VPA acted through the inhibition of NF-кB pathway.

Conclusions

Although controversies on the effect of VPA on NF-кB pathway existed, our study revealed an alternative mechanism of VPA in protecting against migraine, which would promote the development of therapeutic strategies of migraine.
Literature
1.
go back to reference Schurks M, Diener HC, Goadsby P (2008) Update on the prophylaxis of migraine. Curr Treat Option Ne 10(1):20–29CrossRef Schurks M, Diener HC, Goadsby P (2008) Update on the prophylaxis of migraine. Curr Treat Option Ne 10(1):20–29CrossRef
2.
go back to reference Welch KM, Goadsby PJ (2002) Chronic daily headache: nosology and pathophysiology. Curr Opin Neurol 15(3):287–295CrossRefPubMed Welch KM, Goadsby PJ (2002) Chronic daily headache: nosology and pathophysiology. Curr Opin Neurol 15(3):287–295CrossRefPubMed
3.
go back to reference Neeb L, Reuter U (2007) Nitric oxide in migraine. CNS Neurol Disord-Dr drug targets 6(4):258–264CrossRef Neeb L, Reuter U (2007) Nitric oxide in migraine. CNS Neurol Disord-Dr drug targets 6(4):258–264CrossRef
4.
go back to reference Sarchielli P, Alberti A, Russo S, Codini M, Panico R, Floridi A, Gallai V (1999) Nitric oxide pathway, Ca2+, and serotonin content in platelets from patients suffering from chronic daily headache. Cephalalgia 19(9):810–816CrossRefPubMed Sarchielli P, Alberti A, Russo S, Codini M, Panico R, Floridi A, Gallai V (1999) Nitric oxide pathway, Ca2+, and serotonin content in platelets from patients suffering from chronic daily headache. Cephalalgia 19(9):810–816CrossRefPubMed
5.
go back to reference Stepien A, Chalimoniuk M (1998) Level of nitric oxide-dependent cGMP in patients with migraine. Cephalalgia 18(9):631–634CrossRefPubMed Stepien A, Chalimoniuk M (1998) Level of nitric oxide-dependent cGMP in patients with migraine. Cephalalgia 18(9):631–634CrossRefPubMed
6.
go back to reference Olesen J (2008) The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Therapeut 120(2):157–171CrossRef Olesen J (2008) The role of nitric oxide (NO) in migraine, tension-type headache and cluster headache. Pharmacol Therapeut 120(2):157–171CrossRef
7.
go back to reference Tassorelli C, Greco R, Morazzoni P, Riva A, Sandrini G, Nappi G (2005) Parthenolide is the component of tanacetum parthenium that inhibits nitroglycerin‐induced Fos activation: studies in an animal model of migraine. Cephalalgia 25(8):612–621CrossRefPubMed Tassorelli C, Greco R, Morazzoni P, Riva A, Sandrini G, Nappi G (2005) Parthenolide is the component of tanacetum parthenium that inhibits nitroglycerin‐induced Fos activation: studies in an animal model of migraine. Cephalalgia 25(8):612–621CrossRefPubMed
8.
go back to reference Knyihar-Csillik E, Toldi J, Mihaly A, Krisztin-Peva B, Chadaide Z, Nemeth H, Fenyo R, Vecsei L (2007) 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) 114(4):417–421. doi:10.1007/s00702-006-0545-z CrossRef Knyihar-Csillik E, Toldi J, Mihaly A, Krisztin-Peva B, Chadaide Z, Nemeth H, Fenyo R, Vecsei L (2007) 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) 114(4):417–421. doi:10.​1007/​s00702-006-0545-z CrossRef
11.
go back to reference Yin Z, Fang Y, Ren L, Wang X, Zhang A, Lin J, Li X (2009) Atorvastatin attenuates NF-κB activation in trigeminal nucleus caudalis in a rat model of migraine. Neurosci Lett 465(1):61–65CrossRefPubMed Yin Z, Fang Y, Ren L, Wang X, Zhang A, Lin J, Li X (2009) Atorvastatin attenuates NF-κB activation in trigeminal nucleus caudalis in a rat model of migraine. Neurosci Lett 465(1):61–65CrossRefPubMed
12.
