Effect of the cyclooxygenase-2 inhibitor tenoxicam on pentylenetetrazole-induced epileptic seizures in rats
Abstract
Objective: Epilepsy is a short-term paroxysmal
disturbances of brain functions observed between sudden, abnormal and
hypersynchronization discharges and seizures of a group of neurons in the
central nervous system. The nonsteroidal anti-inflammatory tenoxicam is
chemical agent that selectively inhibits type 2 cyclooxygenase (COX2), which
converts arachidonic acid to prostaglandins (PGs). The aim of this study was to
investigate the effect of the cyclooxygenase-2 inhibitor tenoxicam on
pentylenetetrazole on epileptic seizures.
Method: Eighteen Wistar Albino male rats (220±20 g) were divided into three
groups: control (n=6), 10 mg/kg/day tenoxicam (n=6) and, 20 mg/kg/day tenoxicam
(n=6). Tenoxicam was administered intramuscularly for ten days. On the tenth
day, pentylenetetrazol (PTZ) was injected intraperitoneally at 70 mg/kg after
45 minutes of drug administration and the animals were observed for 30 min.
Stages were determined according to the Racine seizure scale (RC) and the first
myoclonic jerk time (FMJ) was recorded in seconds. After completing procedure,
whole brain tissues were removed and stained with toluidine blue stain. The
number of dark neurons with
chromatin aggregation in
hypocampal CA1 and dentate gyrus (DG) was determined as percentage.
Results: Epileptic behavior were evaluated according to the RC, 10 mg/kg of
tenoxicam significantly reduced the seizure stage compared to the control
(p<0,05). In addition, 10 mg/kg tenoxicam significantly increased the FMJ
compared to the control (p<0,05). According to the histopathological
findings, neuronal damage was increased in CA1 region of 20 mg/kg of tenoxicam
group compared to control, whereas neuronal damage was reduced significantly in
the dentate gyrus of 10 mg/kg and 20 mg/kg of tenoxicam groups (p<0,05).
Conclusions: This study shows that dose-dependent administration of tenoxicam might
have a potential to reduce epileptic seizures and post-seizure neuron damage.
References
- 1. Vezzani A, Granata T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia. 2005; 46: 1724-43.
- 2. Vezzani A, Baram TZ. New roles for interleukin-1 Beta in the mechanisms of epilepsy. Epilepsy Curr 2007; 7: 45-50.
- 3. Choi J, Koh S. Role of brain inflammation in epileptogenesis. Yonsei Med J. 2008; 49: 1-18.
- 4. Takemiya T, Matsumura K, Yamagata K. Roles of prostaglandin synthesis in excitotoxic brain diseases. Neurochem Int 2007; 51: 112-20.
- 5. Rijkers K, Majoie HJ, Hoogland G, Kenis G, De Baets M, Vles JS. The role of interleukin-1 in seizures and epilepsy: a critical review. Exp Neurol 2009; 216: 258-71.
- 6. Zhang J, Goorha S, Raghow R, Ballou LR. The tissue-specific, compensatory expression of cyclooxygenase-1 and -2 in transgenic mice. Prostaglandins Other Lipid Mediat 2002; 67: 121-35.
- 7. Cole-Edwards KK, Bazan NG. Lipid signaling in experimental epilepsy. Neurochem Res 2005; 30: 847-53.
- 8. Kulkarni SK, Dhir A. Cyclooxygenase in epilepsy: from perception to application. Drugs Today 2009; 45: 135-54.
- 9. Polascheck N, Bankstahl M, Löscher W. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp Neurol 2010; 224: 219-33.
- 10. Van Antwerpen P, Neve J. In vitro comparative assessment of the scavenging activity against three reactive oxygen species of non-steroidal anti-inflammatory drugs from the oxicam and sulfoanilide families. Eur J Pharmacol 2004; 496: 55-61.
- 11. Naziroğlu M, Uğuz AC, Gokçimen A, Bülbül M, Karatopuk DU, Türker Y, Cerçi C. Tenoxicam modulates antioxidant redox system and lipid peroxidation in rat brain. Neurochem Res 2008; 33: 1832-7.
- 12. Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 1972; 32: 281-94.
- 13. Uyanikgil Y1,2, Özkeşkek K3, Çavuşoğlu T1,2, Solmaz V4, Tümer MK5, Erbas O6 Positive effects of ceftriaxone on pentylenetetrazol-induced convulsion model in rats. Int J Neurosci 2016;126: 70-5.
- 14. Okada K, Yuhi T, Tsuji S, Yamashita U. Cyclooxygenase-2 expression in the hippocampus of genetically epilepsy susceptible El mice was increased after seizure. Brain Res 2001; 894: 332-5.
- 15. Tu B, Bazan NG. Hippocampal kindling epileptogenesis upregulates neuronal cyclooxygenase-2 expression in neocortex. Exp Neurol 2003; 179: 167-75.
