Page - (000290) - in Biomedical Chemistry: Current Trends and Developments

iGluRs to the surface of the cell and delivery to synaptic locations after treatments. Thus, we draw a parallel to these findings and suggest that full blockage of iGluRs could lead to homeostatic plasticity induction and this would be counterproductive to reducing excitotoxicity, since it would result in an increased expression of just the channels that clinicians are trying to modulate. We hypothesize that a partial antagonist will be effective in reducing spine loss and neuron death due to excitotoxic calcium influx. In fact, one of the few pharmacological agents that actually demonstrates some efficacy on slowing excitotoxic effects is memantine, a partial and weak antagonist of NMDA receptors (Gardoni & Di Luca, 2006). 3.2.8 Emerging Targets for Reducing Calcium-mediated Excitotoxicity As described earlier in this chapter, calcium-permeable AMPA receptors are garnering much attention as they have been found to play a role now in both normal plasticity as well as neurodegenerative. Interestingly, in almost all studies of calcium-permeable AMPA receptors, one common ligand has been employed in many experiments (Meyer, 2012; Wen & Barth, 2012). This molecule is naphthylacetylspermine (NAS) and is a synthetic agent that was designed based on a number of natural toxins biosynthesized by certain spiders and wasps. All of these molecules are use-dependent, full antagonist, pore blockers of calcium-permeable AMPA receptors. Calcium-permeable AMPA receptors are inserted into the membrane after broad AMPA receptor antagonism in cultured neurons, suggesting a role for them in homeostatic plasticity and maintenance of synaptic communication (Beique, 2011). This latter point leads us to believe that partial antagonism may be more fruitful than simply blocking all CP-AMPARs for ALS treatment. There is much experimental evidence that suggests CP-AMPARs are expressed on cultured motor neurons (Carriedo, 1996; Van Den Bosch & Robberecht, 2000; Van den Bosch, 2002). These specific receptors have been shown to be a calcium conduit that could be responsible for excitotoxic levels of calcium entering motor neurons and it is known