Research Grant - 2008

Neuromuscular Award funded by Kathleen Toy Estate and Christopher Warren Hallam Bequest
Does pyridostigmine (Mestinon) make myasthenia gravis worse in the long term?

Dr Stephen Reddel
Concord Repatriation & General Hospital, University of Sydney
Co-Investigator: Dr William D. Phillips

We will test the effect of pyridostigmine on the neuromuscular junction in mice with passively transferred myasthenia gravis. Pyridostigmine and related drugs increase the amount of acetylcholine in the neuromuscular junction synaptic cleft and are used for the treatment of myasthenia gravis. They provide a benefit within minutes. Recent studies into synapse formation have shown that acetylcholine can promote active dis-assembly of postsynaptic acetylcholine receptors and dismantle the neuromuscular junction as a whole, while a second signaling pathway exists, where neural agrin, and the receptor MuSK, acts to stabilize the neuromuscular synapse during development and in later life. Since pyridostigmine works by prolonging the actions of acetylcholine at the synapse, it is important now to test whether pyridostigmine fosters disassembly of the neuromuscular junction with long term adverse consequences, notwithstanding its short term benefit.

This research will have implications for many other disorders of the synapse, including Alzheimer Disease where a related acetycholine esterase inhibitor, donepezil, is in widespread use. A role for the second stabilizing pathway agrin-MuSK has recently been demonstrated in the brain, although interestingly in concert with a different primary neurotransmitter, glutamate. It may be a common motif of synapses that increasing the amount and duration of the primary neurotransmitter has long term downregulatory effects on the post synaptic apparatus, and that a second supportive regulatory pathway exists at all synapses. In this case, stabilisation of the post synaptic apparatus via the second signalling pathway may be a more effective way of treating disorders where reduced synaptic signaling is present, which includes many neurodegenerative disorders such as Alzheimer Disease and Motor Neuron Disease. If our hypothesis is confirmed, it will suggest that the use of pyridostigmine in myasthenia gravis should be limited or curtailed to occasional use, and that upregulation of the post synaptic structure via a search for agrin MuSK small molecule agonists may be provide a more effective therapy for all disorders of the neuromuscular junction.