Aiming, Concerning the calpain topic, one of my deepest fears would be that the 4 month delay in the 3 month animal tox studies might be due to toxic effects related to this calpain/spectrin phenomenon. However, a few weeks ago Neuro posted that he talked to Cortex, and it sounded like there wasn't anything to worry about - they apparently contracted out the 3 month animal tox studies, and the lab doing them has been slow, resulting in the delay.
The calpain phenomenon is a lingering gray area however, since there isn't much info available, and none of us Yahooers are really qualified to fully understand what info is available. In addition to being associated with the protein breakdown occuring after neurological trauma/damage/stress (as in stroke for example), calpain/spectrin elevation is also associated with Long Term Potentiation (LTP), which is the basis of normal memory formation - the process stimulated by Ampakines (as pointed out in Neuro's post and in the Lynch abstract). So the increase in calpain/spectrin activity from long term AMPA upregulation might not have anything to do with neural damage, but may merely be associated with the protein transformation / rebuilding which occurs during LTP.
The plot thickens however. The publication of the first calpain related paper last year created a stir on the Yahoo thread, prompting Neuro to contact Dr. Lynch and then post what he had learned (post 17204). Also, a YH poster (post 18096) said that he had asked Dr. Rogers about the calpain subject at the SHM, and apparently the author of that first paper had published it without first getting Dr. Lynch's OK, and Lynch and the author had a falling out as a result. Looking at the abstracts, Dr. Lynch seems to stress that elevation of calpain/spectrin is associated with normal LTP processes, while the other paper doesn't.
Anyway, things get even murkier, since we don't know definitively if the increase in calpain/spectrin activity is related to high or low impacts. The one calpian study uses CX-614 (a higher impact), but the abstract of the other study (Dr. Lynch's) indicates only that certain Ampakines increase calpain/spectrin activity, without specifying if they are high or low impact. Neuro's post after contacting Dr. Lynch indicates that the low impact CX-717 hadn't shown the deleterious effects one would expect from excessive calpian production. So the high impact CX-614 does significantly elevate calpain, while the low impact CX-717 doesn't.
Another abstract I found on glutamate toxicity / glutamate mediated cell death (implicated in many neurodegenerative diseases/injuries) outlines the process by which excess glutamte induces excitotoxicity, elevates calpain, thereby causing neuronal damage/apoptosis. We know that the high impact compounds developed so far generate varying degrees of excitotoxicity (calcium imbalance at the synapse), similar to the damaging glutamate toxicity seen after stroke. It's probably safe to say that a high impact compound that strongly induces excitotoxicity would very likely also induce calpain mediated neuronal damage eventually. The big question is whether this process might also occur after months/years of low impact dosing. Of course there hasn't been enough long term human data generated yet to answer this question. There has been some longer term dosing done in animals though, which may provide a clue. This would be a great question for the SHM.
