Noopept

Physicochemical and structural analysis of N-phenylacetyl-L-prolylglycine ethyl ester (Noopept) - An active pharmaceutical ingredient with nootropic activity.

Szymon Kamil Araj, Łukasz Szeleszczuk, Tomasz Gubica +5 more

N-Phenylacetyl-L-prolylglycine ethyl ester (Noopept, GVS-111, omberacetam) is an orally available active pharmaceutical ingredient (API), with neuroprotective properties and ability to enhance cognitive function. It belongs to nootropic family of drugs and is included in the group of racetams, although its chemical structure is quite different than the other compounds from this group, including the most popular one - piracetam. The mechanism of action of this API is multifaced and is considered to be involving modulation of various neurotransmitter systems within the brain. Despite the significant amount of works devoted to the pharmacodynamics of Noopept, very little is known about its structural and physicochemical properties. Therefore, the aim of current study was to investigate this API in a very thorough way. In this work, the detailed physicochemical analysis of Noopept has been done using TGA/DSC, 1H and 13C liquid state NMR, 13C CP/MAS NMR, SEM, SCXRD, and PXRD. Additionally, quantum chemical DFT computations under periodic boundary conditions, using CASTEP, were conducted to facilitate the analysis of experimental results. Besides, we've performed a polymorphism screening of this molecule.

Effects of noopept on ocular, pancreatic and renal histopathology in streptozotocin induced prepubertal diabetic rats.

Perihan Gurbuz, Halil Duzova, Asli Cetin Taslidere +1 more

Diabetes mellitus (DM) is a chronic disease at all ages including childhood and puberty. Failure to treat DM can cause retinopathy, nephropathy and neuropathy. Endocrine and metabolic changes during the pubertal period complicate management of DM. Noopept is a cognitive enhancer that exhibits antidiabetic properties. We investigated the effect of noopept on the histopathology of the cornea, retina, kidney and pancreas in pubertal diabetic rats. We allocated 60 prepubertal male rats randomly into six groups of 10: untreated control (C), DM control (DC), noopept control (NC), DM + noopept (D + N), DM + insulin (D + I) and DM + insulin + noopept (D + I + N). DM was induced by streptozotocin in the DC, D + N, D + I and D + I + N groups. Noopept was administered to the NC, D + N and D + I + N groups; insulin was administered to the D + I and D + I + N groups for 14 days. On day 18 of the experiment, animals were sacrificed and eyes, kidneys and pancreata were excised for histological investigation. Renal tubule diameter and corneal and retinal thickness were increased significantly in DC groups compared to the control group. The D + I, D + N and D + I + N groups exhibited fewer DM induced pathological changes than the DC group. The D + I + N group exhibited no significant differences in renal tubule diameter and corneal and retinal thickness compared to the DC group. Our findings suggest that noopept is protective against DM end organ complications in streptozotocin induced diabetic pubertal rats.

Effect of nootropic dipeptide noopept on CA1 pyramidal neurons involves α7AChRs on interneurons in hippocampal slices from rat.

Rodion V Kondratenko, Igor S Povarov, Sergey N Kolbaev +5 more

Noopept (NP) is a proline-containing dipeptide with nootropic and neuroprotective properties. We have previously shown that NP significantly increased the frequency of spontaneous IPSCs in hippocampal CA1 pyramidal cells mediated by the activation of inhibitory interneurons in stratum radiatum. The cholinergic system plays an important role in the performance of cognitive functions, furthermore multiple behavioral and clinical facts link NP with the cholinergic system. The present study was undertaken to reveal the possible interaction of NP with neuronal nicotinic acetylcholine receptors (nAChRs). Currents were recorded from rat hippocampal neurons using the whole-cell, patch-clamp technique. NP (5 µM) increased the action potential firing frequency recorded from GABAergic interneurons in the stratum radiatum (SR) of CA1 region. This effect was almost completely abolished by the application of the α7 nAChR-selective antagonists α-bungarotoxin (α-BGT; 6 nM) and methyllycaconitine (MLA; 20 nM). The increase in the frequency of spontaneous IPSCs in CA1 pyramidal cells induced by NP was also eliminated by α7 nAChRs antagonists. These results imply the involvement of α7 nAChRs in the modulation of hippocampal neuronal activity caused by NP and indicate that a7 nAChRs are an important site of action of NP.

Cognitive Enhancer Noopept Activates Transcription Factor HIF-1.

L F Zainullina, T V Ivanova, S V Sadovnikov +2 more

The effect of noopept (N-phenylacetyl-L-prolyl-glycine ethyl ester) on the DNA-binding activity of HIF-1 in SH-SH5Y cells and the mechanisms of stabilization of this transcription factor were studied in vitro. Noopept was shown to increase both the basal DNA-binding activity of HIF-1 and the activity induced by various hypoxia mimetics. The mechanism of stabilization of the oxygen-sensitive HIF1α subunit by noopept involves the inhibition of HIF-1 prolyl hydroxylase, which is indirectly indicated by the data obtained using the ODD-Luc reporter, and the positive effect on the level of the HIF1α protein. It was revealed that the effect of noopept is accompanied by changes in gene expression, which belong to different metabolic pathways and are controlled by the transcription factor HIF-1.

