Immobilization stress causes increases in tetrahydrobiopterin, dopamine, and neuromelanin and oxidative damage in the nigrostriatal system

• Published in: Journal of neurochemistry Vol. 95; no. 1; pp. 89 - 98
• Main Authors: Kim, Sung Tae, Choi, Ji Hyun, Chang, Jin Woo, Kim, Seong Who, Hwang, Onyou
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.10.2005; Blackwell; Blackwell Publishing Ltd
• Subjects: Animals; Biochemistry; Biological and medical sciences; Biopterins - analogs & derivatives; Biopterins - antagonists & inhibitors; Biopterins - metabolism; Brain - metabolism; Brain - pathology; Catalase - metabolism; Corpus Striatum - metabolism; Corpus Striatum - pathology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; dopamine; Dopamine - metabolism; Enzyme Inhibitors - pharmacology; Hypoxanthines - pharmacology; immobilization stress; Male; Medical sciences; Melanins - metabolism; Mice; Mice, Inbred ICR; Nerve Degeneration - etiology; Nerve Degeneration - pathology; Nerve Fibers - pathology; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; neuromelanin; Neurotransmitters; Oxidation; Oxidative Stress; Parkinson's disease; Restraint, Physical; Stress, Physiological - complications; Stress, Physiological - etiology; Stress, Physiological - metabolism; Substantia Nigra - metabolism; Substantia Nigra - pathology; Superoxide Dismutase - metabolism; tetrahydrobiopterin; Tyrosine 3-Monooxygenase - metabolism; Oxidative stress; tetrahydrobiopterin; Parkinson's disease; Parkinson disease; Lipids; Tyrosine 3-monooxygenase; immobilization stress; Endogenous; neuromelanin; Degenerative disease; Degeneration; Peroxidation; Nervous system diseases; Dopamine; Pathophysiology; Enzyme; Vulnerability; Catecholamine; Protein; Cerebral disorder; GTP cyclohydrolase I; Central nervous system disease; Neurotransmitter; Hydrolases; Dopaminergic neuron; Oxidoreductases; Extrapyramidal syndrome
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2005.03342.x

Oxidative stress is believed to contribute to the pathophysiology of Parkinson's disease, in which nigrostriatal dopaminergic (DA) neurons undergo degeneration. Identification of endogenous molecules that contribute to generation of oxidative stress and vulnerability of these cells is critical in understanding the etiology of this disease. Exposure to tetrahydrobiopterin (BH4), the obligatory cofactor for DA synthesis, was observed previously to cause oxidative damage in DA cells. To demonstrate the physiological relevance of this observation, we investigated whether an overproduction of BH4 and DA might actually occur in vivo, and, if it did, whether this might lead to oxidative damage to the nigrostriatal system. Immobilization stress (IMO) elevated BH4 and DA and their synthesizing enzymes, tyrosine hydroxylase and GTP cyclohydrolase I. This was accompanied by elevation of lipid peroxidation and protein‐bound quinone, and activities of antioxidant enzymes. These increases in the indices of oxidative stress appeared to be due to increased BH4 synthesis because they were abolished following administration of the BH4 synthesis inhibitor, 2,4‐diamino‐6‐hydroxy‐pyrimidine. IMO also caused accumulation of neuromelanin and degeneration of the nigrostriatal system. These results demonstrate that a severe stress can increase BH4 and DA and cause oxidative damages to the DA neurons in vivo, suggesting relevance to Parkinson's disease.