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The effect of adenosine A(2A) receptor antagonists on hydroxyl radical, dopamine, and glutamate in the striatum of rats with altered function of VMAT2.

Gołembiowska K, Dziubina A - Neurotox Res (2012)

Bottom Line: L-3,4-Dihydroxyphenylalanine (L-DOPA) (25 mg/kg) significantly enhanced extracellular DA, had no effect on reserpine-induced hydroxyl radical production and decreased extracellular glutamate concentration.CSC and ZM 241385 did not influence extracellular glutamate level, which was decreased by L-DOPA.Thus, the methylxanthine A(2A) receptor antagonists bearing properties of MAO-B inhibitor, like CSC, may cause a risk of oxidative stress resulting from dysfunctional DA storage mechanism in early PD.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, 12 Smętna Street, Kraków, Poland. nfgolemb@cyf-kr.edu.pl

ABSTRACT
It has been shown that a decreased vesicular monoamine transporter (VMAT2) function and the disruption of dopamine (DA) storage is an early contributor to oxidative damage of dopamine neurons in Parkinson's disease (PD). In our previous study, we demonstrated that adenosine A(2A) receptor antagonists suppressed oxidative stress in 6-hydroxydopamine-treated rats suggesting that this effect may account for neuroprotective properties of drugs. In the present study, rats were injected with reserpine (10 mg/kg sc) and 18 h later the effect of the adenosine A(2A) 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 extracellular DA, glutamate and hydroxyl radical formation was studied in the rat striatum using in vivo microdialysis. By disrupting VMAT2 function, reserpine depleted DA stores, and increased glutamate and hydroxyl radical levels in the rat striatum. CSC (1 mg/kg) but not ZM 241385 (3 mg/kg) increased extracellular DA level and production of hydroxyl radical in reserpinised rats. Both antagonists decreased the reserpine-induced increase in extracellular glutamate. L-3,4-Dihydroxyphenylalanine (L-DOPA) (25 mg/kg) significantly enhanced extracellular DA, had no effect on reserpine-induced hydroxyl radical production and decreased extracellular glutamate concentration. CSC but not ZM 241385 given jointly with L-DOPA increased the effect of L-DOPA on extracellular DA and augmented the reserpine-induced hydroxyl radical production. CSC and ZM 241385 did not influence extracellular glutamate level, which was decreased by L-DOPA. It seems that by decreasing the MAO-dependent DA metabolism rate, CSC raised cytosolic DA and by DA autoxidation, it induced hydroxyl radical overproduction. Thus, the methylxanthine A(2A) receptor antagonists bearing properties of MAO-B inhibitor, like CSC, may cause a risk of oxidative stress resulting from dysfunctional DA storage mechanism in early PD.

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The effects of CSC (1 mg/kg) and ZM 241385 (3 mg/kg) on L-DOPA (25 mg/kg)-induced change in extracellular level of DA (a), hydroxyl radical (3,4-DHBA, b), and glutamate (GLU, c) in the striatum of rats treated with reserpine (10 mg/kg). The injection of drugs is indicated by an arrow. The data are the mean ± SEM (n = 5–7). *P < 0.05; **P < 0.01 versus control; ^P < 0.05; ^^P < 0.01 versus reserpine; +P < 0.05; ++P < 0.01 versus reserpine + L-DOPA
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Fig4: The effects of CSC (1 mg/kg) and ZM 241385 (3 mg/kg) on L-DOPA (25 mg/kg)-induced change in extracellular level of DA (a), hydroxyl radical (3,4-DHBA, b), and glutamate (GLU, c) in the striatum of rats treated with reserpine (10 mg/kg). The injection of drugs is indicated by an arrow. The data are the mean ± SEM (n = 5–7). *P < 0.05; **P < 0.01 versus control; ^P < 0.05; ^^P < 0.01 versus reserpine; +P < 0.05; ++P < 0.01 versus reserpine + L-DOPA

Mentions: CSC (1 mg/kg), but not ZM 241385 (3 mg/kg) enhanced extracellular DA level, increased by L-DOPA (25 mg/kg) (Fig. 4a). Repeated-measures ANOVA showed a significant effect of treatment (F3,16 = 4.04, P = 0.03), time (F14,224 = 7.73, P = 0), and an interaction between both factors (F42,224 = 2.89, P = 0). Post hoc analysis with Tukey’s test showed a significant effect of L-DOPA (P < 0.05–0.01) in comparison with the reserpine group and a significant effect of CSC (P < 0.05–0.01) in comparison with rats treated with reserpine and L-DOPA. The L-DOPA-increased extracellular levels of DOPAC and HVA were unchanged by CSC and ZM 241385 (results not shown).Fig. 4


The effect of adenosine A(2A) receptor antagonists on hydroxyl radical, dopamine, and glutamate in the striatum of rats with altered function of VMAT2.

