Repeated administration of high dose levodopa enhances hydroxyl radical production in the rat striatum denervated with 6-hydroxydopamine

Ishida, Yoshiteru; Hashiguchi, Hiroyuki; Todaka, Kazunari; Ishizuka, Yuta; Mitsuyama, Yoshio

doi:10.1016/s0304-3940(00)01320-3

Cited by 16 publications

(12 citation statements)

References 18 publications

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“…These data contrast with Camp et al (2000), who found that L-dopa, acutely or chronically (5 days), did not elevate extracellular hydroxyl radicals in the rat striatum (Camp et al, 2000). This difference may be due to a longer duration of treatment in the present study (10 days) and the finding that a separate group showed that when L-dopa was given for an even longer duration Chronic L-Dopa Decreases Serotonin Neurons (16 days), hydroxyl radical production was significantly increased (Ishida et al, 2000). Regardless, the current study is consistent with the finding that L-dopa can produce intracellular reactive oxygen species and cell death to cultured 5-HT neurons in a manner that is dependent on the formation of dopamine and the degradation of dopamine by MAO (Stansley and Yamamoto, 2013).…”

Section: Discussioncontrasting

confidence: 83%

Chronic l-Dopa Decreases Serotonin Neurons in a Subregion of the Dorsal Raphe Nucleus

Stansley

Yamamoto

2014

J Pharmacol Exp Ther

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L-Dopa (L-3,4-dihydroxyphenylalanine) is the precursor to dopamine and has become the mainstay therapeutic treatment for Parkinson's disease. Chronic L-dopa is administered to recover motor function in Parkinson's disease patients. However, drug efficacy decreases over time, and debilitating side effects occur, such as dyskinesia and mood disturbances. The therapeutic effect and some of the side effects of L-dopa have been credited to its effect on serotonin (5-HT) neurons. Given these findings, it was hypothesized that chronic L-dopa treatment decreases 5-HT neurons in the dorsal raphe nucleus (DRN) and the content of 5-HT in forebrain regions in a manner that is mediated by oxidative stress. Rats were treated chronically with L-dopa (6 mg/kg; twice daily) for 10 days. Results indicated that the number of 5-HT neurons was significantly decreased in the DRN after L-dopa treatment compared with vehicle. This effect was more pronounced in the caudal-extent of the dorsal DRN, a subregion found to have a significantly higher increase in the 3,4-dihydroxyphenylacetic acid/dopamine ratio in response to acute L-dopa treatment. Furthermore, pretreatment with ascorbic acid (400 mg/kg) or deprenyl (2 mg/kg) prevented the L-dopa-induced decreases in 5-HT neurons. In addition, 5-HT content was decreased significantly in the DRN and prefrontal cortex by L-dopa treatment, effects that were prevented by ascorbic acid pretreatment. Taken together, these data illustrate that chronic L-dopa causes a 5-HT neuron loss and the depletion of 5-HT content in a subregion of the DRN as well as in the frontal cortex through an oxidative-stress mechanism.

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Section: Discussioncontrasting

confidence: 83%

Chronic l-Dopa Decreases Serotonin Neurons in a Subregion of the Dorsal Raphe Nucleus

Stansley

Yamamoto

2014

J Pharmacol Exp Ther

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“…The latter observation we have made is very interesting in the light of controversies related to l-DOPA toxicity. The argument is that in some in vitro and in vivo experimental models, e.g., following rotenone (Nakao et al 1997) or 6-OHDA administration (Cleren et al 1999, Ishida et al 2000), it was shown that oxidative stress may be the cause of l-DOPA toxicity. On the other hand, some reports have indicated neuroprotective effects, since l-DOPA given systematically acutely or repeatedly, as well as by intrastriatal infusion, diminished free radical production in rats with a unilateral 6-OHDA lesion of nigrostriatal neurons (Camp et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Effect of Adenosine A2A Receptor Antagonists and l-DOPA on Hydroxyl Radical, Glutamate and Dopamine in the Striatum of 6-OHDA-Treated Rats

Gołembiowska

Dziubina

2011

Neurotox Res

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A2A adenosine receptor antagonists have been proposed as a new therapy of PD. Since oxidative stress plays an important role in the pathogenesis of PD, we studied the effect of the selective A2A adenosine receptor antagonists 8-(-3-chlorostyryl)caffeine (CSC) and 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) on hydroxyl radical generation, and glutamate (GLU) and dopamine (DA) extracellular level using a microdialysis in the striatum of 6-OHDA-treated rats. CSC (1 mg/kg) and ZM 241385 (3 mg/kg) given repeatedly for 14 days decreased the production of hydroxyl radical and extracellular GLU level, both enhanced by prior 6-OHDA treatment in dialysates from the rat striatum. CSC and ZM 241385 did not affect DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA) extracellular levels in the striatum of 6-OHDA-treated rats. l-DOPA (6 mg/kg) given twice daily for two weeks in the presence of benserazide (3 mg/kg) decreased striatal hydroxyl radical and glutamate extracellular level in 6-OHDA-treated rats. At the same time, l-DOPA slightly but significantly increased the extracellular levels of DOPAC and HVA. A combined repeated administration of l-DOPA and CSC or ZM 241385 did not change the effect of l-DOPA on hydroxyl radical production and glutamate extracellular level in spite of an enhancement of extracellular DA level by CSC and elevation of extracellular level of DOPAC and HVA by ZM 241385. The data suggest that the 6-OHDA-induced damage of nigrostriatal DA-terminals is related to oxidative stress and excessive release of glutamate. Administration of l-DOPA in combination with CSC or ZM 241385, by restoring striatal DA-glutamate balance, suppressed 6-OHDA-induced overproduction of hydroxyl radical.

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“…The toxicity of L-DOPA has been attributed to the generation of reactive oxygen species (ROS), such as hydrogen peroxide (H 2 O 2 ), superoxide (O 2 ÅÀ ) and hydroxyl radicals (OH À ) (Ishida et al, 2000;Soliman et al, 2002). This is due to an increase in the intracellular DA metabolism which is dependent on monoamine oxidase (MAO) and the autooxidation of L-DOPA and DA to quinones (Basma et al, 1995) principally by means of an overflow of DA in the synaptic cleft.…”

Section: Idiopathicmentioning

confidence: 99%

Nitrosative and cognitive effects of chronic l-DOPA administration in rats with intra-nigral 6-OHDA lesion

2015

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Repeated administration of high dose levodopa enhances hydroxyl radical production in the rat striatum denervated with 6-hydroxydopamine

Cited by 16 publications

References 18 publications

Chronic l-Dopa Decreases Serotonin Neurons in a Subregion of the Dorsal Raphe Nucleus

Chronic l-Dopa Decreases Serotonin Neurons in a Subregion of the Dorsal Raphe Nucleus

Effect of Adenosine A2A Receptor Antagonists and l-DOPA on Hydroxyl Radical, Glutamate and Dopamine in the Striatum of 6-OHDA-Treated Rats

Nitrosative and cognitive effects of chronic l-DOPA administration in rats with intra-nigral 6-OHDA lesion

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