go back to reference Linde M, Mulleners WM, Chronicle EP, McCrory DC (2013) Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults. Cochrane DB Syst Rev 6:CD010611. doi:10.1002/14651858.CD010611 Linde M, Mulleners WM, Chronicle EP, McCrory DC (2013) Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults. Cochrane DB Syst Rev 6:CD010611. doi:10.​1002/​14651858.​CD010611
13.
go back to reference Chen PS, Peng GS, Li G, Yang S, Wu X, Wang CC, Wilson B, Lu RB, Gean PW, Chuang DM, Hong JS (2006) Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatr 11(12):1116–1125. doi:10.1038/sj.mp.4001893 CrossRef Chen PS, Peng GS, Li G, Yang S, Wu X, Wang CC, Wilson B, Lu RB, Gean PW, Chuang DM, Hong JS (2006) Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol Psychiatr 11(12):1116–1125. doi:10.​1038/​sj.​mp.​4001893 CrossRef
14.
go back to reference Feng HL, Leng Y, Ma CH, Zhang J, Ren M, Chuang DM (2008) Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 155(3):567–572CrossRefPubMedPubMedCentral Feng HL, Leng Y, Ma CH, Zhang J, Ren M, Chuang DM (2008) Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 155(3):567–572CrossRefPubMedPubMedCentral
15.
go back to reference Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM (2007) Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp The 321(3):892–901. doi:10.1124/jpet.107.120188 CrossRef Kim HJ, Rowe M, Ren M, Hong JS, Chen PS, Chuang DM (2007) Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: multiple mechanisms of action. J Pharmacol Exp The 321(3):892–901. doi:10.​1124/​jpet.​107.​120188 CrossRef
16.
go back to reference Qing H, He G, Ly PT, Fox CJ, Staufenbiel M, Cai F, Zhang Z, Wei S, Sun X, Chen CH, Zhou W, Wang K, Song W (2008) Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models. J Exp Med 205(12):2781–2789. doi:10.1084/jem.20081588 CrossRefPubMedPubMedCentral Qing H, He G, Ly PT, Fox CJ, Staufenbiel M, Cai F, Zhang Z, Wei S, Sun X, Chen CH, Zhou W, Wang K, Song W (2008) Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models. J Exp Med 205(12):2781–2789. doi:10.​1084/​jem.​20081588 CrossRefPubMedPubMedCentral
17.
go back to reference Pardutz A, Hoyk Z, Varga H, Vecsei L, Schoenen J (2007) Oestrogen‐modulated increase of calmodulin‐dependent protein kinase II (CamKII) in rat spinal trigeminal nucleus after systemic nitroglycerin. Cephalalgia 27(1):46–53CrossRefPubMed Pardutz A, Hoyk Z, Varga H, Vecsei L, Schoenen J (2007) Oestrogen‐modulated increase of calmodulin‐dependent protein kinase II (CamKII) in rat spinal trigeminal nucleus after systemic nitroglycerin. Cephalalgia 27(1):46–53CrossRefPubMed
18.
go back to reference Varga H, Pardutz A, Vamos E, Bohar Z, Bago F, Tajti J, Bari F, Vecsei L (2009) Selective inhibition of cyclooxygenase-2 attenuates nitroglycerin-induced calmodulin-dependent protein kinase II alpha in rat trigeminal nucleus caudalis. Neurosci Lett 451(2):170–173CrossRefPubMed Varga H, Pardutz A, Vamos E, Bohar Z, Bago F, Tajti J, Bari F, Vecsei L (2009) Selective inhibition of cyclooxygenase-2 attenuates nitroglycerin-induced calmodulin-dependent protein kinase II alpha in rat trigeminal nucleus caudalis. Neurosci Lett 451(2):170–173CrossRefPubMed
19.