Gołembiowska K, Dziubina A - Neurotox Res (2012)

The effects of CSC (1 mg/kg) and ZM 241385 (3 mg/kg) on L-DOPA (25 mg/kg)-induced change in extracellular level of DA (a), hydroxyl radical (3,4-DHBA, b), and glutamate (GLU, c) in the striatum of rats treated with reserpine (10 mg/kg). The injection of drugs is indicated by an arrow. The data are the mean ± SEM (n = 5–7). *P < 0.05; **P < 0.01 versus control; ^P < 0.05; ^^P < 0.01 versus reserpine; +P < 0.05; ++P < 0.01 versus reserpine + L-DOPA
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Related In: Results  -  Collection

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Fig4: The effects of CSC (1 mg/kg) and ZM 241385 (3 mg/kg) on L-DOPA (25 mg/kg)-induced change in extracellular level of DA (a), hydroxyl radical (3,4-DHBA, b), and glutamate (GLU, c) in the striatum of rats treated with reserpine (10 mg/kg). The injection of drugs is indicated by an arrow. The data are the mean ± SEM (n = 5–7). *P < 0.05; **P < 0.01 versus control; ^P < 0.05; ^^P < 0.01 versus reserpine; +P < 0.05; ++P < 0.01 versus reserpine + L-DOPA
Mentions: CSC (1 mg/kg), but not ZM 241385 (3 mg/kg) enhanced extracellular DA level, increased by L-DOPA (25 mg/kg) (Fig. 4a). Repeated-measures ANOVA showed a significant effect of treatment (F3,16 = 4.04, P = 0.03), time (F14,224 = 7.73, P = 0), and an interaction between both factors (F42,224 = 2.89, P = 0). Post hoc analysis with Tukey’s test showed a significant effect of L-DOPA (P < 0.05–0.01) in comparison with the reserpine group and a significant effect of CSC (P < 0.05–0.01) in comparison with rats treated with reserpine and L-DOPA. The L-DOPA-increased extracellular levels of DOPAC and HVA were unchanged by CSC and ZM 241385 (results not shown).Fig. 4

Bottom Line: L-3,4-Dihydroxyphenylalanine (L-DOPA) (25 mg/kg) significantly enhanced extracellular DA, had no effect on reserpine-induced hydroxyl radical production and decreased extracellular glutamate concentration.CSC and ZM 241385 did not influence extracellular glutamate level, which was decreased by L-DOPA.Thus, the methylxanthine A(2A) receptor antagonists bearing properties of MAO-B inhibitor, like CSC, may cause a risk of oxidative stress resulting from dysfunctional DA storage mechanism in early PD.

View Article: PubMed Central - PubMed

Affiliation: Institute of Pharmacology, Polish Academy of Sciences, 31-343 Kraków, 12 Smętna Street, Kraków, Poland. nfgolemb@cyf-kr.edu.pl

ABSTRACT
It has been shown that a decreased vesicular monoamine transporter (VMAT2) function and the disruption of dopamine (DA) storage is an early contributor to oxidative damage of dopamine neurons in Parkinson's disease (PD). In our previous study, we demonstrated that adenosine A(2A) receptor antagonists suppressed oxidative stress in 6-hydroxydopamine-treated rats suggesting that this effect may account for neuroprotective properties of drugs. In the present study, rats were injected with reserpine (10 mg/kg sc) and 18 h later the effect of the adenosine A(2A) 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 extracellular DA, glutamate and hydroxyl radical formation was studied in the rat striatum using in vivo microdialysis. By disrupting VMAT2 function, reserpine depleted DA stores, and increased glutamate and hydroxyl radical levels in the rat striatum. CSC (1 mg/kg) but not ZM 241385 (3 mg/kg) increased extracellular DA level and production of hydroxyl radical in reserpinised rats. Both antagonists decreased the reserpine-induced increase in extracellular glutamate. L-3,4-Dihydroxyphenylalanine (L-DOPA) (25 mg/kg) significantly enhanced extracellular DA, had no effect on reserpine-induced hydroxyl radical production and decreased extracellular glutamate concentration. CSC but not ZM 241385 given jointly with L-DOPA increased the effect of L-DOPA on extracellular DA and augmented the reserpine-induced hydroxyl radical production. CSC and ZM 241385 did not influence extracellular glutamate level, which was decreased by L-DOPA. It seems that by decreasing the MAO-dependent DA metabolism rate, CSC raised cytosolic DA and by DA autoxidation, it induced hydroxyl radical overproduction. Thus, the methylxanthine A(2A) receptor antagonists bearing properties of MAO-B inhibitor, like CSC, may cause a risk of oxidative stress resulting from dysfunctional DA storage mechanism in early PD.

Show MeSH
Related in: MedlinePlus