Alteration of striatal tetrahydrobiopterin in iron-induced unilateral model of Parkinson's disease.
It has been suggested that transition metal ions such as iron can produce an oxidative injuries to nigrostriatal dopaminergic neurons, like Parkinson's disease (PD) and subsequent compensative increase of tetrahydrobiopterin (BH4) during the disease progression induces the aggravation of dopaminergic neurodegeneration in striatum. It had been established that the direct administration of BH4 into neuron would induce the neuronal toxicity in vitro. To elucidate a role of BH4 in pathogenesis in the PD in vivo, we assessed the changes of dopamine (DA) and BH4 at striatum in unilateral intranigral iron infused PD rat model. The ipsistriatal DA and BH4 levels were significantly increased at 0.5 to 1 d and were continually depleting during 2 to 7 d after intranigral iron infusion. The turnover rate of BH4 was higher than that of DA in early phase. However, the expression level of GTP-cyclohydrolase I mRNA in striatum was steadily increased after iron administration. These results suggest that the accumulation of intranigral iron leads to generation of oxidative stress which damage to dopaminergic neurons and causes increased release of BH4 in the dopaminergic neuron. The degenerating dopaminergic neurons decrease the synthesis and release of both BH4 and DA in vivo that are relevance to the progression of PD. Based on these data, we propose that the increase of BH4 can deteriorate the disease progression in early phase of PD, and the inhibition of BH4 increase could be a strategy for PD treatment.
Department of Pharmacology, College of Medicine, Dankook University, Cheonan 330-714, Korea.
Bijay
B
Aryal
Department of Pharmacology, College of Medicine, Dankook University, Cheonan 330-714, Korea. ; Translational Research Center, Institute of Bio-Science Technology, Dankook University, Cheonan 330-714, Korea.
Jin-Koo
JK
Lee
Department of Pharmacology, College of Medicine, Dankook University, Cheonan 330-714, Korea. ; Translational Research Center, Institute of Bio-Science Technology, Dankook University, Cheonan 330-714, Korea.
Hak Rim
HR
Kim
Department of Pharmacology, College of Medicine, Dankook University, Cheonan 330-714, Korea. ; Translational Research Center, Institute of Bio-Science Technology, Dankook University, Cheonan 330-714, Korea.
Hyung-Gun
HG
Kim
Dopamine; Ferrous citrate; GTP-cyclohydrolase I; Parkinson's disease; Tetrahydrobiopterin