Publication: L-DOPA indüklü sıçan diskinezi modelinde ketaminin rolü
Abstract
Amaç: İlerleyici bir nörodejeneratif hastalık olan Parkinson hastalığı tedavisinde L-DOPA (levodopa) yaklaşık 60 yıldır en etkili standart tedavi olmaya devam etmektedir. Ancak, L-DOPA'nın uzun süreli kullanımı başta L-DOPA ile indüklünen diskinezi (LID) olmak üzere tedaviyi sınırlayan ciddi motor komplikasyonlara yol açar. Klinik öncesi çalışmalarda ve vaka raporlarında ketaminin diskinetik hareketler üzerinde etkili olabileceği gösterilmiştir. Bu çalışmada, sıçan LID modelinde ketamin tedavisinin potansiyel etkileri araştırılmıştır. Gereç ve Yöntem: Çalışmada yetişkin erkek Sprague-Dawley sıçanlar kullanılmıştır. Nigrostriatal yolakta lezyon oluşturmak için sıçanların sağ medial ön beyin demetine (medial forebrain bundle; MFB) 6-hidroksidopamin (6-OHDA) enjeksiyonu yapılmıştır. Apomorfinle tetiklenen rotasyon testi ile lezyon modeli oluştuğu doğrulanan sıçanlarda LID oluşturmak için 7 günlük 12 mg/ kg L-DOPA + 15 mg/ kg benserazid tedavisi uygulanmıştır. Diskinezi seviyesi ve şiddeti Anormal İstemsiz Hareket (AIH) skoru ile değerlendirilmiştir. LID modeli oluştuğu doğrulanan sıçanlara ketamin (10 mg/ kg, 2 saat ara ile 5 i.p. enjeksiyon) veya serum fizyolojik tedavisi uygulanmış ve bu tedavilerin diskinezi üzerine etkileri AIH ve silindir testleri ile değerlendirilmiştir. Bulgular: Çalışmada lezyon oluşturulmuş hayvanlarda tekrarlayan L-DOPA tedavisinin AIH skorlarını anlamlı şekilde artırdığı gösterilmiştir (p<0,0001). Diskinetik sıçanlarda ketamin tedavisi AIH skorlarını kontrole göre anlamlı bir şekilde azaltmıştır (p<0,001). Bu iyileşmenin özellikle 60. dakikada en yüksek olduğu gözlenmiştir. Ketamin tedavisi her AIH alt tipinde (aksiyal, ekstremite, orolingual) benzer etkiler oluşturmuştur. Sonuç: Çalışmadan elde edilen sonuçlar ketamin infüzyon tedavisinin L-DOPA indüklü diskinezi yönetiminde umut verici bir uygulama olduğu fikrini desteklemektedir.
Objective: Parkinson's disease, a progressive neurodegenerative disorder, has been primarily treated with L-DOPA for approximately 60 years. However, long-term use of L-DOPA leads to serious motor complications, notably L-DOPA-induced dyskinesia (LID), limiting the effectiveness of the treatment. Preclinical studies and case reports have suggested that ketamine may be effective in mitigating dyskinetic movements. This study aims to investigate the potential effects of ketamine treatment in a rat model of LID. Materials and Methods: Adult male Sprague-Dawley rats were used in the study. Unilateral medial forebrain bundle (MFB) injections of 6-hydroxydopamine (6-OHDA) were administered to induce lesions in the nigrostriatal pathway in all rats. Rats with confirmed lesion models, verified by apomorphine-induced rotation tests, were subjected to 7 days of 12 mg/ kg L-DOPA + 15 mg/ kg benserazide treatment to induce LID. Dyskinesia levels and severity were assessed using the Abnormal Involuntary Movement (AIM) score. Rats with confirmed LID models were treated with ketamine infusion (10 mg/ kg, 5 i.p. injections) or saline, and the effects of these treatments were evaluated with AIM and cylinder tests. Results: The study demonstrated a significant impact of repeated L-DOPA treatment on AIM scores (p<0.0001). Ketamine treatment in dyskinetic rats significantly reduced AIM scores compared to the control group (p<0.001), with the highest improvement observed at 60th minutes. Ketamine treatment produced similar effects across all AIM subtypes (axial, limb, orolingual). Conclusion: The results obtained from the study support the notion that ketamine infusion therapy is a promising approach in the management of L-DOPA-induced dyskinesia.
Objective: Parkinson's disease, a progressive neurodegenerative disorder, has been primarily treated with L-DOPA for approximately 60 years. However, long-term use of L-DOPA leads to serious motor complications, notably L-DOPA-induced dyskinesia (LID), limiting the effectiveness of the treatment. Preclinical studies and case reports have suggested that ketamine may be effective in mitigating dyskinetic movements. This study aims to investigate the potential effects of ketamine treatment in a rat model of LID. Materials and Methods: Adult male Sprague-Dawley rats were used in the study. Unilateral medial forebrain bundle (MFB) injections of 6-hydroxydopamine (6-OHDA) were administered to induce lesions in the nigrostriatal pathway in all rats. Rats with confirmed lesion models, verified by apomorphine-induced rotation tests, were subjected to 7 days of 12 mg/ kg L-DOPA + 15 mg/ kg benserazide treatment to induce LID. Dyskinesia levels and severity were assessed using the Abnormal Involuntary Movement (AIM) score. Rats with confirmed LID models were treated with ketamine infusion (10 mg/ kg, 5 i.p. injections) or saline, and the effects of these treatments were evaluated with AIM and cylinder tests. Results: The study demonstrated a significant impact of repeated L-DOPA treatment on AIM scores (p<0.0001). Ketamine treatment in dyskinetic rats significantly reduced AIM scores compared to the control group (p<0.001), with the highest improvement observed at 60th minutes. Ketamine treatment produced similar effects across all AIM subtypes (axial, limb, orolingual). Conclusion: The results obtained from the study support the notion that ketamine infusion therapy is a promising approach in the management of L-DOPA-induced dyskinesia.