As discussed in the Lynch paper excerpt below, it's not clear yet why some Ampakines activate calpain activity while others don't. We were previously under the impression that this was a high impact phenomenon, but the observation that cyclothiazide and CX-546 don't activate calpain activity, while CX-614 does, indicates that there is likely more involved than just high impact vrs low impact. As the Lynch paper says, more calpain related research needs to be done on additional Ampakine compounds. Also, these studies were done using hippocampal brain slices for a maximum of 48 hours. In live animals, mega-dosed for up to 3 months, the cellular effects could be far different. Bottom line is that when it comes to AMPA upmodulation, we are still in uncharted waters -
>>> Interestingly, different classes of positive AMPA receptor modulators produced divergent effects on calpain activation. In particular, both cyclothiazide and CX546 did not activate calpain; if anything, CX546 produced a decrease in basal level of activation as evidenced by lower levels of SBDP as compared to control. Positive AMPA receptor modulators have been shown to affect AMPA receptor function through different mechanisms, with some modulators interfering with desensitization kinetics of the receptors, while others affect rates of channel opening or closing (Arai et al., 2002b). For instance, CX614 and CX546 mainly decreased the rate of deactivation of the receptor, thus prolonging the duration of AMPA receptor-mediated synaptic responses. On the other hand, cyclothiazide affects primarily desensitization kinetics, and has been shown to have little effect on AMPA receptor-mediated synaptic transmission. Our results would therefore imply that positive AMPA receptor modulators with similar effects on AMPA receptor kinetics are able to have opposite effects on calpain activation. As an antagonist of AMPA receptors completely blocked CX614-induced calpain activation, our results also indicate that AMPA receptor stimulation is necessary for ampakine-elicited calpain activation. The reasons for the decrease in calpain activation elicited by CX546 are not clear at the moment, but might be related to differential effects of various ampakines on pyramidal neurons versus inhibitory interneurons. Testing the effects of additional ampakines should provide interesting information regarding these interpretations. <<<
