Shizuko Muraoka

Protective effects of selegiline and desmethylselegiline against N-methyl-D-aspartate-induced rat retinal damage

Selegiline, a therapeutic agent of Parkinsons disease, and its metabolite, desmethylselegiline, were explored for their neuroprotective effects against N-methyl-D-aspartate (NMDA)-induced cell death in rat retina. Morphometric analysis of the retina revealed that an intravitreal injection of NMDA induced a significant decrease in cell density in the ganglion cell layer and in thickness of the inner plexiform layer, but not of other retinal layers such as the outer nuclear layer. Concurrent intravitreal injection of selegiline with NMDA did not show a significant protective effect, whereas co-injection of desmethylselegiline provided protection from NMDA-induced retinal damage. Parenteral administration (both single and consecutive dosing) of selegiline significantly prevented loss of ganglion cell layer cells. Counting of retinal ganglion cells by fluorescent tracer labeling confirmed that selegiline protected retinal ganglion cells from NMDA toxicity. The selegiline treatment did not produce a significant increase, though it tended to such as effect, in a brain-derived neurotrophic factor (BDNF) level in the retina, when compared with the NMDA-treated control group. These results indicate that parenteral treatment with selegiline rescues inner retinal cells from NMDA-induced neural damage, and that desmethylselegiline may contribute, in part, to the protective activities of selegiline. The neuroprotective effects exerted by selegiline may be attributed partially to a change in the retinal BDNF expression.

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

HighlightsSelegiline extends l‐Dopa‐induced shortened on time in hemi‐parkinsonian rats.Selegiline does not exacerbate l‐Dopa‐induced dyskinesia in hemi‐parkinsonian rats.Selegiline does not alter PDy and Arc mRNA expression in the lesioned striatum. 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.

Selegiline ameliorates depression-like behaviors in rodents and modulates hippocampal dopaminergic transmission and synaptic plasticity

HighlightsRepeated selegiline injection reduces immobility time in rodent depression tests.Antidepressant‐like action of selegiline is independent of MAO‐A inhibition.Selegiline increases DA content and prevents LTP impairment in the hippocampus. Abstract Selegiline, an irreversible inhibitor of monoamine oxidase (MAO)‐type B, is widely prescribed for Parkinson’s disease and, at higher doses, for major and atypical depression, whereby it is non‐selectively inhibitory to both MAO‐A and MAO‐B activities. MAO inhibitors have been considered to function as antidepressants through MAO‐A inhibition. We have previously reported that selegiline exerts antidepressant‐like effects in the mouse forced swim test (FST) via dopamine D1 receptor activation. Our objective was to elucidate the mechanisms underlying the antidepressant‐like effects of selegiline. We also tested another propargylamine MAO‐B inhibitor, rasagiline. Triple subcutaneous injection (at 24, 5, and 1 h prior to behavioral testing) with selegiline (10 mg/kg/injection), but not rasagiline (1, 3, or 10 mg/kg/injection), reduced the immobility time in the mouse FST and rat tail suspension test. In the hippocampus and prefrontal cortex of mice subjected to the FST, selegiline and rasagiline completely inhibited MAO‐B activities. However, selegiline suppressed MAO‐A activities and monoamine turnover rates at a lesser degree than rasagiline at the same doses, indicating that the antidepressant‐like effects of selegiline are independent of MAO‐A inhibition. Moreover, selegiline, but not rasagiline, increased the hippocampal dopamine content. A single subcutaneous administration of 10 mg/kg selegiline, but not of rasagiline, significantly prevented hippocampal CA1 long‐term potentiation impairment, induced by low‐frequency stimulation prior to high‐frequency stimulation in rats. These results suggest that the antidepressant‐like effects of selegiline are attributable to enhancement of dopaminergic transmission and prevention of the impairment of synaptic plasticity in the hippocampus.