Prolonged NMDA/DAA Administration and Cytotoxicity
Just trying to get a better understanding of the possible long-term risks that may accompany their use.
In Alzheimer's disease, it is proposed that elevated background concentrations of glutamate between the pre and postsynaptic neurons causes the postsynaptic membrane to become more frequently depolarized, thus resulting in the displacment of the voltage-dependent Mg2+ ion that normally blocks the NMDA ion channel, followed by excitotoxic Ca2+ influx. This in turn negatively impairs physiological signaling mechanisms/synaptic plasticity/learning/memory ect.
The literature indicates that postsynaptic glutamate transporters remove glutamate from the synaptic cleft in a rapid fashion under normal physiological conditions. However, my concern is that NMDA supplementation [may] alter glutamate transport homeostasis, resulting in the inadequate removal of glutamate from the synaptic cleft, as a result of prolonged supraphysiological exposure to glutamate.
Now the implication from other respected members was that the voltage-gated NMDAR requires previous activation of the AMPA receptor for membrane depolarization. However if that's the case, I'd like to hear some discussion on the following....
"Originally Posted by Espinosa et al, 2009 "
"we propose that the residual NMDA receptor component of spontaneous mEPSCs stems from continual incomplete Mg2+block of NMDA receptors at the resting membrane potential rather than unblock triggered by concurrent AMPA receptor activity."
"partial blockade of AMPA receptors does not affect the NMDA receptor-mediated component of mEPSCs arguing against the possibility that the NMDA component is due to relief of Mg2+ block via local depolarization mediated by AMPA receptors."
"These findings are consistent with our observations, and they strongly suggest that NMDA receptors are active at rest during spontaneous neurotransmission, despite their reduced ion conductance due to Mg2+ block."
"These findings indicate that mEPSC driven signaling is more widespread than previously thought and reinforce the premise that mEPSCs can drive biochemical signaling in addition to electrical activity."
"spontaneous glutamate release may constitute a bone fide pathway for interneuronal signaling independent of pre and postsynaptic activity."
Additionally, it has been suggested that NMDARs must bind to glutamate and to glycine prior to activation however, according to Papouin et al, 2012, D-serine displays preferential affinity for [synaptic] NMDARs, whereas glycine's affinity is [extrasynaptic]. The authors notate that excitotoxicity & LTP are exclusively governed by the coagonist D-serine in synaptic NMDARs.
"The NMDA receptor is a voltage-gated channel which requires previous activation of the AMPA receptor for membrane depolarization
since the compound "NMDA" cannot agonize the AMPA receptor, its ability to activate the NMDA receptor would be limited, and so a direct neurotoxic effect will not likely occur from oral supplementation
if you take a neuron in a vacuum (en vitro), its normal electrical homeostasis is disrupted, and the NMDA receptor no longer is voltage gated. if you bath this neuron in NMDA, excitotoxicity will occur, whereas en vivo it can't"
"The bottom line is that we don't know what dose of oral NMDA can cause excitoxicity. Oral doses are far safer than injections into the brain because one of the primary functions of the BBB is to prevent excitoxic insult. I do not know how much NMDA penetrates the BBB per mg taken orally, but I do know that it will be less than an equivalent amount of DAA due to the active transport of AAs at the barrier. Assuming some methylation of DAA and conversion to NMDA in the brain (mediated endogenously of course), it's likely that the dose of NMDA provided by intimidate will be met through basic DAA supplementation (this assumes a 1% conversion rate). So, in my opinion, excitotoxicity is unlikely with intimidate.(NMDA product)"
"This is a study of miniature excitatory postsynaptic currents (mEPSCs), not evoked EPSCs. The former is due to random release of unprovoked pre-synaptic neurotransmitter release, and the latter is due to the classical action potential induced sequence.
What this study says is that magnesium isn't permanently docked on the NMDAr, and that their may be times where the NMDA receptor is activated when magnesium is displaced. This is fairly obvious since the intracellular/extracellular polarity is not completely electrically static.
And since the AMPA receptor has its utilitiy in depolarizing the intracellular compartment allowing magnesium displacement, and thereby NMDA activation, if magensium is not docked on the NMDA receptor in the first place, then AMPA has lost its function (extremely temporarily).
AMPA receptor pre-activation is still required for the vast majority of glutaminergic NMDA signaling, and so the significance of this study is unknown.
It is worth noting that the article mentioned this:
Ultimately, I would say this study is interesting, but certainly does not alter the classical paradigm in any way.
Here is the authors final thoughts. Keep in mind that the context is key:
Collectively these results indicate that NMDA receptors significantly contribute to signaling at rest in the absence of dendritic depolarizations or concomitant AMPA receptor activity."
