Periferik Sinir Hasarının Neden Olduğu Nöropatik Ağrıda Levetirasetam ve Gabapentin'in Etkinliğinin Karşılaştırılması: Deneysel Bir Çalışma

Abstract

Amaç Bu deneysel çalışmanın amacı, periferik sinir hasarı modelinde indüklenen nöropatik ağrının tedavisinde Gabapentin ve Levetirasetam kullanımını değerlendirmektir. Gereç ve Yöntemler Çalışmada toplam 31 Wistar albino sıçan dört gruba ayrıldı: Grup I (Kontrol) (n = 4), Grup II (Sham) (n = 9), Grup III (Gabapentin) (n = 9) ve Grup IV (Levetirasetam) (n = 9). Tüm gruplarda (Kontrol hariç) siyatik sinir bölgesine 1 cm'lik cerrahi kesi ile ulaşıldı; Sham grubu dışındaki gruplarda sinir ligasyon yöntemiyle hasar oluşturuldu. Gabapentin ve Levetirasetam tedavileri hasar oluşturulmasının ardından ilgili gruplara uygulandı. Çalışmanın 31. gününde anestezi altında elektrofizyolojik değerlendirme yapıldı; ardından tüm hayvanlar sakrifiye edilerek sinir dokuları histomorfolojik ve immünohistokimyasal inceleme için uygun koşullarda muhafaza edildi. Verilerin analizinde tanımlayıcı istatistikler, homojenlik ve normallik dağılım testleri kullanıldı. Bulgular Elektrofizyolojik bulgular, Levetirasetam grubunun Gabapentin grubuna kıyasla benzer sinir iletim parametreleri sergilediğini ortaya koydu. S100 protein yoğunluğu değerlendirmesinde Levetirasetam grubunda 77.41 ± 5.84 ve Gabapentin grubunda 80.41 ± 5.95 olarak saptanan değerler, Sham grubunun 74.10 ± 4.56 değerine göre istatistiksel olarak anlamlı derecede yüksek bulundu (P < 0.001). Nörofilament immünohistokimyasal değerlendirmesinde ise Levetirasetam grubunun 79.13 ± 8.16 değeriyle Gabapentin grubuna kıyasla istatistiksel olarak anlamlı üstünlük sergilediği saptandı (P < 0.001). Sonuç Levetirasetam, periferik sinir hasarıyla ilişkili nöropatik ağrısı olan hastalarda Gabapentin tedavisine alternatif bir tedavi seçeneği olarak düşünülebilir ve Levetirasetam umut vadeden bir ajandır.

Keywords

• Hayvan Çalışması
• Gabapentin
• Levetirasetam
• Periferik Sinir Hasarı
• Trigeminal Nevralji

Supporting Institution

ERCİYES ÜNİVERSİTESİ BİLİMSEL ARAŞTIRMA PROJELERİ KOORDİNASYON BİRİMİ

Project Number

TSA-2018-7853

Ethical Statement

Bu çalışma, Erciyes Üniversitesi Hayvan Deneyleri Yerel Etik Kurulu'nun 13.12.2017 tarihli ve 17/137 numaralı onayıyla gerçekleştirilmiştir.

Thanks

Bu çalışmanın gerçekleşmesine destekleriyle olanak sağlayan Erciyes Üniversitesi Bilimsel Araştırma Birimine ve Erciyes Üniversitesi Deneysel Araştırmalar Uygulama ve Araştırma Merkezi (DEKAM) yöneticilerine ve çalışanlarına teşekkür ederiz.

Comparison of the Efficiency of Levetiracetam and Gabapentin on Neuropathic Pain Induced by Peripheral Nerve Damage: An Experimental Study

Abstract

Objectives The purpose of this experimental study was to evaluate the usage of Gabapentin and Levetiracetam for the treatment of induced neuropathic pain in a peripheral nerve injury model. Material and Methods In this study, a total of 31 Wistar albino rats were divided into 4 groups: Group I (Control) (n = 4), Group II (Sham) (n = 9), Group III (Gabapentin) (n = 9), and Group IV (Levetirasetam) (n = 9). In all groups (except Control), the sciatic nerve region was accessed via a 1 cm surgical incision; in all groups except Sham, nerve damage was induced by ligation. Gabapentin and Levetiracetam treatments were administered to the relevant groups after nerve damage was induced. After conducting an electrophysiological evaluation under anesthesia on day 31 of the study, all animals were sacrificed, and nerve tissues were kept under suitable conditions for histomorphological and immunohistochemistry analysis. Descriptive statistics, homogeneity tests, and normality tests were used in the analysis of the data. Results Electrophysiological findings revealed that the Levetiracetam group exhibited similar nerve conduction parameters compared to the Gabapentin group. In the S100 protein density assessment, the values were found to be statistically significantly higher in the Levetiracetam group (77.41 ± 5.84) and Gabapentin group (80.41 ± 5.95), compared to the Sham group's value of 74.10 ± 4.56 (P < 0.001). In the neurofilament immunohistochemical assessment, the Levetiracetam group showed a statistically significant superiority with a value of 79.13 ± 8.16 compared to the Gabapentin group (P < 0.001). Conclusion Levetiracetam could be considered as an alternative treatment option to Gabapentin treatment in patients with neuropathic pain associated with peripheral nerve injury, and Levetiracetam is a promising agent.

