Noopept Experiments in Rats

Unusually for a peptide-derived compound, noopept displays both high oral bioavailability and good blood-brain barrier penetration in rats. A previous study concluded that “GVS-111 itself was not found in rat brain 1 hour after 5 mg/kg i.p. administration up to limit of detection” and that administration of Noopept only increases the concentration of endogenous nootropic Cyclo-L-prolylglycine, and human studies have shown promising results, with potential application in the treatment of Alzheimer’s disease.

A study of the antiamnestic effect of nootropic substances in rats. It has been established in experiments in rats that some nootropic substances (oxyracetam, aniracetam, nooglutil, mexidol, new 3-hydroxypyridine derivative SK-170, piracetam and noopept) produced marked antiamnestic effect on various models of amnesia (induced by microwave irradiation, acute hypoxia, and motion sickness). At the same time, meclophenoxate exhibited antiamnestic effect in the first and second models of amnesia, while 9-aminoacridine derivative HTOS-404 was only effective in the model of amnesia casued by microwave irradiation. The antiamnestic effect of nooglutil and SK-170 was caused to a significant degree by activation of non-NMDA receptors of excitatory amino acids (generally AMPA receptors), while the effect of mexidol was related to GABA(A) receptors.

A study over specific effects of nootropic drugs on glutamate receptors in the rat brain. The influence of nootropic drugs of different groups (piracetam, phenotropil, nooglutil, noopept, semax, meclofenoxate, pantocalcine, and dimebon) on the binding of the corresponding ligands to AMPA, NMDA, and mGlu receptors of rat brain has been studied by the method of radio-ligand binding in vitro. It is established that nooglutil exhibits pharmacologically significant competition with a selective agonist of AMPA receptors ([G-3H]Ro 48-8587) for the receptor binding sites (with IC50 = 6.4 +/- 0.2 microM), while the competition of noopept for these receptor binding sites was lower by an order of magnitude (IC50 = 80 +/- 5.6 microM).

The heptapeptide drug semax was moderately competitive with [G-3H]LY 354740 for mGlu receptor sites (IC50 = 33 +/- 2.4 microM). Dimebon moderately influenced the specific binding of the ligand of NMDA receptor channel ([G-3H]MK-801) at IC50 = 59 +/- 3.6 microM. Nootropic drugs of the pyrrolidone group (piracetam, phenotropil) as well as meclofenoxate, pantocalcine (pantogam) in a broad range of concentrations (10(-4)-10(-10) M) did not affect the binding of the corresponding ligands to glutamate receptors (IC50 100 pM).

Thus, the direct neurochemical investigation was used for the first time to qualitatively characterize the specific binding sites for nooglutil and (to a lower extent) noopept on AMPA receptors, for semax on metabotropic glutamate receptors, and for dimebon on the channel region of NMDA receptors. The results are indicative of a selective action of some nootropes on the glutamate family.

A study in efficiency of noopept in streptozotocin-induced diabetes in rats. The effects of new nootropic and neuroprotective drug Noopept was studied in various dosage regimens on the dynamics of glycemia, body weight, and pain sensitivity in rats receiving diabetogenic toxin streptozotocin. In experimental diabetic rats, Noopept alleviated glycemia and weight loss and normalized enhanced pain sensitivity. The normalizing effect of Noopept was most pronounced when it was administered as a preventive agent prior to injection of the toxin. Both preventive and therapeutic administration of Noopept (delayed injections included) significantly weakened the examined metabolic effects of diabetogenic toxin. Possible mechanisms of the antidiabetic action of Noopept are analyzed.

A study in the effects of nootropics (Piracetam vs.Noopept) on the EEG in conscious rats and their modification by glutamatergic inhibitors. To study the effects of acute and repeated injections of nootropics and to learn how glutamate receptors might be involved in their mediation, the frequency spectra of cortical and hippocampal electroencephalogram (EEG) were analyzed in non-narcotized rats subcutaneously injected repeatedly with Piracetam (400mg/kg) or its analogue, Noopept (0.2mg/kg), after intracerebroventricular infusions of saline (5 μl) or the antagonists of NMDA and quisqualate/AMPA receptors: CPP (0.1 nmol) and GDEE (1 μmol), respectively. Piracetam increased alpha/beta1 EEG activity in the left frontal cortex, and alpha activity in both the right cortex and hippocampus, with a 10-min latency and 40-min duration.

Noopept increased alpha/beta1 activity, with 30-min latency and 40-min duration in all brain areas. CPP pretreatment eliminated Piracetam EEG effects; reduced Noopept effects in the cortex and completely suppressed them in the hippocampus. After four injections of Piracetam, EEG effects were very small in the cortex, and completely lacking in the hippocampus, while GDEE pretreatment partially recovered them. The effect of Noopept in the alpha/beta1 ranges was replaced by increased beta2 activity after the eighth injection, while no effects were observed after the ninth one. GDEE pretreatment restored the effect of Noopept in the beta2 frequency range.

