Toxic Peripheral Neuropathy with Demyelination in Sprague-Dawley Rats Given CGS 21595 —A 5-Lipoxygenase Inhibitor

Abstract

Abstract. Male and female Sprague-Dawley rats were given CGS 21595, a pro-drug that is almost immediately metabolized to CGS 192 13, a naphthoquinone that acts as a 5-lipoxygenase inhibitor. The compound was administered by gavage to five groups of Sprague-Dawley rats (group Nos. 1, 5 , n = 30; group Nos. 2-4, n = 20) at daily doses of 0, 50, 150, 500, or 1,000 mg/kg for 13 weeks. Rats in the higher dose groups had a reduced weight gain, but significant neurologic signs were not observed. A peripheral neuropathy consisting predominantly of myelin destruction in the spinal nerve roots and sciatic nerves was seen in male rats treated with L 150 mg/kg CGS 21 595 and in female rats treated with 2 5 0 mg/kg CGS 21595 for 13 weeks. This lesion was not fully reversible after a recovery period of 4 weeks. Lesions consisted of ballooning of myelin sheaths, infiltration by macrophages, demyelination, and occasional areas of remyelination. Axons were generally preserved, and the brain and spinal cord were not affected. Male and female rats in all treatment groups had cytoplasmic hyaline droplets in the proximal renal tubules. This change was reversible after 4 weeks and was not associated with any other adverse effects on the kidney.

Toxic neuropathies

“…The direct targets of a toxin may be a presumed single molecular or receptor target or a toxin can affect multiple targets. Cell and animal models have aided the understanding of the mechanisms of toxicity of occupational or environmental agents, such as acrylamide [20], 2,5 Hexanedione [21,22], Thallium [23], Arsenic [24], Tin [25], or of medication-induced neuropathies such as Taxol [26], 5-lipoxygenase inhibitors (used in asthma, rheumatoid arthritis, and psoriasis) [27], Amiodarone [28], isoniazid [29], nuclear reverse transcriptase inhibitors [30,31], Thalidomide [32].…”