Korean J Physiol Pharmacol.  2014 Apr;18(2):129-134. 10.4196/kjpp.2014.18.2.129.

Alteration of Striatal Tetrahydrobiopterin in Iron-Induced Unilateral Model of Parkinson's Disease

• Aryal B
• Lee JK
• Kim HR
• Kim HG

• KMID: 2285501
• DOI: http://doi.org/10.4196/kjpp.2014.18.2.129

Abstract

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.

Keyword

Dopamine; Ferrous citrate; GTP-cyclohydrolase I; Parkinson's disease; Tetrahydrobiopterin

MeSH Terms

Disease Progression
Dopamine
Dopaminergic Neurons
Ions
Iron
Models, Animal
Neurons
Oxidative Stress
Parkinson Disease*
RNA, Messenger
Dopamine
Ions
Iron
RNA, Messenger

Figure

• 

  Fig. 1 Histological verification of unilateral intranigral iron infusion. Coronal section image after unilateral intranigral iron infusion (A). Arrow indicate injected site of microdialysis probe tip. Crystal violet staining in ferrous citrate infused SN (ipsilateral SN) (B). SNC, substantia nigra pars compacta; SNR, substantia nigra pars reticular.

• 

  Fig. 2 Alterations of ipsistriatal DA levels in intranigral iron infused rats. Wet tissue was isolated from both ipsistriatum and contrastriatum of intranigral unilateral saline (4.0 µL) or ferrous citrate (4.0 µL, 2 mM) infused rats at 0, 0.5, 1, 2, 4, and 7 days after challenge. DA level was measured by LC-MS/MS. The levels of DA (ng/wet tissue weight g) convert to % of ipsistriatal / contrastriatal level. Values are mean±SEM (*p<0.05, **p<0.01, ***p<0.001; compared to control group, n=6).

• 

  Fig. 3 Alterations of ipsistriatal BH4 levels in intranigral iron infused rats. Wet tissue was isolated from both ipsistriatum and contrastriatum of intranigral unilateral saline (4.0 µL) or ferrous citrate (4.0 µL, 2 mM) infused rats at 0, 0.5, 1, 2, 4, and 7 days after challenge. BH4 level was measured by LC-MS/MS. The levels of BH4 (ng/wet tissue weight g) convert to % of ipsistriatal / contrastriatal level. Values are mean±SEM (*p<0.05, **p<0.01, ***p<0.001; compared to control group, n=6).

• 

  Fig. 4 Changes of ipsistriatal GTP-CH I mRNA levels in intranigral iron infused rats. Total RNA was isolated from both ipsistriatum and contrastriatum of intranigral unilateral saline (4.0 µL) or ferrous citrate (4.0 µL, 2 mM) infused rats at 0, 0.5, 1, 2, 4, and 7 days after challenge. Gene expression of GTP-CH I was measured by quantitative real-time PCR using Rotor-Gene 3000. The mRNA level of GTP-CH I (ipsistriatum / contrastriatum) was normalized with GAPDH gene expression. Data were obtained from triplicated PCR reactions, and values are mean±SEM (*p<0.05, **p<0.01, ***p<0.001; compared to control group, n=6).

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