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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.

journal_name

Behav Brain Res

journal_title

Behavioural brain research

authors

Tsunekawa H,Takahata K,Okano M,Ishikawa T,Satoyoshi H,Nishimura T,Hoshino N,Muraoka S

doi

10.1016/j.bbr.2018.03.002

subject

Has Abstract

pub_date

2018-07-16 00:00:00

pages

350-359

eissn

0166-4328

issn

1872-7549

pii

S0166-4328(18)30032-9

journal_volume

347

pub_type

杂志文章

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