Dopamine Agonist Pergolide Prevents Levodopa-Induced Quinoprotein Formation in Parkinsonian Striatum and Shows Quenching Effects on Dopamine-Semiquinone Generated in Vitro

Abstract

The neurotoxicity of dopamine (DA) quinones that appears in dopaminergic neuron-specific oxidative stress has recently been shown to play a role in the pathogenesis and/or progression of Parkinson disease. To clarify the effects of a DA agonist, pergolide, on the levodopa-induced elevation of quinones, the authors examined striatal changes in quinoprotein using a hemi-parkinsonian mouse model. The level of striatal quinoprotein was significantly elevated specifically on the parkinsonian side, but not on the control side, after repeated levodopa administration. This levodopa-induced increase in striatal quinoprotein was almost completely suppressed by adjunctive administration with pergolide on the lesioned side. Furthermore, it was clarified that pergolide scavenged DA-semiquinones generated in vitro in a dose-dependent manner. These suppressive and quenching effects of pergolide against cytotoxic DA quinones may play a key role in its neuroprotective mechanism in the parkinsonian brain.

Approaches to Prevent Dopamine Quinone-Induced Neurotoxicity

“…We reported that pergolide and pramipexole scavenged DA-semiquinone generated in vitro in a dose-dependent manner [33]. Pergolide completely blocked the increase of striatal quinoprotein level, which elevated specifically on the parkinsonian side of hemi-parkinsonian mice with repeated L-DOPA administration [8]. These quenching effects of DA agonists against cytotoxic DA quinones could play a key role in its neuroprotective mechanism in the parkinsonian brain.…”

“…Furthermore, the ELLDOPA study, which tried to clarify whether or not L-DOPA is toxic and accelerates the progression of Parkinson's disease, showed that long-term L-DOPA treatment improved clinical PD symptoms but decreased striatal DA uptake (b-CIT) in SPECT as a functional marker of DAT and caused adverse events of dyskinesia [32]. Indeed, we previously reported that repeated L-DOPA administration (50 mg/kg/day) for 7 days elevated striatal DA turnover (2.7-fold) and quinone generation (2.4-fold) specifically on the parkinsonian side, but not on the control side, of hemi-parkinsonian models [8,33,34]. Therefore, the excess amount of cytosolic DA outside the synaptic vesicles after L-DOPA treatment may exert functional inhibitory effects on DA re-uptake through dysfunction of DAT (decline of b-CIT uptake) by probably quinone generation, but not neurodegenerative effects on dopaminergic neurons.…”

“…These quinones generated from DA or L-DOPA exert cytotoxicity in or beside dopaminergic neurons by interacting with various bioactive molecules. In our previous reports, it has been shown that quinone formation plays an important role in a model of Parkinson's disease [8] and in methamphetamine (METH)-induced dopaminergic neurotoxicity [9]. Furthermore, several studies have clarified that the cytotoxicity of quinone formation is closely linked to other hypotheses of pathogenesis of Parkinson's disease and METH neurotoxicity such as mitochondrial dysfunction, inflammation and proteasome impairment [10][11][12][13].…”

Nonsteroidal anti-inflammatory drugs in Parkinson’s disease: possible involvement of quinone formation

“…We recently revealed that the DA agonists pergolide and pramipexole possess not only ROS/RNS-scavenging activities and glutathione-increasing effects, but also a quenching effect on DA-semiquinone radicals generated in vitro [109,110]. In particular, pergolide dramatically prevents repeated L-DOPA administration-induced striatal quinone generation specifically in the lesioned side of hemiparkinsonian models [109]. Regarding the specificity to the dopaminergic neuronal system and the clinical efficacy, DA agonists may be the most potential therapeutic reagents against DA quinone-induced toxicity.…”

“…Furthermore, the Earlier versus Later Levodopa (ELLDOPA) study, which tried to clarify whether or not L-DOPA is toxic and accelerates the progression of PD, showed that L-DOPA-treated patients had an increased rate of decline in striatal DA uptake (β-CIT) in single photon emission computed tomography (SPECT), although patients treated with L-DOPA showed less clinical deterioration [107]. We previously revealed that repeated L-DOPA administration (50 mg/kg/day) for 7 days elevated striatal DA turnover (2.7-fold) and quinone generation (2.4-fold) specifically in the parkinsonian side, but not in the control side, of hemiparkinsonian models [108][109][110]. Therefore, the excess amount of cytosolic DA outside of the synaptic vesicles after L-DOPA treatment may exert neurodegenerative effects through quinone generation, at least in the damaged dopaminergic nerve terminals.…”