The prevailing conception [at least within a community that utilizes supplemental NMDA] is that it poses no risk, as the NMDAR is voltage-gated, and that due to the fact that NMDA does not directly agonize the AMPA receptor, there is no forseeable risk to it's supplementation. Now this may, or may not be the case however, discussions like these reguarding theoretical implications on the subject are beneficial for educational purposes, at least to some degree.
So following the creation of this thread, we've established the fact that the NMDA compound does [not] have to directly agonize the AMPA receptor for postsynaptic depolarization to take place. Additionally, it appears as though both spontaneous and evoked neurotransmission can activate certain sets of NMDA and/or AMPA receptors.
Astrocytic PAR1-triggered glutamate efflux [may] be another mechanism by which depolarization relieves the Mg+2 block to potentiate NMDA receptor-mediated excitatory postsynaptic currents, however addmittedely, I haven't done much research on the subject.
Nonetheless, these factors at least open the possibility of excitotoxic insult - be it low risk or not.
--"These results support the notion that spontaneous and evoked neurotransmission activate distinct sets of AMPA receptors and bolster the hypothesis that synapses harbor separate microdomains of evoked and spontaneous signaling." - Yildirim et al, 2011
"Collectively, these results support the premise that spontaneous and evoked neurotransmissions activate distinct sets of NMDA receptors and signal independently to the postsynaptic side." - Deniz Atasoy et al, 2008
"Sustained, pathologically excessive Ca2+ influx is necessary for an apoptotic/necrotic cascade, and that requires a glutamate dump. If anything, calcium transients as a result of excess NMDA in the synapse would end up being beneficial, depending on the region and type of neuron, in new memory formation."
--So if the Ca2+ influx is transient, it won't likely be pathologically deleterious, even with prolonged use."
"That's the physiologically sound consideration, yes.
Also regarding aggression, there's significant reason to believe LH and FSH can contribute to behavioral effects. I've been thinking about this for a long time because testosterone administration alone does not induce behavioral effects but anecdotal evidence abounds for some natural testosterone boosters, and it's been going on for too long for me to believe it's purely psychosomatic in every case."
Condescending Guy Dumbs It Down-
"Specific conditions must be met in order for NMDA activation (Mg2+ displacement)/excitotoxicity to occur, i.e. presynaptic NMDAR glutamate binding, and depolarization (which occurs with AMPAR glutamate binding, and an influx of Na+).
NO HYPE is questioning if NMDA activation/Mg2+ displacement can occur through alternative means, such as mEPSCs, or astrocytic PAR1-triggered glutamate efflux.
tms;du (too much science, didn't understand) Certain conditions must be met in order for excitotoxicity to occur, NO HYPE is questioning whether such toxicity may occur by other means."
Under physiological conditions N-methyl-D-aspartate (NMDA) receptor activation requires coincidence of presynaptic glutamate release and postsynaptic depolarization due to the voltage-dependent block of these receptors by extracellular Mg(2+). Therefore spontaneous neurotransmission in the absence of action potential firing is not expected to lead to significant NMDA receptor activation. Here we tested this assumption in layer IV neurons in neocortex at their resting membrane potential (approximately -67 mV). In long-duration stable recordings, we averaged a large number of miniature excitatory postsynaptic currents (mEPSCs, >100) before or after application of dl-2 amino 5-phosphonovaleric acid, a specific blocker of NMDA receptors. The difference between the two mEPSC waveforms showed that the NMDA current component comprises approximately 20% of the charge transfer during an average mEPSC detected at rest. Importantly, the contribution of the NMDA component was markedly enhanced at membrane potentials expected for the depolarized up states (approximately -50 mV) that cortical neurons show during slow oscillations in vivo. In addition, partial block of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor component of the mEPSCs did not cause a significant reduction in the NMDA component, indicating that potential AMPA receptor-driven local depolarizations did not drive NMDA receptor activity at rest. Collectively these results indicate that NMDA receptors significantly contribute to signaling at rest in the absence of dendritic depolarizations or concomitant AMPA receptor activity.
"Neuroprotective effects of creatine administration against NMDA and malonate toxicity.
Malcon C, Kaddurah-Daouk R, Beal MF.
Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
We examined whether creatine administration could exert neuroprotective effects against excitotoxicity mediated by N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainic acid. Oral administration of 1% creatine significantly attenuated striatal excitotoxic lesions produced by NMDA, but had no effect on lesions produced by AMPA or kainic acid. Both creatine and nicotinamide can exert significant protective effects against malonate-induced striatal lesions. We, therefore, examined whether nicotinamide could exert additive neuroprotective effects with creatine against malonate-induced lesions. Nicotinamide with creatine produced significantly better neuroprotection than creatine alone against malonate-induced lesions. Creatine can, therefore, produce significant neuroprotective effects against NMDA mediated excitotoxic lesions in vivo and the combination of nicotinamide with creatine exerts additive neuroprotective effects."