AMPA antagonists

The role of glutamate in ALS pathophysiology remains speculative and the exact mechanism underlying selective motor neuron loss in the disease is unknown. However, a role of AMPA receptors in selective motor neuron vulnerability is emerging. The AMPA receptor is a tetrameric complex of four subunits (GluR1-GluR4). Its Ca2 + permeability is regulated by posttranscriptional RNA editing of the GluR2 subunit, such that, normally, permeability is low. Failure in the RNA-editing process can lead to a receptor with altered permeability properties. Reduced editing efficiency of GluR2 mRNA has been reported in spinal motor neurons from human sporadic ALS patients.103 Transgenic animals harboring modified GluR2 subunits with increased Ca2 + permeability display late-onset degeneration of spinal motor neurons and decline of motor function.104 The increased Ca2 + influx via modified GluR2 AMPA receptors promotes misfolding of SOD-1105 and crossing modified GluR2 transgenic animals to mutant SOD-1 (G93A) animals accelerates disease progression and decline in motor function and exacerbates death.104

RPR-119990 93 is a selective, potent (Ki = 107 nM) AMPA receptor antagonist that improved muscle strength in SOD-1 mutant (G93A) mice and prolonged survival relative to vehicle-treated animals.106 FP-0011 an antiglutamatergic agent of unknown mechanism is in phase I trials.

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