Nuclear and mitochondrial changes of co-cultivated spinal cord, spinal ganglia and muscle fibers following treatment with various doses of zidovudine

Abstract

Long-term zidovudine (also termed azidothymidine, AZT) treatment of AIDS patients may cause severe myopathy characterized by conspicuous mitochondrial and nuclear changes. The mitochondrial changes are attributed to an inhibitory effect of AZT on the mitochondrial gamma-polymerase in a variety of cells. Inhibition of the nuclear alpha-polymerase is another well-known side effect of AZT, whereas the (nuclear) beta-polymerase appears to be rather insensitive. The nuclear changes seen in AIDS patients are usually considered secondary to the human immunodeficiency virus infection. To eliminate the influence of the virus on the nuclei, we studied the effect of AZT on non-infected, organotypic co-cultures of spinal ganglia, spinal cord, and skeletal muscle from fetal rats. We noted significant changes not only in the mitochondria but also in the nuclei of spinal ganglia, spinal cord, and muscle cells, which depended more on the duration of AZT application (1, 3, 5, and 8 days) than on the concentration (0.1, 1, 10, 100 and 1000 microM). The alterations of the mitochondria consisted mainly of swelling, loss of cristae and, finally, disappearance. The nuclei showed nucleolar segregation, marginal condensation of heterochromatin, formation of interchromatin and perichromatin granules, nuclear protrusions and pseudoinclusions and, finally, disintegration. The changes were not as pleomorphic as those seen in biopsy specimens from AIDS patients who had received long-term treatment with AZT. However, this difference can easily be attributed to the short duration of drug application in tissue culture compared to the long-term medication in patients.

Mitochondrial DNA Depletion, Oxidative Stress, and Mutation: Mechanisms 0f Dysfunction from Nucleoside Reverse Transcriptase Inhibitors

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“…Mixed (competitive and noncompetitive) K i with cardiac DNA pol-␥ against various templates. Benbrik et al, Cherrington et al, 1995Corcuera et al, 1996Corcuera Pindado et al, 1994Eriksson et al, 1995Hobbs et al, 1995Martin et al, 1994Nusbaum and Joseph, 1996Semino-Mora et al, 1994Schroder et al, 1996Wang et al, 1996 Modica-Napolitano, 1993 AZT inhibits mitochondrial permeability transition:…”

Prolonged perinatal exposure to AZT affects aggressive behaviour of adult CD-1 mice

“…Nucleoside analogue toxicity has been confirmed by both in vitro and in vivo studies. Mitochondrial toxicity due to AZT was reported in several tissue culture studies (Schroder et al 1996;Brinkman et al 1998). Perinatal exposure to AZT may thus cause mutagenic as well as carcinogenic effects (Ayers et al 1997;Olivero et al 1997;Zhang et al 1998).…”

Effects of short-term zidovudine exposure on mitochondrial DNA content and succinate dehydrogenase activity of rat skeletal muscle cells

“…Induction of skeletal muscle mitochondrial abnormalities by AZT were observed in human and rodents either in vivo [14][15][16][17][18] or in vitro, using human and rodent muscle cell cultures [15,[19][20][21][22][23][24][25][26][27]. Depletion of mtDNA was also observed in rats receiving oral AZT [16][17][18], as well as in rat skeletal muscle culture [26].…”