huperzine block nmda receptors.... wont this block NMDA in the hypothalamus doing the OPPOSITE of what testforce does??
This response was typed by Synapsin, who is much more intelligent on the scientific end of things that me:
Some background info:
The NMDA receptor is an ionotropic receptor that allows for the transfer of electrical signals between neurons in the brain and in the spinal column. For electrical signals to pass, the NMDA receptor must be open. To remain open, an NMDA receptor must bind to glutamate and to glycine. An NMDA receptor that is bound to glycine and glutamate and has an open ion channel is called
"activated."
NMDA receptors aren't activated easily. The receptor is blocked by Mg2+ so it needs to have sufficient depolarization. Even if you have Aspartic acid there (or Glutamate), you need Glycine to be there as well. So you need a few things at once to activate the NMDA receptors, the key thing being the depolarization of say an AMPA receptor near by before any of the binding even matters. Test force gets around the issue of Glycine by using Sarcosine.
NMDA receptors have different subunits, and the effects of the subunits upon activation. Basic message to take home is that DAA is likely not going to elicit toxicity (due to A and B noted below) because toxicity most likely only comes from NR2B subunit. But if it DOES elicist neurotoxicity, keep reading on how to address this.
A) NR2B-NR2A developmental switch (hypothesis)
B) NR2A probably has a higher affinity than NR2B when it comes L/D-Aspartate
Chemicals that deactivate the NMDA receptor are called antagonists. NMDAR antagonists fall into four categories:
1) Competitive antagonists, which bind to and block the binding site of the neurotransmitter glutamate;
2) Glycine antagonists, which bind to and block the glycine site;
3) Noncompetitive antagonists, which inhibit NMDARs by binding to allosteric sites; and
4) Uncompetitive antagonists, which block the ion channel by binding to a site within it.
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Now for Huperzine A:
Huperzine A (?100 µM) had no effect on the binding of [3H]glutamate (low- and high-affinity glutamate sites), [3H]MDL 105,519 (NMDA glycine regulatory site), [3H]ifenprodil (NMDA polyamine site) or [3H]CGS 19755 (NMDA antagonist).
These are the things we really worry about when we talk about DAA and NMDA receptors.
In contrast with these results, HUP-A non-competitively (Hill slope < 1) inhibited [3H]MK-801 and [3H]TCP binding (co-located NMDA ion channel PCP site) with pseudo Ki ? 6 µM.
Therefore, HUP-A most likely attenuates excitatory amino acid toxicity by blocking the NMDA ion channel and subsequent Ca2+ mobilization at or near the PCP and MK-801 ligand sites
So lets say our main focus is on the NR2A site. MK-801 has an average affinity for it. We don't even need to worry about it then.
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More detail of the NDMA receptor and Huperzine A:
Huperzine A treatment protects against N-methyl-d-aspartate-induced seizure/status epilepticus in rats
Our results demonstrate that the in vivo mechanism of [+]-Hup A protection
mainly involves NMDA antagonism. This is the first
report to indicate that [+]-Hup A acts in vivo throughNMDA
antagonism. In a previous report, we showed that [?]-Hup
A binds toNMDA receptors and antagonizes glutamate toxicity
tend to produce phencyclidine (PCP) symptoms [41]. However,
the physical activity data suggest that locomotor
stimulation is not found in these animals after an effective
treatment of [+]-Hup A. We also found that [+]-Hup A
does not have any adverse effects on body temperature or
heart rate, suggesting that [+]-Hup A has a strong affinity
for NMDA receptor with little effect on other physiological
variables, whereas most NMDA antagonists with strong
affinities for the NMDA receptor do affect physiological processes
[42]. Why NMDA antagonism by [+]-Hup A does
not induce PCP-like symptoms needs to be studied further.
Most likely this is an issue of low-medium affinity for the
channel blocking site in vivo or it is also possible that [+]-
Hup A might bind at a different site. Either way, an NMDA
antagonist that does not produce PCP-like symptoms will
be a powerful tool against excitotoxicity and major depression,
among other things [5,24-29,43,44].
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The NMDA receptor ion channel: a site for binding of Huperzine A, J.
Appl. Toxicol. 21 (Suppl. 1) (2001) S47-S51.
Since HUP-A modulated glutamate-induced toxicity,4 we
evaluated the effect of HUP-A on glutamate receptors.
Figure 2 shows that there was no inhibition of
[3H]glutamate binding. Next, we evaluated the NMDA
glutamate receptor subtype because it is implicated in cell
toxicity via disruption of Ca2+ hemostasis. Huperzine A
(doses ? 1 × 10?4 M) did not inhibit binding of [3H]CGS
19755 and [3H]CPP (antagonists that bind to the NMDA
agonist site), [3H]MDL 105,519 and dichlorokynurenic
acid (antagonists that bind to the NMDA glycine regulatory
sites), or [3H]ifenprodil (an antagonist that binds to
the NMDA polyamine regulatory site).
We have shown that HUP-A interacted with the
NMDA ion channel when characterized by inhibition of
[3H]MK-801 and [3H]TCP binding in brain synaptosomal
plasma membranes (Fig. 3) but not the glycine, polyamine
or NMDA ligand-specific sites (Fig. 2). The observed
non-competitive binding results suggest that HUP-A
interacts close to the MK-801 and PCP binding sites.
In agreement with the interaction at the ion channel of
the NMDA receptor, HUP-A dose-dependently reduced
NMDA-induced toxicity in cultured primary neuronal
cells (Fig. 4).
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The take home message is that Huperzine A won't stop the DAA from having effect. If anything, it could help you with the potential neurotoxicity you always hear about. If you really don't believe any of this, just take DAA first and take Huperzine A later in the day.
...very impressed with this one and Agmatine for pumps:thumbsup:
