Subchronic dosing of macaques with 2,5-hexanedione causes long-lasting motor dysfunction but reversible visual loss

Abstract

Visual sensitivity and neurological status were monitored in four female macaque monkeys dosed orally with 2,5-hexanedione (0.64 m m/kg, 5 days per week) for 15 or 17 weeks. The first sign of toxicity was intention tremor seen after 3 months of dosing. This was followed, a week later, by a moderate decrease in visual contrast sensitivity, which returned to baseline 6 to 11 weeks after the end of dosing. Acuity and flicker resolution were not disrupted. A progressive general weakness ensued for 5 to 7 weeks after dosing had ended. Some slow recovery was seen, although the animals remained severely disabled 20 weeks after dosing was discontinued. Pathologic changes were examined 3 weeks (one monkey) and 20 weeks (three monkeys) after dosing. Soon after the end of dosing, axonal swellings were present throughout the distal optic tracts, peripheral nerves, and long tracts of the spinal cord. Twenty weeks after dosing, there was no indication of degeneration in the retinocortical pathway. Peripheral nerves showed widespread axonal loss, residual ongoing degeneration, and only slight regeneration. Axon loss and gliosis were evident in distal dorsal columns, and to a lesser extent, dorsal spinocerebellar and corticospinal tracts. These effects of 2,5-hexanedione on the macaque differ from those found previously for two other axonotoxic compounds, acylamide monomer and carbon disulfide, which caused marked permanent degeneration that was most prominent in the visual system.