These results demonstrate similarities in EEG effects and their mediatory mechanisms for Piracetam and its much more effective analogue, Noopept. Activation of NMDA receptors is involved in the effects of a single injection of the nootropics, whereas activation of quisqualate/AMPA receptors is associated with the decrease in their efficacy after repeated use. Some highlights to note from this experiment are that Piracetam and Noopept produce similar EEG spectral profiles, Piracetam and Noopept acute effects mediated by NMDA receptors, and Piracetam and Noopept chronic effects attenuation is mediated by quisqualate/AMPA receptors.

A study over decrease in activity of stress-induced kinases and increase in expression of neutrophines. The influence of noopept–a drug combining the nootrope and neuroprotector properties–on the activity of mitogen-activated protein kinases (MAPKs) and the level of NGF and BDNF gene and protein expression in the frontal cortex, hippocampus, and hypothalamus has been studied in rats. Under conditions of chronic administration (28 days, 0.5 mg/day, i.p.), noopept decreased the activity of stress-induced kinases (SAPK/JNK 46/54 and pERK1/2) in rat hippocampus and increases the level of mRNA of the BDNF gene in both hypothalamus and hippocampus. The content of BDNF protein in the hypothalamus was also somewhat increased.

In the context of notions about the activation of stress-induced kinases, as an important factor of amyloidogenesis and tau-protein deposition in brain tissue, and the role of deficiency of the neurotrophic factors in the development of neurodegenerative processes, the observed decrease in the activity of stress-activated MAPKs and increased expression of BDNF as a result of noopept administration suggest that this drug has a specific activity with respect to some pathogenetic mechanisms involved in the Alzheimer disease.

A study in depression in two animal studies have noted that Noopept is associated with abolishing the effects of learned helplessness in rats at 0.05-0.10 mg/kg injections, which is thought to be a model of depression as it is related to extraneous factors. Currently, the only study in humans assessing depression noted that in persons with cognitive injury there was less depressive symptoms associated with 20 mg Noopept for 56 days as assessed by MMSE, BPRS, and CCSE.

A study in noopept restoration of spatial memory and increase in immunoreactivity to amyloid in an Alzheimer’s disease model. The effects of the novel proline-containing nootropic and neuroprotective dipeptide, noopept were investigated in NMRI mice following olfactory bulbectomy. We have shown previously that these animals developed Alzheimer’s disease (AD)-like behaviour, morphology and biochemistry including impairment of spatial memory, regional neuronal degeneration and elevated Abeta peptide brain levels.

In the current investigation, spatial memory was assessed using the Morris water maze and serum antibodies to in vitro morphologically characterized amyloid structures of both Abeta((25-35)) peptide and equine lysozyme, as well as to neurotrophic glial factor S100b, were analyzed by enzyme-linked immunosorbent assay (ELISA).

Noopept (administered at a dose of 0.01 mg/kg for a period of 21 days and during a further 5 days training) restored spatial memory and increased serum antibody levels to oligomers of Abeta((25-35)) peptide but not to equine lysozyme amyloid or S100b protein in bulbectomized animals. The positive immunotropic effect of noopept to Abeta((25-35)) peptide prefibrillar aggregates was more marked in sham-operated compared to the bulbectomized subjects which were characterized by an overall suppression of immunoreactivity.

Enhancement of the immune response to Abeta((25-35)) peptide prefibrils caused by noopept may attenuate the neurotoxic consequences of amyloid fibrillization and also be associated with an improvement in spatial memory in bulbectomized mice. These actions of noopept, combined with its previously reported neuroprotective and cholinomimetic properties, suggests that this dipeptide may well be useful for improving cognitive deficits induced by neurodegenerative diseases.

Another study in Noopept improvement in spatial memory and stimulant prefibrillar beta-amyloid (25-35) antibody production in mice.The effects of the novel proline-containing nootropic and neuroprotective dipeptide noopept were studied on NMRI mice upon olfactory bulbectomy, which had been previously shown to imitate the main morphological and biochemical signs of Alzheimer’s disease (AD).

The spatial memory was assessed using the Morris (water maze) test; the immunological status was characterized by ELISA with antibodies to prefibrillar beta-amyloid(25-35), S100b protein, and protofilaments of equine lysozyme, which are the molecular factors involved in the pathogenesis of AD. The control (sham-operated) animals during the Morris test preferred a sector where the safety platform was placed during the learning session. Bulbectomized animals treated with saline failed to recognize this sector, while bulbectomized animals treated with noopept (0.01 mg/kg for 21 days) restored this predominance, thus demonstrating the improvement of the spatial memory. These animals also demonstrated an increase in the level of antibodies to beta-amyloid(25-35)–the effect, which was more pronounced in the sham-operated than in bulbectomized mice.

The latter demonstrated a profound decrease of immunological reactivity in a large number of tests. Noopept, stimulating the production of antibodies to beta-amyloid(25-35), can attenuate the well-known neurotoxic effects of beta-amyloid. The obtained data on the mnemotropic and immunostimulant effects noopept are indicative of good prospects for the clinical usage of this drug in the therapy of patients with neurodegenerative diseases.

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