Selegiline increases on time without exacerbation of dyskinesia in 6-hydroxydopamine-lesioned rats displaying l-Dopa-induced wearing-off and abnormal involuntary movements.

Abstract

3,4-Dihydroxy-l-phenylalanine (l-Dopa) remains the most effective drug for treating the motor symptoms of Parkinson's disease (PD). However, its long-term use is limited due to motor complications such as wearing-off and dyskinesia. A clinical study in PD patients with motor complications has demonstrated that selegiline, a monoamine oxidase type B inhibitor, is effective in reducing off time without worsening dyskinesia, although another study has shown worsening dyskinesia. Here, using unilateral 6-hydroxydopamine-lesioned rats showing degeneration of nigrostriatal dopaminergic neurons and l-Dopa-induced motor complications, we determined the efficacy of selegiline in controlling l-Dopa-induced motor fluctuations and exacerbated dyskinesia. Repeated administration of l-Dopa/benserazide (25/6.25 mg/kg, intraperitoneally, twice daily for 22 days) progressively shortened rotational response duration (on time) and augmented peak rotation in lesioned rats. Single subcutaneous injection of selegiline (10 mg/kg) extended l-Dopa-induced shortened on time without augmenting peak rotation. Furthermore, l-Dopa/benserazide (25/6.25 mg/kg, intraperitoneally, once daily for 7 days) progressively increased abnormal involuntary movements (l-Dopa-induced dyskinesia, LID) and peak rotation. Single subcutaneous injection of selegiline (10 mg/kg) did not exacerbate LID or alter mRNA expression of prodynorphin (PDy) and activity-regulated cytoskeleton-associated protein (Arc), both mRNAs associated with LID in the lesioned striatum. Despite undetectable plasma concentrations of selegiline and its metabolites at 24 h post-administration, these on time and LID effects did not decrease, suggesting involvement of irreversible mechanisms. Altogether, these results indicate that selegiline is effective in increasing on time without worsening dyskinesia.

• Authors: Hiroko Tsunekawa, Kazue Takahata, Motoki Okano, Toshiko Ishikawa, Hiroshi Satoyoshi, Tetsuya Nishimura, Naoya Hoshino, Shizuko Muraoka
• Journal: Behavioural brain research (Behav Brain Res) Vol. 347 Pg. 350-359 (07 16 2018) ISSN: 1872-7549 [Electronic] Netherlands
• PMID: 29526790 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antiparkinson Agents
• Cytoskeletal Proteins
• Enkephalins
• Nerve Tissue Proteins
• Protein Precursors
• RNA, Messenger
• activity regulated cytoskeletal-associated protein
• Selegiline
• Levodopa
• Benserazide
• Oxidopamine
• preproenkephalin

Topics

• Animals
• Antiparkinson Agents (adverse effects, pharmacology)
• Benserazide (adverse effects, pharmacology)
• Cytoskeletal Proteins (metabolism)
• Disease Models, Animal
• Drug Therapy, Combination
• Dyskinesia, Drug-Induced (drug therapy, pathology, physiopathology)
• Enkephalins (metabolism)
• Levodopa (adverse effects, pharmacology)
• Male
• Movement (drug effects)
• Nerve Tissue Proteins (metabolism)
• Oxidopamine
• Parkinsonian Disorders (drug therapy, pathology, physiopathology)
• Protein Precursors (metabolism)
• RNA, Messenger (metabolism)
• Rats, Sprague-Dawley
• Selegiline (pharmacology)
• Time Factors