go back to reference Reuter U, Bolay H, Jansen-Olesen I, Chiarugi A, Sanchez del Rio M, Letourneau R, Theoharides TC, Waeber C, Moskowitz MA (2001) Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 124(Pt 12):2490–2502CrossRefPubMed Reuter U, Bolay H, Jansen-Olesen I, Chiarugi A, Sanchez del Rio M, Letourneau R, Theoharides TC, Waeber C, Moskowitz MA (2001) Delayed inflammation in rat meninges: implications for migraine pathophysiology. Brain 124(Pt 12):2490–2502CrossRefPubMed
21.
go back to reference Messlinger K, Lennerz JK, Eberhardt M, Fischer MJM (2012) CGRP and NO in the trigeminal system: mechanisms and role in headache generation. Headache 52(9):1411–1427CrossRefPubMed Messlinger K, Lennerz JK, Eberhardt M, Fischer MJM (2012) CGRP and NO in the trigeminal system: mechanisms and role in headache generation. Headache 52(9):1411–1427CrossRefPubMed
22.
go back to reference Placer ZA, Cushman L, Johnson BC (1966) Estimation of products of lipid peroxidation (malonyl dialdehyde) in biological fluids. Anal Biochem 16:359–364 Placer ZA, Cushman L, Johnson BC (1966) Estimation of products of lipid peroxidation (malonyl dialdehyde) in biological fluids. Anal Biochem 16:359–364
23.
go back to reference Desai ID (1984) Vitamin E analysis methods for animal tissues. Method Enzymol 105:138–147CrossRef Desai ID (1984) Vitamin E analysis methods for animal tissues. Method Enzymol 105:138–147CrossRef
24.
go back to reference Suzuki J, Katoh N (1990) A simple and cheap method for measuring vitamin A in cattle using only a spectrophotometer. The Japanese Journal of Veterinary Science 52:1282–1284 Suzuki J, Katoh N (1990) A simple and cheap method for measuring vitamin A in cattle using only a spectrophotometer. The Japanese Journal of Veterinary Science 52:1282–1284
25.
go back to reference Jagota SK, Dani HM (1982) A new colorimetric technique for the estimation of vitamin C using Folin phenol reagent. Anal Biochem 127(1):178–182CrossRefPubMed Jagota SK, Dani HM (1982) A new colorimetric technique for the estimation of vitamin C using Folin phenol reagent. Anal Biochem 127(1):178–182CrossRefPubMed
26.
go back to reference Fehrenbacher JC, Taylor CP, Vasko MR (2003) Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain 105(1-2):133–141CrossRefPubMed Fehrenbacher JC, Taylor CP, Vasko MR (2003) Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain 105(1-2):133–141CrossRefPubMed
27.
go back to reference Offenhauser N, Zinck T, Hoffmann J, Schiemann K, Schuh‐Hofer S, Rohde W, Arnold G, Dirnagl U, Jansen‐Olesen I, Reuter U (2005) CGRP release and c‐fos expression within trigeminal nucleus caudalis of the rat following glyceryltrinitrate infusion. Cephalalgia 25(3):225–236CrossRefPubMed Offenhauser N, Zinck T, Hoffmann J, Schiemann K, Schuh‐Hofer S, Rohde W, Arnold G, Dirnagl U, Jansen‐Olesen I, Reuter U (2005) CGRP release and c‐fos expression within trigeminal nucleus caudalis of the rat following glyceryltrinitrate infusion. Cephalalgia 25(3):225–236CrossRefPubMed
28.
go back to reference Team RC (2014) R (2012) A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0 Team RC (2014) R (2012) A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0
29.
go back to reference Moskowitz MA (1992) Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol Sci 13(8):307–311CrossRefPubMed Moskowitz MA (1992) Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol Sci 13(8):307–311CrossRefPubMed
33.
go back to reference Varoglu AO, Yildirim A, Aygul R, Gundogdu OL, Sahin YN (2010) Effects of valproate, carbamazepine, and levetiracetam on the antioxidant and oxidant systems in epileptic patients and their clinical importance. Clin neuropharmacol 33(3):155–157CrossRefPubMed Varoglu AO, Yildirim A, Aygul R, Gundogdu OL, Sahin YN (2010) Effects of valproate, carbamazepine, and levetiracetam on the antioxidant and oxidant systems in epileptic patients and their clinical importance. Clin neuropharmacol 33(3):155–157CrossRefPubMed
34.
