The paper “The Effect of the Synthetic Neuroprotective Dipeptide Noopept on Glutamate Release from Rat Brain Cortex Slices”^[1]https://link.springer.com/article/10.1134/S1819712407020055 goes into some cool detail on Noopept and it’s possible method of neuroprotection.

This paper discusses how glutamate release into the intercellular space during strokes and brain injury causes the death of neurons and something that diminishes the neurotoxic effect of glutamate would serve as one of the most important mechanisms of neuroprotection.

They looked at piracetam and saw that it was insufficient at preventing neurotoxicity from glutamate, which is one of the reasons they started a search for new nootropic agents, specifically neuropeptide analogues.

The Institute of Pharmacology of the Russian Academy of Medical Sciences specialized in making peptide analogues for non-peptide agents for the last 20 years and so they took a fragment of vasopressin (a natural peptide occurring in the body) and combined it with piracetam (they spell it pyracetam) and made a bunch of N-acyl derivates of proline, among which agents with nootropic activity were found.

Out of all of the new compounds, arose Noopept, the ethyl ether of N-phenylacetyl-L-prolylglycine. In addition to its ability to improve cognitive functions, Noopept exhibited a neuroprotective effect on a model of blood clots in the prefrontal cortex. It also showed neuroprotection in chemical cultures of cerebellar neurons subjected to glucose-oxygen deprivation and to neurons from aborted fetuses with Down’s syndrome.

They also knew that Noopept has been shown to increase the survival of granular neurons in cell cultures of the cerebellum in response to cytotoxic glutamate action. It is also known that agents that affect glutamate release are effective neuroprotectors. So since one of the possible ways of stopping the neurotoxic glutamate effect is to stop it from being released in the first place, they decided to test if Noopept could inhibit the release.

They took the brains of rats and sliced them up and put them into chambers where they could manipulate them and observe the changes. In the first experiment, the control, they observed naturally occurring (“spontaneous”) release of glutamate. Then they performed a “stimulated” test, where they increased KCl and decreased NaCl concentration to stimulate the release of neurotransmitter in response to membrane depolarization.

In the second experiment, they measured the effect of Noopept on the levels of spontaneous and stimulated glutamate released at levels of 10^-5 and 10^-6 M and also with Noopept 10^-5/10^-6 + 45 mM KCl. Note that 10^-5 is .00001 and 10^-6 is 0.000001, e.g. that 10^-6 is actually the smaller dose of the two.

What they found was that at a concentrations of 10^-5 and 10^-6 M, there was significantly decreased spontaneous glutamate release. Part (a) in the attached chart shows the level of spontaneous release decreased by 27% at a Noopept concentration of 10^-6 M, and 22% for the Noopept at a concentration of 10^-5. In the presence of 45 mM KCl, the release level was 360% of the spontaneous level (b). Noopept significantly decreased the level of stimulated glutamate release in the cortex slices. The level was 200% at a concentration of 10^-5 M and at 165% at 10^-6 M compared to the control samples.

So Noopept significantly decreased the level of both spontaneous and stimulated glutamate release. The level of the decrease was dependent on the concentration of the peptide and in this case the lower concentration, 10^-6 M actually worked better. (Read: less Noopept = greater effect). This decreasing effect at higher concentrations is consistent with the bell-shaped curve of the dose-effect relationship seen in other peptides.

The researchers are interested in the effects of Noopept compared to other nootropic agents that work on the glutamatergic system, including piracetam. They note that piracetam does not have an effect on the reversed uptake, release, and metabolism of glutamate in the brain, except in doses that are impossible to achieve at therapeutic doses. Another study also showed that piracetam did not decrease glutamate toxicity.

They also point out that glutamate release is dependent on calcium and since they have previously demonstrated that Noopept blocks certain calcium channels, this is further evidence that the neuroprotective effects of Noopept are related to the inhibition of the release of presynaptic glutamate.