TY  - UNPB
AV  - public
Y1  - 1991///
M1  - Doctoral
TI  - A morphological study of the effects of cycloleucine on the central and peripheral nervous systems of the mouse
ID  - discovery10122112
UR  - https://discovery.ucl.ac.uk/id/eprint/10122112/
EP  - 216
N2  - 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.
N1  - Thesis digitised by ProQuest.
PB  - UCL (University College London)
A1  - Lee, Chin-Cheng Michael
KW  - Biological sciences
ER  -