Lee, Chin-Cheng Michael; (1991) A morphological study of the effects of cycloleucine on the central and peripheral nervous systems of the mouse. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Cycloleucine (CL) is a very potent inhibitor of S-adenosyl methionine transferase causing a rapid decline in CNS S-adenosyl methionine levels and increase in methionine in the nervous system. CL interrupts the transmethylation reaction in the CNS similar to that caused by deficiency of vitamin B12 or folic acid. CL was administered as a single dose intraperitoneally (2mg/g body weight) to mice of varying ages (21 days - 5 months). The 21 day old mice given CL 2mg/g body weight showed evidence of toxicity within 24 hours and thereafter developed progressive muscle weakness and ataxia. Animals did not survive longer than 1 week. Light and electron microscopic examination o f the central and peripheral nervous systems, from 12 hours to 7 days post-injection showed that intramyelinic vacuolation developed in the white matter of brain and cord within 12 hours but no myelin vacuolation occurred in peripheral nerves. Axonal lesions in the distal parts of motor nerves occurred within 1 2 - 2 4 hours resulting in degeneration of intramuscular nerve fibres and terminals. Motor end-plates became denervated. There was no degeneration of motor or sensory nerves in the muscle spindles. Later there was evidence of axonal degeneration in tibial and sciatic nerves. Many dorsal root ganglion cells became vacuolated or necrotic three days after administration of CL and numerous degenerated fibres were noted in the white matter of the spinal cord, especially in funiculus gracilis. The intramyelinic vacuolation in the white matter of brain and cord persisted and became more severe during the course of the experiment. In adult mice (6 weeks - 5 months) the pathology consisted mainly of distal motor axonal degeneration which developed at 1 - 2 days. Only slight intramyelinic vacuolation in white matter was noted. At 3 days later, numerous degenerated fibres were seen in the posterior columns of cervical cord, especially in the funiculus gracilis. In a second series of experiments valine (3 mg/g body weight) was given every 12 hours for 6 doses beginning either 24 or 48 hours after CL. Valine (VL) is a very effective antidote against cycloleucine and reversed its toxicity. The intramyelinic vacuolation disappeared from the white matter in the CNS leaving little residual pathology. Regenerating axons and remyelinated fibres were found in previously degenerated distal peripheral nerves and denervated motor end-plates. The reinnervation took place more rapidly in animals given VL from 24 hours after CL than 48 hours after CL. In conclusion it can be stated that CL causes a distal motor axonopathy and sensory ganglion cell necrosis in addition to the previously reported myelinic vacuolation in the CNS. The mechanism of toxicity of CL is likely to be related to the failure of transmethylation processes affecting particularly myelin basic protein and perhaps membrane turnover at active sites of transmitter release such as the neuromuscular junction.

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