AGMATINE ADMINISTRATION ALLEVIATES NERVE DAMAGE AND IMPROVES NERVE FUNCTION IN METHOTREXATE INDUCED PERIPHERAL NEUROPATHY IN RATS

Year 2024, Volume: 25 Issue: 3, 317 - 336, 30.09.2024

Hatice Fulya Yılmaz , Özlem Bozkurt Girit

https://doi.org/10.69601/meandrosmdj.1535051

Abstract

Objective: Chemotherapeutic agents can produce neurodegenerative changes. This study was conducted to assess the therapeutic potential of agmatine, a neuromodulator, on methotrexate induced neurodegeneration in sciatic nerve.
Materials and Methods: 40 male Wistar albino rats were assigned into four groups at random as control, methotrexate, agmatine and methotrexate-agmatine. Methotrexate was injected intraperitoneally at a 37.5 mg/kg/week dose for 3 weeks. Afterwards, agmatine was administered intraperitoneally twice a day at a 40 mg/kg dose for 7 days. Sciatic functional index, nociceptive pain perception and behavioral changes were analyzed every week. Nerve conduction velocity was evaluated. Apoptotic activity and mitophagy, histopathological changes in sciatic nerves were examined.
Results: Methotrexate administration resulted in a prolonged escape time to the platform and decreased the time spent in the quadrant in the water maze test; elevated nociceptive latencies; decreased the number of frames passed in the open field test; reduced sciatic NCV and SFI score. Besides, methotrexate administration caused a reduction in myelin thickness and axon diameter in sciatic nerve and a more intense glial fibrillary acidic protein immunoreactivity. Methotrexate administration triggered an increase in the Bax/Bcl-2 protein expression ratio without changing the expression level of Parkin, indicating a slight apoptotic activation. agmatine administration improved methotrexate induced changes in behavioral performances, nociceptive pain perception, nerve conduction, SFI scores and histopathological changes.
Conclusion: Agmatine has been demonstrated to possess a therapeutic potential in methotrexate induced degeneration and peripheral neuropathy in the rat sciatic nerve.

Keywords

Methotrexate, Agmatine, Sciatic nerve, Peripheral neuropathy

Ethical Statement

The Adnan Menderes University Experimental Animal Ethics Committee granted approval for this study (approval number: 64583101/2020/074).

Supporting Institution

This study was supported by Aydın Adnan Menderes University Scientific Research Projects Coordinatorship through the grant number TPF-21004.

Project Number

TPF-21004

Thanks

Hatice Fulya Yilmaz was a scholarship holder of the Higher Educational Council (YÖK) 100/2000 Neurophysiology program. The authors would like to thank Prof. Erkut Turan for his guidance and support throughout the ENMG experiments.

SIÇANLARDA METOTREKSATLA OLUŞTURULAN PERİFERİK NÖROPATİDE AGMATİN UYGULAMASININ SİNİR HASARINI AZALTICI VE FONKSİYONUNU İYİLEŞTİRİCİ ETKİSİ

Abstract

Amaç: Kemoterapötik ajanlar nörodejeneratif değişiklere neden olabilmektedir. Bu çalışmada, bir nöromodülator olan agmatinin, siyatik sinirde metotreksat ile indüklenen nörodejenerasyon üzerine olan terapötik etkinliğinin araştırılması amaçlanmıştır.
Materyal ve Metot: 40 adet erkek Wistar albino sıçan kontrol, metotreksat, agmatinin ve metotreksat-agmatinin olmak üzere dört deney grubuna ayrıldı. metotreksat uygulaması 3 hafta boyunca 37,5 mg/kg dozda metotreksat’in haftada bir kez intraperitonal yolla enjekte edilmesiyle gerçekleştirildi. agmatinin uygulaması ise 7 gün boyunca günde iki kez 40 mg/kg dozda intraperitonal yolla enjekte edilerek gerçekleştirildi. Nosiseptif ağrı algısı, siyatik fonksiyonel indeks değişimleri ve davranış değişiklikleri analiz edildi. Sinir ileti hızı ölçümleri yapıldı. Siyatik sinirdeki apoptotik-mitofajik aktivite ile akson ve miyelin düzeyindeki histopatolojik değişimler incelendi.
Bulgular: metotreksat uygulaması su labirenti testinde platforma kaçış süresinde uzamaya ve kadranda geçirilen sürede kısalmaya; açık alan testinde gezilen kare sayısında azalmaya ve nosiseptif ağrı algısında azalmaya neden oldu. metotreksat grubunda siyatik sinir iletim hızında azalma ve siyatik fonksiyon indeksi değerlerinde düşüş gözlemlendi. metotreksat uygulaması sonucu, siyatik sinirde artmış GFAP immünreaktivitesi ile azalmış akson çapı ve miyelin kalınlığı değerleri elde edildi. Ayrıca metotreksat gruplarında Bax/Bcl-2 protein ekspresyon oranının arttığı, Parkin protein ekspresyonunda ise değişim olmadığı gözlemlendi. metotreksat sonrasında uygulanan agmatinin, metotreksat grubuna kıyasla nosiseptif ağrı algısında, davranış performanslarında, sinir iletiminde, siyatik fonksiyon indeksi değerlerinde ve histopatolojik değişimlerde metotreksat'in neden olduğu değişiklikleri iyileştirdi.
Sonuç: Agmatinin, sıçan siyatik sinirinde metotreksat ile indüklenen periferal nöropatide tedavi edici potansiyele sahip olduğu görülmüştür.

Keywords

Metotreksat, Agmatin, Siyatik sinir, Periferal Nöropati

Project Number

TPF-21004

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