go back to reference Wang JF, Azzam JE, Young LT (2003) Valproate inhibits oxidative damage to lipid and protein in primary cultured rat cerebrocortical cells. Neuroscience 116(2):485–489CrossRefPubMed Wang JF, Azzam JE, Young LT (2003) Valproate inhibits oxidative damage to lipid and protein in primary cultured rat cerebrocortical cells. Neuroscience 116(2):485–489CrossRefPubMed
35.
go back to reference Zhang YJ, Zhang M, Wang XC, Yu YH, Jin PJ, Wang Y (2011) Effects of sodium valproate on neutrophils’ oxidative metabolism and oxidant status in children with idiopathic epilepsy. Zhonghua er ke za zhi Chinese Journal of pediatrics 49(10):776–781PubMed Zhang YJ, Zhang M, Wang XC, Yu YH, Jin PJ, Wang Y (2011) Effects of sodium valproate on neutrophils’ oxidative metabolism and oxidant status in children with idiopathic epilepsy. Zhonghua er ke za zhi Chinese Journal of pediatrics 49(10):776–781PubMed
36.
go back to reference Taylor CP, Angelotti T, Fauman E (2007) Pharmacology and mechanism of action of pregabalin: the calcium channel α 2–δ (alpha 2–delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res 73(2):137–150CrossRefPubMed Taylor CP, Angelotti T, Fauman E (2007) Pharmacology and mechanism of action of pregabalin: the calcium channel α 2–δ (alpha 2–delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res 73(2):137–150CrossRefPubMed
38.
go back to reference Cutrer FM, Limmroth V, Ayata G, Moskowitz MA (1995) Attenuation by valproate of c-fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin. Brit J Pharmacol 116(8):3199–3204CrossRef Cutrer FM, Limmroth V, Ayata G, Moskowitz MA (1995) Attenuation by valproate of c-fos immunoreactivity in trigeminal nucleus caudalis induced by intracisternal capsaicin. Brit J Pharmacol 116(8):3199–3204CrossRef
39.
40.
41.
42.
go back to reference Cutrer FM, Limmroth V, Moskowitz MA (1997) Possible mechanisms of valproate in migraine prophylaxis. Cephalalgia 17(2):93–100CrossRefPubMed Cutrer FM, Limmroth V, Moskowitz MA (1997) Possible mechanisms of valproate in migraine prophylaxis. Cephalalgia 17(2):93–100CrossRefPubMed
43.
go back to reference Morgan JI, Cohen DR, Hempstead JL, Curran T (1987) Mapping patterns of c-fos expression in the central nervous system after seizure. Science 237(4811):192–197CrossRefPubMed Morgan JI, Cohen DR, Hempstead JL, Curran T (1987) Mapping patterns of c-fos expression in the central nervous system after seizure. Science 237(4811):192–197CrossRefPubMed
44.
go back to reference Meberg PJ, Kinney WR, Valcourt EG, Routtenberg A (1996) Gene expression of the transcription factor NF-κ B in hippocampus: regulation by synaptic activity. Molr Brain Res 38(2):179–190CrossRef Meberg PJ, Kinney WR, Valcourt EG, Routtenberg A (1996) Gene expression of the transcription factor NF-κ B in hippocampus: regulation by synaptic activity. Molr Brain Res 38(2):179–190CrossRef
45.
go back to reference Reuter U, Chiarugi A, Bolay H, Moskowitz MA (2002) Nuclear factor-κB as a molecular target for migraine therapy. Ann Neurol 51(4):507–516CrossRefPubMed Reuter U, Chiarugi A, Bolay H, Moskowitz MA (2002) Nuclear factor-κB as a molecular target for migraine therapy. Ann Neurol 51(4):507–516CrossRefPubMed
46.