- 16. Kawaguchi K, Hickey RW, Rose ME, Zhu L, Chen J, Graham SH. Cyclooxygenase-2 expression is induced in rat brain after kainate-induced seizures and promotes neuronal death in CA3 hippocampus. Brain Res 2005; 1050: 130-7.
- 17. Dhir A, Naidu PS, Kulkarni SK. Effect of cyclooxygenase-2 (COX-2) inhibitors in various animal models (bicuculline, picrotoxin, maximal electroshock-induced convulsions) of epilepsy with possible mechanism of action. Indian J Exp Biol 2006; 44: 286-91.
- 18. Desjardins P, Sauvageau A, Bouthillier A, Navarro D, Hazell AS, Rose C, Butterworth RF. Induction of astrocytic cyclooxygenase-2 in epileptic patients with hippocampal sclerosis. Neurochem Int 2003; 42: 299-303.
- 19. Du Y, Kemper T, Qiu J, Jiang J. Defining the therapeutic time window for suppressing the inflammatory prostaglandin E2 signaling after status epilepticus. Expert Rev Neurother 2016; 16: 123-30
- 20. Kunz T, Oliw EH. The selective cyclooxygenase-2 inhibitor rofecoxib reduces kainate-induced cell death in the rat hippocampus. Eur J Neurosci 2001; 13: 569-75.
- 21. Kawaguchi K, Hickey RW, Rose ME, Zhu L, Chen J, Graham SH. Cyclooxygenase-2 expression is induced in rat brain after kainate-induced seizures and promotes neuronal death in CA3 hippocampus. Brain Res 2005; 1050:130-7.
- 22. Holtman L, van Vliet EA, van Schaik R, Queiroz CM, Aronica E, Gorter JA. Effects of SC58236, a selective COX-2 inhibitor, on epileptogenesis and spontaneous seizures in a rat model for temporal lobe epilepsy. Epilepsy Res 2009; 84: 56-66.
- 23. Baik EJ, Kim EJ, Lee SH, Moon C. Cyclooxygenase-2 selective inhibitors aggravate kainic acid induced seizure and neuronal cell death in the hippocampus. Brain Res 1999; 843: 118-29.
- 24. Polascheck N, Bankstahl M, Löscher W. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp Neurol 2010; 224: 219-33.
- 25. Karimzadeh F., Hosseini M., Mangeng D. Anticonvulsant and neuroprotective effects of Pimpinella anisum in rat brain. BMC Complement Altern Med 2012; 12: 76.
- 26. Seghatoleslam M, Alipour F, Shafieian R, Hassanzadeh Z, Edalatmanesh MA, Sadeghnia HR, Hosseini M. The effects of Nigella sativa on neural damage after pentylenetetrazole induced seizures in rats. J Tradit Complement Med 2015; 6: 262-8.
- 27. Baracskay P, Szepesi Z, Orbán G, Juhász G, Czurkó A. Generalization of seizures parallels the formation of "dark" neurons in the hippocampus and pontine reticular formation after focal-cortical application of 4-aminopyridine (4-AP) in the rat. Brain Res 2008; 1228: 217-28.
- 28. Mansouri S, Ataei ML, Hosseini M, Bideskan AR. Tamoxifen mimics the effects of endogenous ovarian hormones on repeated seizures induced by pentylenetetrazole in rats. Exp Neurobiol 201; 22: 116-23.
- 29. Kherani ZS, Auer RN. Pharmacologic analysis of the mechanism of dark neuron production in cerebral cortex. Acta Neuropathol 2008; 116:447-52.
- 30. Pitkanen A., Tuunanen J., Kalviainen R., Partanen K., Salmenpera T. Amygdala damage in experimental and human temporal lobe epilepsy. Epilepsy Res 1998; 32: 233–253.
- 31. Salmenpera T., Kalviainen R., Partanen K., Pitkanen A. Hippocampal and amygdaloid damage in partial epilepsy: a cross-sectional MRI study of 241 patients. Epilepsy Res 2001; 46: 69-82.
Siklooksijenaz-2 inhibitörü tenoksikam'ın pentilentetrazol ile oluşturulan epileptik nöbetler üzerine etkisi
Abstract
Amaç: Epilepsi merkezi sinir
sisteminde bir grup nöronun ani, anormal ve hipersenkronize deşarjları ile
nöbetler halinde gözlenen beyin fonksiyonlarının kısa süreli paroksimal
rahatsızlığı olarak tanımlanır. Nonsteroid anti inflamatuarlardan olan
tenoksikam araşidonik asidi prostaglandinlere dönüştüren tip 2 siklooksijenaz
(COX2) enzimini selektif olarak inhibe eden kimyasal bir ajandır. Bu çalışmanın
amacı siklooksijenaz-2 inhibitörü tenoksikam'ın pentilentetrazol ile
oluşturulan epileptik nöbetlere üzerine etkisini araştırmaktır.
