Sıçanlarda Pentilentetrazol ile İndüklenen Akut Epilepsi Modelinde Valproik Asidin NO/cGMP Üzerindeki Etkileri

Öz

Epilepsi, tekrarlayan nöbetlerle nöronal hasara, bilinç kaybına neden olan bir hastalıktır. Nitrik oksit (NO); beyinde nöromodülatör olarak ve hücreler arasında yayılabilen bir gazdır. Fizyolojik olaylarda, iltihaplanma ve dejeneratif hastalıklar gibi birçok hastalığın patolojisinde önemli rolü vardır. Bu araştırmanın amacı, sıçanlarda pentilentetrazol ile indüklenen deneysel akut epileptik modelde valproik asidin NO/cGMP yolağının aktivitesini araştırmaktır.Çalışmada 18 adet yetişkin erkek Wistar Albino sıçan kullanıldı. Sıçanlar rastgele kontrol grubu,pentilentetrazol (PTZ) 45 mg kg-1, valproik asit (VPA) 150 mg kg-1 olarak 3 gruba (n=6) ayrıldı. PTZ uygulamasından 24 saat sonra tüm sıçanların beyin dokuları çıkarıldı, korteks ve hipokampus ayrıldı.PTZ hipokamp ve korteks NO/cGMP düzeylerini kontrole göre artırırken (p <0,01), VPA hipokamp ve korteks NO düzeylerini PTZ'ye göre düşürdü (p<0,001). Ancak VPA korteks cGMP düzeylerini düşürürken (p <0,05), hipokampus cGMP düzeylerini değiştirmedi (p> 0,05). Bu çalışma, VPA'nın antiepileptik aktivitesini NO/cGMP yolu ile gösterebileceğini düşündürmektedir.

Anahtar Kelimeler

• Epilepsi
• Pentilentetrazol (PTZ)
• Valproik asit (VPA)
• NO/cGMP

The Effects of Valproic Acid on NO/cGMP in Pentylenetetrazole-Induced Acut Epilepsy Model in Rats

Öz

Epilepsy is a disease which causes neuronal damage and loss of consciousness in consequence of recurrent seizures. Nitric oxide as a neuromodulator in brain is a gas which can penetrate into cells. It has a significant role on physiological cases,pathology of many diseases such as inflammation and degenerative diseases. The purpose of this research is to search the activity of NO/cGMP pathway of valproic acid in an experimental acuteepileptic model which is induced with pentylenetetrazol in rats.18 adult male Wistar Albino rats were used in the study. The rats were randomly divided into 3 groups (n=6) as control group, pentylenetetrazol (PTZ+salin) 45 mg kg-1, valproic acid (PTZ+VPA) 150 mg kg-1. After 24 hours of PTZ application, all rats brain tissues were removed and then cortex and hippocampus were separated. While PTZ increased the hippocampus and cortex NO/cGMP levels compared to control (p <0.01), VPA decreased the hippocampusand cortex NO levels by comparison with PTZ (p <0.001). On the other hand, while VPA decreased cortex cGMP levels (p<0,05) it did not change cGMP levels in hippocampus (p> 0.05). This study has suggested that VPA can show antiepileptic activity via NO/cGMP pathway.

Anahtar Kelimeler

• Epilepsy
• Pentylenetetrazole
• Valproin Acid
• NO/cGMP

Kaynakça

1. [1]Dawson TM, Snyder SH. Gases as biological messengers: nitric oxide and carbon monoxide in the brain.J Neurosci. 1994;14(9):5147-5159.
2. [2]Moncada S, Palmer RM, Higg, EA. Nitric oxide: physiology, pathophysiology, and pharmacology.Pharmacol Rev. 1991;43(2):109-142.
3. [3]Bruckdorfer R. The basics about nitric oxide.Mol Aspects Med. 2005;26(1-2):3-31.
4. [4]Wyllie E. Wyllie’s treatment of epilepsy: principles and practice. 6th ed. Philadelphia, PA: Wolters Kluwer Health; 2015.
5. [5]Tastemur Y, Gumus E, Ergul M, Ulu M, Akkaya R, Ozturk A, et al. Positive effects of angiotensin-converting enzyme (ACE) inhibitor, captopril, on pentylenetetrazole-induced epileptic seizures in mice. Trop J Pharm Res. 2020; 19(3):637–643.
6. [6]Mikami Y, KanemaruK, Okubo Y, Nakaune T, Suzuki J, Shibata K, et al. Nitric Oxide-induced Activation of the Type 1 Ryanodine Receptor Is Critical for Epileptic Seizure-induced Neuronal Cell Death.EBio Medicine. 2016; 11:253-261.
7. [7]Snyder SH, Bredt DS. Nitric oxide as a neuronal messenger.Trends Pharmacol Sci. 1991;12(4):125-128.
8. [8]Kaster MP, Rosa AO, Santos AR, Rodrigues AL. Involvement of nitric oxide-cGMP pathway in the antidepressant-like effects of adenosine in the forced swimming test.Int J Neuropsychopharmacol. 2005;8(4):601-606.

