Jennifer A. Sandberg

Temporal development of 2′,3′-dideoxyinosine (ddI)–induced peripheral myelinopathy

The anti-HIV therapeutic dideoxyinosine (ddI) has been reported to produce a painful, dose-limiting peripheral myelinopathy in HIV-infected patients after chronic administration. We have previously demonstrated ddI-induced myelinopathy in a non-HIV-infected rat model after 20 weeks of dosing, characterized by myelin splitting and intramyelin edema. The present study examined the time course needed to produce the ddI-induced neuropathy. Adult male Sprague-Dawley rats were gavaged with vehicle or 415 mg/kg ddI twice daily for up to 20 weeks. Groups of treated (n = 6-8) and control (n = 3-5) animals were killed after 5, 10, 15, and 20 weeks of dosing and the distal end of the sciatic nerve was removed. The nerve was postfixed by immersion in neutral phosphate-buffered formalin, dehydrated in graded alcohols, and embedded in plastic embedding media. One-micrometer-thick sections were cut and stained with toluidine blue and basic fuchsin. Plasma levels of ddI on the day the animals were killed were greater than 10 microgram/ml within the first hour after dosing and fell rapidly to less than 1 microgram/ml (clinical range 1-2 microgram/ml) within 3 h after dosing. The abnormalities observed in the sciatic nerve were few, if any, after 5 or 10 weeks, but very prominent after 15 weeks of dosing. Four of the six ddI-treated rats exhibited abnormal morphology as evidenced by myelin splitting and ballooned myelin sheaths. Although abnormal morphology was present at 20 weeks of dosing, the effect was not as robust as at 15 weeks. This suggests that the nerve may partially recover from the effects of ddI with time. Published by Elsevier Science Inc.

Effects of fumonisin B1 treatment on blood-brain barrier transfer in developing rats.

Fumonisin B1 (FB1), a toxic metabolite of the fungus Fusarium moniliforme found in contaminated corn, is considered an etiologic agent of equine leukoencephalomalacia. Because FB1 exposure is associated with alteration of sphingolipid metabolism, the purpose of this study was to elucidate whether blood sphinganine (Sa) levels affect brain Sa levels. Sa and sphingosine (So) levels in brain tissue and plasma were analyzed by HPLC. Area under the curve (AUC0-20h) ratios of brain Sa to plasma Sa levels were about 40 after a single 0.8 or 8 mg/kg SC dose of FB1. The AUC0-12h ratio of brain FB1 to plasma FB1 was 0.02. The fact that FB1 alters brain Sa levels and Sa/So ratios indicates that sphingolipid metabolism in the central nervous system of developing rats is vulnerable to FB1 exposure. These data support our hypothesis that alterations of the brain Sa levels are related to the direct action of FB1 on the brain rather than transport of peripheral Sa to the brain.