Yöntem: Çalışmamızda 18
tane 220-240 gr Wistar Albino erkek sıçan kullanılmıştır. Hayvanlar kontrol
(n=6), 10 mg/kg/gün tenoksikam (n=6) ve 20 mg/kg/gün tenoksikam (n=6) olmak
üzere üç gruba ayrıldı. On gün süre ile kontrol grubuna çözücü ve diğer iki
gruba belirtilen dozlarda tenoksikam intramusküler olarak uygulandı. Onuncu gün
ilaç uygulamalarından 45 dk sonra pentilentetrazol (PTZ) 70 mg/kg
intraperitoneal olarak enjekte edildi. Hayvanlar 30 dk boyunca gözlemlendi.
Racine nöbet skalasına göre evreleri belirlendi ve ilk miyoklonik jerk zamanı
(FMJ) saniye olarak kaydedildi. İşlem bitiminden sonra hayvanların beyin
dokuları alındı. Beyin dokuları rutin histolojik takip sonrası toluidin blue
boyası ile boyanandı. Hipokampüste CA1 ve dentat girus bölgelerinde nöronal
hasarı gösteren ‘Dark nöron’ sayıları
yüzde olarak belirlendi.
Bulgular: Epileptik davranış sonuçları Racine nöbet skalasına (RC) göre
değerlendirildiğinde, 10 mg/kg tenoksikam kontrole göre nöbet evresini anlamlı
olarak azalttı (p<0,05). Ayrıca 10 mg/kg tenoksikam kontrole göre ilk
miyoklonik jerk zamanını anlamlı olarak arttırdı (p<0,05). Histopatolojik
olarak gruplar değerlendirildiğinde, CA1 bölgesinde 20 mg/kg tenoksikam
kontrole göre nöronal hasarı arttıdığı, buna karsışık dentat girus bölgelesinde
10 mg/kg ve 20 mg/kg tenoksikam nöronal hasarı anlamlı olarak azalttı
(p<0,05).
Sonuç: Bu
çalışma tenoksikam uygulamasının epileptik nöbetleri ve nöbet sonrası nöron
hasarını doz bağımlı olarak azaltabileceğini göstermektedir.
References
- 1. Vezzani A, Granata T. Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia. 2005; 46: 1724-43.
- 2. Vezzani A, Baram TZ. New roles for interleukin-1 Beta in the mechanisms of epilepsy. Epilepsy Curr 2007; 7: 45-50.
- 3. Choi J, Koh S. Role of brain inflammation in epileptogenesis. Yonsei Med J. 2008; 49: 1-18.
- 4. Takemiya T, Matsumura K, Yamagata K. Roles of prostaglandin synthesis in excitotoxic brain diseases. Neurochem Int 2007; 51: 112-20.
- 5. Rijkers K, Majoie HJ, Hoogland G, Kenis G, De Baets M, Vles JS. The role of interleukin-1 in seizures and epilepsy: a critical review. Exp Neurol 2009; 216: 258-71.
- 6. Zhang J, Goorha S, Raghow R, Ballou LR. The tissue-specific, compensatory expression of cyclooxygenase-1 and -2 in transgenic mice. Prostaglandins Other Lipid Mediat 2002; 67: 121-35.
- 7. Cole-Edwards KK, Bazan NG. Lipid signaling in experimental epilepsy. Neurochem Res 2005; 30: 847-53.
- 8. Kulkarni SK, Dhir A. Cyclooxygenase in epilepsy: from perception to application. Drugs Today 2009; 45: 135-54.
- 9. Polascheck N, Bankstahl M, Löscher W. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp Neurol 2010; 224: 219-33.
- 10. Van Antwerpen P, Neve J. In vitro comparative assessment of the scavenging activity against three reactive oxygen species of non-steroidal anti-inflammatory drugs from the oxicam and sulfoanilide families. Eur J Pharmacol 2004; 496: 55-61.
- 11. Naziroğlu M, Uğuz AC, Gokçimen A, Bülbül M, Karatopuk DU, Türker Y, Cerçi C. Tenoxicam modulates antioxidant redox system and lipid peroxidation in rat brain. Neurochem Res 2008; 33: 1832-7.
- 12. Racine RJ. Modification of seizure activity by electrical stimulation. II. Motor seizure. Electroencephalogr Clin Neurophysiol 1972; 32: 281-94.
- 13. Uyanikgil Y1,2, Özkeşkek K3, Çavuşoğlu T1,2, Solmaz V4, Tümer MK5, Erbas O6 Positive effects of ceftriaxone on pentylenetetrazol-induced convulsion model in rats. Int J Neurosci 2016;126: 70-5.
