The neuromuscular junction (NMJ) has the distinction of being the first site of a defined autoantibody mediated neurological disease, namely myasthenia gravis (MG), which is due to autoantibodies to the acetylcholine receptor (AChR) (Vincent, 2002). Other targets at the NMJ include muscle specific kinase (MuSK) in MG patients without AChR antibodies. About 20% of MG patients with generalized disease in Europe, North America and Japan do not have AChR antibodies. These so called 'seronegative' MG patients can be divided into two groups: those with antibodies to MuSK and those without [AChR/MuSK seronegative MG (SN-MG) (Hoch etal, 2001).
In normal neuromuscular transmission depolarization of the presynaptic nerve terminal produces an influx of calcium through voltage-gated calcium channels. Vesicles containing acetylcholine (ACh) then fuse with the presynaptic nerve terminal membrane. After release, ACh interacts with the acetylcholine receptor (AChR) on the muscle endplate surface. This opens the AChR channel, resulting in an influx of cations, largely sodium. Depolarization of the muscle surface produces an excitatory endplate potential, and if the endplate potential is of sufficient amplitude, muscle surface voltage-gated sodium channels are opened. This generates an action potential that eventually results in excitation-contraction coupling and muscle movement. ACh binds transiently to its receptor and then either diffuses from the neuromuscular junction or is hydrolyzed by acetylcholinesterase (AChE), providing a self-limited response to nerve depolarization.
In MG, antibodies are directed against the acetylcholine receptors (AChR antibodies). AChR antibodies interfere with neuromuscular transmission through one of three mechanisms- First, some bind to the AChR cholinergic binding site, blocking the binding of ACh. Second, some AChR antibodies cross-link muscle surface AChRs, increasing their rate of internalization into muscle and reducing the numbers of available AChRs. Third, and perhaps most importantly, AChR antibodies that bind complement result in destruction of the muscle endplate, and a more long-lasting loss of AChRs. Drugs like acetylcholinestrase inhibitors nhibits AChE, increasing the amount of ACh available to interact with available AChRs, thus prolonging the action of Ach, and allowing muscle contraction.
Acetylcholinesterase inhibitors are the first pharmacological choice in the treatment of MG. Acetylcholinesterase is an acetylcholine-hydrolyzing enzyme which binds the overflowing acetylcholine in the neuromuscular junction, keeping the junction clean from excessive transmitter. Acetylcholinesterase inhibitors bind to the acetylcholinesterase, inhibiting its action. Pyridostigmine is a more recent long-acting reversible acetylcholinesterase inhibitor. Acetylcholinesterase inhibitors increase the amount of available acetylcholine in the neuromuscular junction. This leads to enhanced binding of acetylcholine to the diminished number of AChRs on the myasthenic muscle cell membrane, causing contractility improvement (Millard and Broom field, 1995)
When additional pharmacological tre