Keywords

• Animal Experimentation
• Gabapentin
• Levetiracetam
• Peripheral Nerve Injuries
• Trigeminal Neuralgia

Project Number

TSA-2018-7853

Ethical Statement

This study was performed with the approval of Erciyes University Animal Experiments Local Ethics Committee dated 13.12.2017 and numbered 17/137. Additionally, this experimental study was organized according to Guide for the Care and Use of the Labo ratory Animals.

Thanks

We would like to thank Erciyes University Scientific Research Unit and the managers and staff of Erciyes University Experimental Research Application and Research Center (DEKAM) for their support in making this study possible.

References

1. Renton T, Yilmaz Z. Managing iatrogenic trigeminal nerve injury: a case series and review of the literature. Int J Oral Maxillofac Surg. 2012; 41: 629-37. doi: 10.1016/j.ijom.2011.11.002
2. Klazen Y, Van der Cruyssen F, Vranckx M, et al. Iatrogenic trigeminal post-traumatic neuropathy: a retrospective two-year cohort study. Int J Oral Maxillofac Surg. 2018; 47: 789-93. doi: 10.1016/j.ijom.2018.02.004
3. Agbaje OJ, Salem AS, Lambrichts I, et al. Systematic review of the incidence of inferior alveolar nerve injury in bilateral sagittal split osteotomy and the assessment of neurosensory disturbances. Int J Oral Maxillofac Surg. 2015; 44: 447-51. doi: 10.1016/j.ijom.2014.11.010
4. Elmadawy A, Hegab A, Alahmady H, et al. Clinical and electromyographic assessment of facial nerve function after temporomandibular joint surgery. Int J Oral Maxillofac Surg. 2015; 44: 1275-80. doi: 10.1016/j.ijom.2015.04.013
5. Khojasteh A, Hosseinpour S, Nazeman P, et al. The effect of a platelet-rich fibrin conduit on neurosensory recovery following inferior alveolar nerve lateralization: a preliminary clinical study. Int J Oral Maxillofac Surg. 2016; 45: 1303-8. doi: 10.1016/j.ijom.2016.06.003
6. Coderre TJ, Kumar N, Lefebvre CD, et al. A comparison of the glutamate release inhibition and anti-allodynic effects of gabapentin, lamotrigine, and riluzole in a model of neuropathic pain. J Neurochem. 2007; 100: 1289-99. doi: 10.1111/j.1471-4159.2006.04304.x
7. Quintero GC. Review about gabapentin misuse, interactions, contraindications and side effects. J Exp Pharmacol. 2017; 9: 13-21. doi: 10.2147/JEP.S124391
8. Wiffen PJ, Derry S, Bell RF, et al. Gabapentin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2017; 6: CD007938. doi: 10.1002/14651858.CD007938.pub4

