Research reportDopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist
Introduction
Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic (DAergic) neurons of the nigrostriatal system and dopamine (DA) replacement therapy with levodopa is currently the gold standard for symptomatic treatment for PD. Although the introduction of levodopa has markedly improved the prognosis of PD, gradual progression of the disease occurs despite levodopa therapy, resulting in severe impairment of quality of life (QOL) 10 years or more after the disease onset. Furthermore, if high-dose levodopa therapy is continued for several years, the majority of patients begin to experience various adverse reactions, including the wearing-off phenomenon, on–off phenomenon, dyskinesia and psychiatric symptoms 8, 12, 27.
Various mechanisms have been implicated in the progression of PD. Among them, the free radical/oxidative stress hypothesis has been accepted as the most plausible mechanism of disease progression 1, 10, 21, 35. High-dose levodopa therapy has also been suggested to produce free radicals and increase oxidative stress, and some experimental and clinical studies have suggested that treatment with levodopa may accelerate the progression of PD 1, 9, 14, 18, 45, although direct evidence is lacking and the subject is controversial 7, 39.
Based on the free radical hypothesis for PD, and in view of the complications associated with levodopa therapy, an alternative approach to treatment of this disorder would be the use of antioxidant or neuroprotective therapy to prevent or slow down PD progression 20, 25, 31. Among possible neuroprotective agents, DA agonists, particularly of the ergot derivative, such as pergolide or bromocriptine, are reported to have neuroprotective effects in experimental models 20, 25, 31, and may prevent observable clinical progression of the disease 16, 19, 26. Ergot derivatives with DAergic activity have been reported to scavenge free radicals in vitro 15, 17, 28, 34, 42, 44 and show a neuroprotective effect in vivo 4, 24, 34. Non-ergot DA agonists have also been recently used in the treatment of PD despite a lack of substantial evidence of any free radical scavenging or antioxidant activity. The present study was conducted to assess the in vitro free radical scavenging activity and antioxidant activity of ropinirole, a non-ergot DA agonist, and its in vivo neuroprotective properties.
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Drugs and chemical agents
Ropinirole was provided by SmithKline Beecham (Middlesex, UK). Methylcellulose (used as a vehicle for ropinirole) was purchased from Wako (Tokyo, Japan). 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy–PTIO) and 3-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-propanamine (NOC-7) were purchased from Labotec (Tokyo) and from Dojin Laboratories (Kumamoto, Japan), respectively. 4-Hydroxy-TEMPO, 6-hydroxydopamine hydrobromide (6-OHDA) and sulpiride were purchased from
HO⋅ scavenging activity
HO⋅ radicals produced by Fenton's reaction between Fe2+ and H2O2 were trapped by DMPO and the DMPO–HO⋅ adducts generated were quantified by ESR spectrometry. Ropinirole reduced the level of DMPO–HO⋅ adducts in a concentration-dependent manner (Fig. 1A). Ropinirole showed a clear scavenging effect at 80 μM with an approximate IC50 of 1.5 mM (Fig. 1B). Ropinirole had a lower scavenging activity than the other two ergot DA agonists, pergolide and bromocriptine, and their IC50 values were 300 μM
Discussion
The free radical hypothesis is thought to be the most plausible mechanism explaining the progression of PD. Indeed, an increased deposition of iron [11], which promotes the production of free radicals, has been reported in the brains of patients with PD. In addition, biochemical measurements on postmortem brains have shown increased lipid peroxidation and reduced levels of free radical scavengers such as GSH, GSH peroxidase and catalase 3, 23, 37.
Furthermore, it should be noted that free
Acknowledgements
This work was supported in part by Grants-in-Aid for Scientific Research on Priority Areas and Scientific Research (C) from the Japanese Ministry of Education, Science, Sports and Culture, and grants from the Research Committee on CNS Degenerative Diseases, Comprehensive Research on Aging and Health and Research on Brain Science from the Japanese Ministry of Health and Welfare. We would like to thank Miss Kumi Sato for her technical support.
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2020, Ageing Research ReviewsCitation Excerpt :Pramipexole was shown to normalize the level of Glutathione (GSH) and GSH peroxidase (Lieberknecht et al., 2017) in animal models of PD. Ropinirole is believed to increase the activities of GSH, catalase, and Superoxide dismutase which scavenge ROS, while pretreatment with D2R/D3R antagonist blockers abolished this protective effect (Iida et al., 1999). Although most authors believed that D3R activation is necessary for the demonstrated reduction in ROS injury (Li et al., 2010a), some have shown that this can be independent of D3R activation (Le et al., 2000).