go back to reference Go HS, Seo JE, Kim KC, Han SM, Kim P, Kang YS, Han SH, Shin CY, Ko KH (2011) Valproic acid inhibits neural progenitor cell death by activation of NF-B signaling pathway and up-regulation of Bcl-XL. J Biomed Sci 18(1):48CrossRefPubMedPubMedCentral Go HS, Seo JE, Kim KC, Han SM, Kim P, Kang YS, Han SH, Shin CY, Ko KH (2011) Valproic acid inhibits neural progenitor cell death by activation of NF-B signaling pathway and up-regulation of Bcl-XL. J Biomed Sci 18(1):48CrossRefPubMedPubMedCentral
47.
go back to reference Rao JS, Bazinet RP, Rapoport SI, Lee HJ (2007) Chronic treatment of rats with sodium valproate downregulates frontal cortex NF-κB DNA binding activity and COX‐2 mRNA1. Bipolar Disord 9(5):513–520CrossRefPubMed Rao JS, Bazinet RP, Rapoport SI, Lee HJ (2007) Chronic treatment of rats with sodium valproate downregulates frontal cortex NF-κB DNA binding activity and COX‐2 mRNA1. Bipolar Disord 9(5):513–520CrossRefPubMed
48.
go back to reference Wang Z, Leng Y, Tsai L-K, Leeds P, Chuang D-M (2011) Valproic acid attenuates blood–brain barrier disruption in a rat model of transient focal cerebral ischemia: the roles of HDAC and MMP-9 inhibition. J Cerebr Blood F Met 31(1):52–57CrossRef Wang Z, Leng Y, Tsai L-K, Leeds P, Chuang D-M (2011) Valproic acid attenuates blood–brain barrier disruption in a rat model of transient focal cerebral ischemia: the roles of HDAC and MMP-9 inhibition. J Cerebr Blood F Met 31(1):52–57CrossRef
49.
go back to reference Faraco G, Pittelli M, Cavone L, Fossati S, Porcu M, Mascagni P, Fossati G, Moroni F, Chiarugi A (2009) Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo. Neurobiol Di 36(2):269–279CrossRef Faraco G, Pittelli M, Cavone L, Fossati S, Porcu M, Mascagni P, Fossati G, Moroni F, Chiarugi A (2009) Histone deacetylase (HDAC) inhibitors reduce the glial inflammatory response in vitro and in vivo. Neurobiol Di 36(2):269–279CrossRef
50.
go back to reference Ichiyama T, Okada K, Lipton JM, Matsubara T, Hayashi T, Furukawa S (2000) Sodium valproate inhibits production of TNF-α and IL-6 and activation of NF-κB. Brain Res 857(1):246–251CrossRefPubMed Ichiyama T, Okada K, Lipton JM, Matsubara T, Hayashi T, Furukawa S (2000) Sodium valproate inhibits production of TNF-α and IL-6 and activation of NF-κB. Brain Res 857(1):246–251CrossRefPubMed
51.
go back to reference Li Y, Yuan Z, Liu B, Sailhamer EA, Shults C, Velmahos GC, Alam HB (2008) Prevention of hypoxia-induced neuronal apoptosis through histone deacetylase inhibition. J Trauma Acute Care 64(4):863–871CrossRef Li Y, Yuan Z, Liu B, Sailhamer EA, Shults C, Velmahos GC, Alam HB (2008) Prevention of hypoxia-induced neuronal apoptosis through histone deacetylase inhibition. J Trauma Acute Care 64(4):863–871CrossRef
Metadata
Title
Valproate ameliorates nitroglycerin-induced migraine in trigeminal nucleus caudalis in rats through inhibition of NF-кB
Authors
Yuanchao Li
Qin Zhang
Dandan Qi
Li Zhang
Lian Yi
Qianqian Li
Zhongling Zhang
Publication date
01-12-2016
Publisher
Springer Milan
Published in
The Journal of Headache and Pain / Issue 1/2015
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI
https://doi.org/10.1186/s10194-016-0631-z

Other articles of this Issue 1/2015

The Journal of Headache and Pain 1/2015 Go to the issue