Comment · Thu, October 31, 2013 · Ceretropic
IDRA-21 Safety
Original post in this thread
pidginduck · 35 points
I haven't seen any studies that show safety for chronic/long-term use. Now that NSN is selling IDRA-21, I think it is important we talk about its safety profile. This paper should be of concern.
Thiazides also dramatically increase AMPA receptor-mediated neuronal death in vitro and in vivo.
It is likely that in hippocampal neuron cultures other AMPA receptor modulators with similar physiological actions as CYZ, diazoxide, IDRA 21 and 1-BCP would also exhibit AMPA receptor-mediated excitotoxicity.
The author of that article is also the one that wrote that IDRA-21 potentiates neurotoxicity during ischemia, strokes, and seizures. This is interesting because that is the opposite effect that -racetams have. Piracetam lessens damage from strokes and cerebral ischemia
What they were answering
willonz · 2 points
Is it possible that memantine could be investigated for this use?
AMPA facillitates NMDA activation at a certain charge threshold, popping out the Mg blocking the NMDA, allowing Ca+2 to flow in (increasing depolarization). The less Ca+2 in the cell from NMDA antagonism results in less production on CaMKii, which would facilitate down-regulation of AMPA. This down-regulation of AMPA will in turn facilitate less NMDA activation.
So by providing an NMDA antagonist, you would be reducing the number of AMPA receptors at the synapse leaving less for IDRA-21 to actively bind to. Do you think this could be a mechanism to limit AMPA-mediated excitotoxicity from IDRA-21, via NMDA antagonism?
Also, NASPM would be reducing Ca2+ flow through AMPA receptors with only the GluR2 subunit. So I would think it would be important to have this GluR2 subunit expressed for NASPM to be effective.
Maybe the subunit is expressed moreso in stronger synapses? Your input would be greatly appreciated!
u/MisterYouAreSoDumb · Ceretropic
I am not sure if memantine would lead to the down-regulation of the CA^2+ permeable AMPA receptors.
Without the GluR2 sub-unit, the receptors are almost always permeable to CA^2+. This is due to the fact that arginine takes the place of glutamine in the GluR2 sub-unit's pore-forming segment. That arginine molecule prevents the influx of Ca^2+, where glutamine does not. So what we should be trying to do is increase surface expression of the GluR2 sub-unit. That would make the AMPAR less permeable to Ca^2+ influx, and consequently less prone to excitotoxicity.
This paper shows that increasing N-ethylmaleimide-sensitive fusion protein increases surface expression of the GluR2 sub-unit. It also shows that endogenous neuronal nitric oxide facilitates the activation of NSF. We know that pramiracetam increases NO levels in the brain. So perhaps that could be beneficial in this case.