Purified trichosanthin (GLQ223®) exacerbation of indirect HIV-associated neurotoxicity in vitro

Abstract

A formulated preparation of trichosanthin (GLQ223, Pharmaceutical Development Group, Genelabs Inc., Redwood City, California, USA) has been shown to selectively inhibit HIV replication in vitro in lymphocytes and macrophages. In view of recent anecdotal reports of central nervous system (CNS) complications associated with trichosanthin use in some HIV-infected patients, we evaluated any potential drug effects leading to neurotoxicity using a human brain cell aggregate model. Brain cell aggregate cultures were incubated with dilutions of purified trichosanthin alone (trichosanthin), supernatants of HIV-infected macrophage cultures (S-HIV), supernatants of uninfected macrophage cultures (S-U), supernatants of purified trichosanthin-treated uninfected macrophage cultures (S-trichosanthin), or supernatants of purified trichosanthin-treated HIV-infected macrophage cultures (S-HIV-trichosanthin). Treatment with purified trichosanthin alone at up to 2 micrograms/ml, with S-U or with S-trichosanthin, produced no morphological signs of toxicity to brain cell aggregate cultures. S-trichosanthin treatment at 2 micrograms/ml did not result in a significant change in cyclic nucleoside phosphorylase (CNP) activity. Treatment of the brain aggregates with S-HIV and S-HIV-trichosanthin did, however, result in morphological alteration of the brain aggregates, with S-HIV-trichosanthin-treated brain aggregates showing the most severe damage. Although purified trichosanthin did not appear to be directly toxic to human brain aggregate cultures, trichosanthin treatment of infected macrophages may have increased the morphological alterations caused by supernatants of HIV-infected macrophages. These experimental observations may explain anecdotal reports of adverse CNS reactions in association with trichosanthin treatment of HIV-infected patients and emphasize the neurotoxic potential of any therapy targeted at HIV-infected macrophages.