Altered amantadine effects after repetitive treatment for l-dopa-induced involuntary movements in a rat model of Parkinson's disease. (29th May 2023)

• Record Type: Journal Article
• Authors: Murakami, Yoshiki; Nishijima, Haruo; Nakamura, Takashi; Furukawa, Tomonori; Kinoshita, Iku; Kon, Tomoya; Suzuki, Chieko; Tomiyama, Masahiko
• Is Part Of: Neuroscience letters. Volume 806(2023)
• Publication Date: 2023-05-29
• Subjects: 6-hydroxydopamine -- Dendritic spine -- Dopamine -- Drebrin -- Dyskinesia -- Wearing off; 6-OHDA 6-hydroxydopamine -- AIM abnormal involuntary movement -- ALO axial, forelimb, and orolingual -- AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid -- LA-L l-dopa plus amantadine treatment for 15 days, followed by l-dopa treatment for 16 days -- LA-LA l-dopa plus amantadine treatment for 31 days -- l-dopa levo-dihydroxyphenylalanine -- LID l-dopa-induced dyskinesia -- L-L l-dopa treatment for 31 days -- L-LA l-dopa treatment for 15 days, followed by l-dopa plus amantadine treatment for 16 days -- MFB medial forebrain bundle -- NIH National Institutes of Health -- NMDA N-methyl-d-aspartate -- PD Parkinson's disease -- PFA paraformaldehyde; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2023.137248
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: Motor fluctuations with L-dopa treatment are characteristic of Parkinson's disease. Long-term amantadine therapy efficacy remains unknown. Effect of repetitive L-dopa with or without amantadine was investigated in rat models. Anti-dyskinesia effect of amantadine disappeared after repetitive treatment. Off-time reduction by amantadine appeared after chronic treatment. Abstract: Background: l -3, 4-dihydroxyphenylalanine (l -dopa) is the most effective drug for Parkinson's disease (PD); however, most PD patients develop motor fluctuations including wearing-off and l -dopa-induced dyskinesia (LID). Amantadine is beneficial for improving the motor symptoms, reducing "off" time, and ameliorating LID, although its long-term efficacy remains unknown. Objectives: To investigate the effects of amantadine on PD and LID using a rat model with repetitive drug treatment. Method: We utilized 6-hydroxydopamine injections to develop a hemiparkinsonian rat model. The rats were assigned to four groups: five rats received l -dopa and benserazide for 31 days, six rats received l -dopa and benserazide plus amantadine for 31 days, five rats received l -dopa and benserazide for 15 days followed by l -dopa and benserazide plus amantadine for 16 days, and five rats received l -dopa and benserazide plus amantadine for 15 days followed by l -dopa and benserazide treatment for 16 days. We evaluated the l -dopa-induced abnormal involuntary movements on treatment days 1, 7, 14, 16, 22, and 29. Subsequently, immunohistochemistry for drebrin was performed. Results: l -dopa-induced abnormal movements were reduced on the first day of amantadine treatment, and these effects disappeared with repetitive treatment. In contrast, the extension of l -dopa "on" time was observed after repetitive amantadine treatment. All groups showed enlarged drebrin immunoreactive dots in the dopamine-denervated striatum, indicating that amantadine did not prevent priming effects of repetitive l -dopa treatment. Conclusion: Anti-LID effect of amantadine diminished after repetitive treatment, and the effect of amantadine on wearing-off emerged after repetitive treatment in a hemiparkinsonian rat model. Fluctuations in amantadine effects should be considered when using it in clinical settings.