Volume 11 Supplement 1

Abstracts of the Ninth International Congress on Drug Therapy in HIV Infection

Open Access

Uridine supplementation with Mitocnol antagonizes antiretroviral nucleoside analogue-induced mitochondrial peripheral and cerebral neuropathy in vivo

  • D Lebrecht1,
  • C Deveaud2,
  • B Beauvoit2,
  • J Bonnet2,
  • J Kirschner3,
  • K Mueller4,
  • N Venhoff1 and
  • UA Walker1
Journal of the International AIDS Society200811(Suppl 1):P148

DOI: 10.1186/1758-2652-11-S1-P148

Published: 10 November 2008

Purpose of the study

Peripheral neuropathy and CNS neurodegeneration may be a toxic effect of some antiretroviral nucleoside analogues on mitochondria. We investigated if this neuropathology may be antagonized by uridine supplementation in vivo.

Methods

BalbC mice (7 weeks of age) were fed with zalcitabine (13 mg/kg/d) or zidovudine (100 mg/kg/d) with or without Mitocnol (340 mg/kg/d) a dietary supplement with high uridine bioavailability for 9 weeks. Hippocampus and ischiadic nerve ultrastructure and mitochondrial functions were assessed.

Summary of results

Zalcitabine and to a lower extent zidovudine induced a significant peripheral and cerebral neuropathy with disrupted mitochondrial architecture, depleted mitochondrial DNA (mtDNA), and reduced levels of cytochrome C-oxidase activity (COX) and mtDNA-encoded cytochrome C subunit I (COX I). Mitocnol had no side-effects but attenuated or fully normalized all pathology of the peripheral and central nervous system (Table 1).

Table 1

 

Control

Mitocnol

Zidovudine (100 mg/kg/d)

Zidovudine (100 mg/kg/d) + Mitocnol

Zalcitabine (13 mg/kg/d)

Zalcitabine (13 mg/kg/d) + Mitocnol

Ischiadic nerve

      

mtDNA copies ‡

374 ± 49

372 ± 38

290 ± 65*

346 ± 35†

237 ± 61**

335 ± 48*†

Hippocampus

      

mtDNA copies ‡

211 ± 51

219 ± 80

104 ± 32**

145 ± 21*†

151 ± 30*

181 ± 53*

COX activity @

11 ± 3

9 ± 3

4 ± 2**

6 ± 2**†

5 ± 2**

8 ± 3*†

COX/SDH-ratio %

100 ± 9

107 ± 9

48 ± 19**

90 ± 18††

50 ± 15**

92 ± 20††

Citrate activity @

1152 ± 201

1086 ± 179

1124 ± 275

1265 ± 314

1791 ± 33*

1361 ± 173*†

COX II/COX IV-ratio %

100 ± 5

122 ± 26

57 ± 25**

89 ± 22†

45 ± 20**

94 ± 20††

*, p < 0.05 vs. controls; † vs. no Mitocnol. **, p < 0.001 vs. control; †† vs. no Mitocnol; %, of control; ‡, copies/nucleus; @, μmoles/min/g protein.

Conclusion

Zidovudine and zalcitabine induce a mitochondrial peripheral and cerebral neuropathology, both of which are antagonized by Mitocnol.

Authors’ Affiliations

(1)
Dept. Rheumatology and Clinical Immunology, University Hospital Freiburg
(2)
Institut de Biochimie et de Génétique Cellulaires, UMR 5095 CNRS-Université Victor Ségalen Bordeaux cedex
(3)
Department of Neuropediatrics and Muscle Disorders, University Hospital Freiburg
(4)
Department of Neuropathology, University Hospital Freiburg

Copyright

© Lebrecht et al; licensee BioMed Central Ltd. 2008

This article is published under license to BioMed Central Ltd.

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