9. [9]Buisson A, Lakhmeche N, Verrecchia C, Plotkine M, Boulu RG. Nitric oxide: an endogenous anticonvulsant substance.Neuroreport. 1993;4(4):444-446.
10. [10]Johannessen CU, Johannessen SI. Valproate: past, present, and future.CNS Drug Rev. 2003;9(2):199-216.
11. [11]Dziki M, Hönack D, Löscher W. Kindled rats are more sensitive than non-kindled rats to the behavioural effects of combined treatment with MK-801 and valproate.Eur J Pharmacol. 1992;222(2-3):273-278.
12. [12]Peker E, Oktar S, Ari M, Kozan R, Doğan M, Cağan E, et al. Nitric oxide, lipid peroxidation, and antioxidant enzyme levels in epileptic children using valproic acid.Brain Res. 2009; 1297:194-197.
13. [13]Erdogan MA, Yusuf D, Erdogan A, Erbas. Levodropropizine suppresses seizure activity in rats with pentylenetetrazol-induced epilepsy. Epilepsy Res.2019; 150:32–37.
14. [14]Zhu X, Dong J, Han B, Huang R, Zhang A, Xia Z, et al. Neuronal Nitric Oxide Synthase Contributes to PTZ Kindling Epilepsy-Induced Hippocampal Endoplasmic Reticulum Stress and Oxidative Damage.FrontCell Neurosci. 2017; 11:377.
15. [15]Kwon YS, Pineda E, Auvin S, Shin D, Mazarati A, Sankar R. Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain.J Neuroinflammation. 2013; 10:30.
16. [16]Akula KK, Dhir A, Kulkarni SK. Nitric oxide signaling pathway in the anti-convulsant effect of adenosine against pentylenetetrazol-induced seizure threshold in mice.Eur J Pharmacol. 2008;587(1-3):129-134.
17. [17]Nakamura TA, Yamada K, Hasegawa T, Nabeshima T. Possible involvement of nitric oxide in quinolinic acid-induced convulsion in mice.Pharmacol Biochem Behav. 1995;51(2-3):309-312.
18. [18]Lallement G, Shih TM Pernot-Marino, I, Baubichon D, Foquin A, McDonough JH. The role of nitric oxide in soman-induced seizures, neuropathology, and lethality.Pharmacol Biochem Behav. 1996;54(4):731-737.
19. [19]Han D, Yamada K, Senzaki K, Xiong H, Nawa H, Nabeshima T. Involvement of nitric oxide in pentylenetetrazole-induced kindling in rats.J Neurochem. 2000;74(2):792-798.
20. [20]Royes LF, Fighera MR, Furian AF, Oliveria MS, Fiorenza NG, Myskiw JC, et al. Involvement of NO in the convulsive behavior and oxidative damage induced by the intrastriatal injection of methylmalonate.Neurosci Lett. 2005;376(2):116-120.
21. [21]Shehab S, Coffey P, Dean P, Redgrave P. Regionalexpression of fos-like immunoreactivity following seizures induced by pentylenetetrazole and maximal electroshock.Exp Neurol. 1992;118(3):261-274.
22. [22]Giorgi O, Orlandi M, Lecca D, Corda MG. MK-801 prevents chemical kindling induced by pentylenetetrazol in rats.Eur J Pharmacol. 1991;193(3):363-365.
23. [23]Garthwaite J. Glutamate, nitric oxide and cell-cell signalling in the nervous system.Trends Neurosci. 1991;14(2):60-67.
24. [24]Balter-Seri J, Yuhas Y, Weizman A, Nofech-Mozes Y, Kaminsky, E, Ashkenazi, S. Role of nitric oxide in the enhancement of pentylenetetrazole-induced seizures caused by Shigella dysenteriae.Infect Immun. 1999;67(12):6364-6368.
25. [25]El-Abhar HS, El Gawad HM. Modulation of cortical nitric oxide synthase, glutamate, and redox state by nifedipine and taurine in PTZ-kindled mice.Epilepsia. 2003;44(3):276-281.
26. [26]X. Zhu, J. Dong, K. Shen, Y. Bai, Y. Zhang, X. Lv, et al. NMDA receptor NR2B subunits contribute to PTZ-kindling-induced hippocampal astrocytosis and oxidative stress. Brain Res Bull. 2015;114: 70-78.
27. [27]X. Zhu, J. Dong, K. Shen, Y. Bai, J. Chao, H. Yao Neuronal nitric oxide synthase contributes to pentylenetetrazole-kindling-induced hippocampal neurogenesis. Brain Res Bull. 2016;121:138-147.
28. [28]Mülsch A, Busse R, Mordvintcev PI, et al. Nitric oxide promotes seizure activity in kainate-treated rats.Neuroreport. 1994;5(17):2325-2328.
29. [29]Karabiber H, Yakinci C, Durmaz Y, Temel I, Mehmet N. Serum nitrite and nitrate levels in epileptic children using valproic acid or carbamazepine. Brain Dev. 2004;26(1):15-8.
30. [30]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.