Edwards, Jonathan Paul; (1993) The effects of cycloleucine on nerve, muscle, and neuromuscular transmission in the mouse: An electrophysiological and morphological study. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Cycloleucine (CL) is a synthetic annino acid which inhibits the vitamin B12/folate dependent methyl-transfer reaction. A single dose of CL (2mg/g body weight) was administered intraperitoneally to 21-day-old and adult mice. Animals were allowed to survive for between 12 hours and 7 days. The 21-day-old mice showed paralysis of the hindlimbs within 24 hours, whereas this symptom became apparent in the adult mice at 48 hours. In the adult mice the twitch and tetanic responses of extensor digitorum longus (Edl) and soleus evoked by neural stimulation fell dramatically within 24 hours. In both the 21-day-old and the adult mice intracellular recordings made at 24 hours in soleus and Edl revealed that a significant number of end-plates were denervated, while other end-plates demonstrated intermittent failures in transmission and end- plate potentials (epps) with prolonged latencies. End-plates with abnormally high frequencies of miniature end-plate potentials (mepps) were commonly encountered in soleus and Edl, of 21-day-old mice at 12 hours, and in the adult mice at 24 hours. Morphological abnormalities in both the intramuscular nerves and the neuromuscular junctions of soleus and Edl were seen in both the young and adult mice at 24 hours. These abnormalities included areas of electron lucent axoplasm and swollen degenerative mitochondria and nerve terminals lacking synaptic vesicles. The innervation of proximal muscles was unaffected at this time. Over the next 2-3 days further reductions in the number of soleus and Edl fibres demonstrating mepps or epps occurred in both young and adult mice. The muscle spindles in soleus were found to be both functionally and structurally intact. At 7 days a limited recovery of function occurred in both soleus and Edl of young and adult mice. In biceps brachii of young mice, however, denervated end-plates and abnormally high mepp frequencies were found at 7 days. It is suggested that the distal motor axonopathy induced by CL is caused by the failure of the methyl-transfer pathway which leads to abnormalities in the phospholipid composition of the axolemma at the neuromuscular junction. These changes are believed to cause an increase in microviscosity of the axolemma and hence a decrease in efficiency of ion channels/pumps which are responsible for maintaining electrochemical gradients essential for the structural and functional integrity of the neuromuscular junction.

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