Oral uridine supplementation antagonizes the peripheral neuropathy and encephalopathy induced by antiretroviral nucleoside analogues.
OBJECTIVE
Peripheral neuropathy and central nervous system neurodegeneration may result from the mitochondrial toxicity of some antiretroviral nucleoside analogues. We investigated whether this neuropathology may be antagonized by uridine supplementation in vivo.


METHODS
Because of the obvious difficulties in obtaining human neural tissues, the mitochondrial neurotoxicity of the nucleoside analogues was studied in mice.


METHODS
BALB/C mice (7 weeks of age) were fed for 9 weeks with zalcitabine (13 mg/kg per day) or zidovudine (100 mg/kg per day) with or without mitocnol (340 mg/kg per day), a dietary supplement with high uridine bioavailability. Hippocampal and sciatic nerve mitochondria were analyzed.


RESULTS
Zalcitabine and to a lesser extent zidovudine induced a significant peripheral neuropathy and encephalopathy with disrupted mitochondrial ultrastructure, depleted mitochondrial DNA, reduced levels of cytochrome c oxidase activity and diminished expression of mitochondrial DNA-encoded cytochrome c oxidase subunit I. Mitocnol had no intrinsic effects but attenuated or fully normalized all measured disorder of the peripheral and central nervous system.


CONCLUSIONS
Zidovudine and zalcitabine induce a mitochondrial disorder in the peripheral and central nervous system, both of which are antagonized by uridine supplementation.
Venhoff
Nils
N
Department of Rheumatology and Clinical Immunology, Medizinische Universitätsklinik, Freiburg, Germany.
Lebrecht
Dirk
D
Deveaud
Catherine
C
Beauvoit
Bertrand
B
Bonnet
Jacques
J
Müller
Klaus
K
Kirschner
Janbernd
J
Venhoff
Ana C
AC
Walker
Ulrich A
UA
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects*; D004272:DNA, Mitochondrial / Q000032:analysis / Q000187:drug effects; D004347:Drug Interactions; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017237:Mitochondrial Encephalomyopathies / Q000139:chemically induced / Q000517:prevention & control; D017240:Mitochondrial Myopathies / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control*; D014529:Uridine / Q000008:administration & dosage / Q000494:pharmacology*; D016047:Zalcitabine / Q000009:adverse effects*; D015215:Zidovudine / Q000009:adverse effects*
D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D015215:Zidovudine; D016047:Zalcitabine; D014529:Uridine