Oral uridine pro-drug PN401 decreases neurodegeneration, behavioral impairment, weight loss and mortality in the 3-nitropropionic acid mitochondrial toxin model of Huntington's disease
| Autor: | Zhongyi Hu, Lian Sheng Liu, Rolando Garcia, Joel A. Saydoff, Reid W. von Borstel, Donna Li |
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| Rok vydání: | 2003 |
| Předmět: |
Male
Respiratory chain Administration Oral Substantia nigra Acetates Motor Activity Pharmacology Mitochondrion Biology Neuroprotection Mice chemistry.chemical_compound Huntington's disease Oral administration Weight Loss medicine Animals Prodrugs Uridine Molecular Biology General Neuroscience Neurodegeneration Nitro Compounds medicine.disease Mitochondria Huntington Disease Biochemistry chemistry Nerve Degeneration Neurology (clinical) Propionates Developmental Biology |
| Zdroj: | Brain Research. 994:44-54 |
| ISSN: | 0006-8993 |
| DOI: | 10.1016/j.brainres.2003.09.049 |
| Popis: | Huntington's disease (HD) is associated with decreased activity of mitochondrial succinate dehydrogenase (complex II). De novo biosynthesis of uridine nucleotides is directly coupled to the respiratory chain. Cells with impaired mitochondrial function become uridine auxotrophs and can be maintained with high micromolar concentration of uridine and pyruvate. The therapeutic role of pyrimidines and possible changes in uridine content has not been assessed in neurological diseases involving mitochondrial dysfunction in vivo. Oral administration of PN401 delivers much higher levels of uridine to the circulation than oral administration of uridine itself. Administration of complex II inhibitor 3-nitropropionic acid (3NP) induced neuronal damage in the striatum, substantia nigra and/or thalamus in 80% of the mice and led to 38% mortality. Treatment with PN401 almost completely prevented the neuronal damage due to 3NP and completely prevented mortality. In two subsequent experiments, 3NP-induced weight loss, mortality and behavioral impairment in rotarod performance and spontaneous motor activity were attenuated by treatment with oral PN401. 3NP did not reduce forebrain total uridine nucleotides (TUN), though higher doses of PN401 associated with optimal neuroprotection did elevate TUN to supranormal levels. Thus, oral PN401 treatment has neuroprotective effects in a HD model of mitochondrial dysfunction and the mechanism is more complex than correction of a pyrimidine deficit. |
| Databáze: | OpenAIRE |
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