- 14. Okada K, Yuhi T, Tsuji S, Yamashita U. Cyclooxygenase-2 expression in the hippocampus of genetically epilepsy susceptible El mice was increased after seizure. Brain Res 2001; 894: 332-5.
- 15. Tu B, Bazan NG. Hippocampal kindling epileptogenesis upregulates neuronal cyclooxygenase-2 expression in neocortex. Exp Neurol 2003; 179: 167-75.
- 16. Kawaguchi K, Hickey RW, Rose ME, Zhu L, Chen J, Graham SH. Cyclooxygenase-2 expression is induced in rat brain after kainate-induced seizures and promotes neuronal death in CA3 hippocampus. Brain Res 2005; 1050: 130-7.
- 17. Dhir A, Naidu PS, Kulkarni SK. Effect of cyclooxygenase-2 (COX-2) inhibitors in various animal models (bicuculline, picrotoxin, maximal electroshock-induced convulsions) of epilepsy with possible mechanism of action. Indian J Exp Biol 2006; 44: 286-91.
- 18. Desjardins P, Sauvageau A, Bouthillier A, Navarro D, Hazell AS, Rose C, Butterworth RF. Induction of astrocytic cyclooxygenase-2 in epileptic patients with hippocampal sclerosis. Neurochem Int 2003; 42: 299-303.
- 19. Du Y, Kemper T, Qiu J, Jiang J. Defining the therapeutic time window for suppressing the inflammatory prostaglandin E2 signaling after status epilepticus. Expert Rev Neurother 2016; 16: 123-30
- 20. Kunz T, Oliw EH. The selective cyclooxygenase-2 inhibitor rofecoxib reduces kainate-induced cell death in the rat hippocampus. Eur J Neurosci 2001; 13: 569-75.
- 21. Kawaguchi K, Hickey RW, Rose ME, Zhu L, Chen J, Graham SH. Cyclooxygenase-2 expression is induced in rat brain after kainate-induced seizures and promotes neuronal death in CA3 hippocampus. Brain Res 2005; 1050:130-7.
- 22. Holtman L, van Vliet EA, van Schaik R, Queiroz CM, Aronica E, Gorter JA. Effects of SC58236, a selective COX-2 inhibitor, on epileptogenesis and spontaneous seizures in a rat model for temporal lobe epilepsy. Epilepsy Res 2009; 84: 56-66.
- 23. Baik EJ, Kim EJ, Lee SH, Moon C. Cyclooxygenase-2 selective inhibitors aggravate kainic acid induced seizure and neuronal cell death in the hippocampus. Brain Res 1999; 843: 118-29.
- 24. Polascheck N, Bankstahl M, Löscher W. The COX-2 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy. Exp Neurol 2010; 224: 219-33.
- 25. Karimzadeh F., Hosseini M., Mangeng D. Anticonvulsant and neuroprotective effects of Pimpinella anisum in rat brain. BMC Complement Altern Med 2012; 12: 76.
- 26. Seghatoleslam M, Alipour F, Shafieian R, Hassanzadeh Z, Edalatmanesh MA, Sadeghnia HR, Hosseini M. The effects of Nigella sativa on neural damage after pentylenetetrazole induced seizures in rats. J Tradit Complement Med 2015; 6: 262-8.
- 27. Baracskay P, Szepesi Z, Orbán G, Juhász G, Czurkó A. Generalization of seizures parallels the formation of "dark" neurons in the hippocampus and pontine reticular formation after focal-cortical application of 4-aminopyridine (4-AP) in the rat. Brain Res 2008; 1228: 217-28.
- 28. Mansouri S, Ataei ML, Hosseini M, Bideskan AR. Tamoxifen mimics the effects of endogenous ovarian hormones on repeated seizures induced by pentylenetetrazole in rats. Exp Neurobiol 201; 22: 116-23.
- 29. Kherani ZS, Auer RN. Pharmacologic analysis of the mechanism of dark neuron production in cerebral cortex. Acta Neuropathol 2008; 116:447-52.
- 30. Pitkanen A., Tuunanen J., Kalviainen R., Partanen K., Salmenpera T. Amygdala damage in experimental and human temporal lobe epilepsy. Epilepsy Res 1998; 32: 233–253.
- 31. Salmenpera T., Kalviainen R., Partanen K., Pitkanen A. Hippocampal and amygdaloid damage in partial epilepsy: a cross-sectional MRI study of 241 patients. Epilepsy Res 2001; 46: 69-82.
Details
| Subjects | Health Care Administration |
|---|---|
| Journal Section | Basic Science Research Articles |
| Authors | |
| Publication Date | December 18, 2017 |
| Acceptance Date | October 24, 2017 |
| Published in Issue | Year 2017Volume: 39 Issue: 4 |