9. Ramsay RE. Gabapentin toxicity. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic Drugs. 4th ed. New York: Raven Press, 1995, p. 857-60.
10. Belcastro V, Pierguidi L, Tambasco N. Levetiracetam in brain ischemia: clinical implications in neuroprotection and prevention of post-stroke epilepsy. Brain Dev. 2011; 33: 289-93. doi: 10.1016/j.braindev.2010.06.008
11. Erbaş O, Oltulu F, Yılmaz M, et al. Neuroprotective effects of chronic administration of levetiracetam in a rat model of diabetic neuropathy. Diabetes Res Clin Pract. 2016; 114: 106-16. doi: 10.1016/j.diabres.2015.12.016
12. Marini H, Costa C, Passaniti M, et al. Levetiracetam protects against kainic acid-induced toxicity. Life Sci. 2004; 74: 1253-64. doi: 10.1016/j.lfs.2003.08.006
13. Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci. 2004; 101: 9861-6. doi: 10.1073/pnas.0308208101
14. Micov A, Tomić M, Popović B, et al. The antihyperalgesic effect of levetiracetam in an inflammatory model of pain in rats: mechanism of action. Br J Pharmacol. 2010; 161: 384-92. doi: 10.1111/j.1476-5381.2010.00877.x
15. Sliva J, Dolezal T, Prochazkova M, et al. Preemptive levetiracetam decreases postoperative pain in rats. Neuroendocrinol Lett. 2008; 29: 953.
16. Jorns TP, Johnston A, Zakrzewska JM. Pilot study to evaluate the efficacy and tolerability of levetiracetam (Keppra) in treatment of patients with trigeminal neuralgia. Eur J Neurol. 2009; 16: 740-4. doi: 10.1111/j.1468-1331.2009.02585.x
17. Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain. 1990; 43: 205-18. doi: 10.1016/0304-3959(90)91074-S
18. Ozbek Z, Aydin HE, Kocman AE, et al. Neuroprotective effect of genistein in peripheral nerve injury. Turk Neurosurg. 2017; 27: 816-22. doi: 10.5137/1019-5149.JTN.18549-16.1
19. Yay A, Onses MS, Sahmetlioglu E, et al. Raman spectroscopy: a novel experimental approach to evaluating cisplatin induced tissue damage. Talanta. 2020; 207: 120343. doi: 10.1016/j.talanta.2019.120343
20. Hurley RW, Cohen SP, Williams KA, et al. The analgesic effects of perioperative gabapentin on postoperative pain: a meta-analysis. Reg Anesth Pain Med. 2006; 31: 237-47. doi: 10.1016/j.rapm.2006.01.005
21. Tiippana EM, Hamunen K, Kontinen VK, et al. Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety. Anesth Analg. 2007; 104: 1545-56. doi: 10.1213/01.ane.0000261517.27532.80
22. Kardes O, Civi S, Bulduk EB, et al. Effect of gabapentin on primary surgical treatment of experimental sciatic nerve injury in rats. Ulus Travma Acil Cerrahi Derg. 2018; 24: 481-7. doi: 10.5505/tjtes.2018.66712
23. Câmara CC, Araújo CV, de Sousa KKO, et al. Gabapentin attenuates neuropathic pain and improves nerve myelination after chronic sciatic constriction in rats. Neurosci Lett. 2015; 607: 52-8. doi: 10.1016/j.neulet.2015.09.021
24. Mitsikostas DD, Pantes GV, Avramidis TG, et al. An observational trial to investigate the efficacy and tolerability of levetiracetam in trigeminal neuralgia. Headache. 2010; 50: 1371-7. doi: 10.1111/j.1526-4610.2010.01743.x
25. Jakhar P, Chouhan O, Gehlot A, et al. A comparative study of the effect of gabapentin, topiramate, levetiracetam and zonisamide for neuropathic pain induced by anticancer drug (vincristine) in rats. J Pharm Res Clin Pract. 2014; 4: 1-6.
26. Wiffen PJ, Derry S, Moore RA. Levetiracetam for neuropathic pain in adults. Cochrane Database Syst Rev. 2014; 7: CD010943. doi: 10.1002/14651858.CD010943.pub2
27. Ueda Y, Doi T, Takaki M, et al. Levetiracetam enhances endogenous antioxidant in the hippocampus of rats: in vivo evaluation by brain microdialysis combined with ESR spectroscopy. Brain Res. 2009; 1266: 1-7. doi: 10.1016/j.brainres.2009.02.040
28. Niespodziany I, Klitgaard H, Margineanu DG. Levetiracetam inhibits the high-voltage-activated Ca2+ current in pyramidal neurones of rat hippocampal slices. Neurosci Lett. 2001; 306: 5-8. doi: 10.1016/s0304-3940(01)01884-5
29. Al-Bishri A, Dahlin L, Sunzel B. Systemic betamethasone accelerates functional recovery after a crush injury to rat sciatic nerve. J Oral Maxillofac Surg. 2005; 63: 973-7. doi: 10.1016/j.joms.2004.10.010
30. Torul D, Bereket MC, Onger EM, et al. Comparison of the regenerative effects of platelet-rich fibrin and plasma rich in growth factors on injured peripheral nerve: an experimental study. J Oral Maxillofac Surg. 2018; 76: 1823. doi: 10.1016/j.joms.2018.04.012
31. Wu CB, Guo YF, Zhou Q. Preparation of trigeminal neuralgia animal model through stereotactic trigeminal nerve compression technology. Int J Clin Exp Med. 2017; 10: 3204-10.
32. Luo DS, Zhang T. An animal model for trigeminal neuralgia by compression of the trigeminal nerve root. Pain Physician. 2012; 15: 187-96.