MANAGEMENT OF AMNESTIC AND BEHAVIORAL DISORDERS AFTER KETAMINE ANESTHESIA.

I Belenichev, B Burlaka, A Puzyrenko +3 more

General anesthesia may cause damage of the central nervous system and cognitive dysfunction in the postoperative period. A new intranasal form of Noopept (N-Phenylacetyl-L-prolylglycine ethyl ester) was developed by our team at the Department of the medical technology (Zaporizhzhia State Medical University, Ukraine). The objectives of this investigation were the study of neuroprotective action of Noopept and to prove using in the clinic for correction of amnestic and behavioral disorders after ketamine anesthesia. We discovered that the intranasal administration of noopept after ketamine anesthesia significantly decreases anxiety and excitability, raises the animal's activity, shows an intensive antiamnesic effects and increases animal's training ability. Noopept significantly exceeds piracetam and cerebrocurin according to neuroprotective effects.

Effects of noopept on cognitive functions and pubertal process in rats with diabetes.

Perihan Gürbüz, Halil Düzova, Azibe Yildiz +6 more

Type 1 diabetes (T1DM) is a common chronic disease in childhood. Increasing insulin resistance in puberty gives rise to higher doses of insulin usage in treatment. Of this reason new approaches in treatment are needed. Noopept researches suggest it to have anti-diabetic properties. We tried to determine the effects of noopept on pubertal diabetes.

Neuroprotective effect of novel cognitive enhancer noopept on AD-related cellular model involves the attenuation of apoptosis and tau hyperphosphorylation.

Rita U Ostrovskaya, Yulia V Vakhitova, Uliyana Sh Kuzmina +5 more

Noopept (N-phenyl-acetyl-L-prolylglycine ethyl ester) was constructed as a dipeptide analog of the standard cognition enhancer, piracetam. Our previous experiments have demonstrated the cognition restoring effect of noopept in several animal models of Alzheimer disease (AD). Noopept was also shown to prevent ionic disbalance, excitotoxicity, free radicals and pro-inflammatory cytokines accumulation, and neurotrophine deficit typical for different kinds of brain damages, including AD. In this study, we investigated the neuroprotective action of noopept on cellular model of AD, Aβ 25-35-induced toxicity in PC12 cells and revealed the underlying mechanisms.

[Role of functional state of neuronal mitochondria of cerebral cortex in mechanisms of nootropic activity of neuroprotectors in rats with alloxan hyperglycemia].

V I Zhiliuk, V I Mamchur, S V Pavlov

The influence of citicoline, phenylpiracetam, pentoxifylline and N-phenylacetyl-L-prolylglycine on cognitive processes and functional state of mitochondria in the neocortex of alloxan-diabetic rats has been studied. The drug effects on cognitive processes were assessed using passive avoidance tests in the dark-light camera. Latent period and the number of animals with amnesia skill on 6th and 20th days of drug administration were recorded. Functional status of mitochondria was assessed by mitochondrial pore opening and mitochondrial transmembrane potential (Y) on 20th day. It has been established that course administration of phenylpiracetam, citicoline and to a lesser extent N-phenylacetyl-L-prolylglycine, but not pentoxifylline, improves the processes of learning and storing conditional skill. At the same time, the nootropic activity of studied drugs was comparable to their effect on the functional state of mitochondria in neocortical neurons in rats with chronic hyperglycemia. According to mitoprotective activity (prevention of opening of mitochondrial cyclosporin-A-sensitive pores and restoration of mitochondrial transmembrane potential), the maximum potential was observed for citicoline and phenylpiracetam, and the minimum--for pentoxifylline. The results point out the importance of mitoprotective properties in nootropic effects of studied drugs.

[Noopept in the treatment of mild cognitive impairment in patients with stroke].

A V Amelin, A Iu Iliukhina, A A Shmonin

Noopept is a neuroprotector and nootropics. Literature data revealed the treatment effect of noopept on mild cognitive impairment in patients with discirculatory encephalopathy. The present open prospective study included 60 patients with stroke treated with noopept during 12 months. Cognitive functions were assessed before and after treatment using neuropsychological tests. An analysis of MMSE scores and lateral and categorical associations revealed the significant improvement of cognitive functions after 2 months in patients of the main group compared to the controls. The global assessment of efficacy revealed the mild improvement in the main group while no changes were found in the control group. The results have demonstrated that noopept, used in dose 20 mg daily during 2 months, improves cognitive functions in stroke patients and has a high level of safety.

[Current possibilities in the treatment of posttraumatic cognitive disturbances].

M M Odinak, S V Vorob'ev, V Iu Lobzin +2 more

[Vascular cognitive impairment in young patients].

I N Dolgova, A I Starodubtsev

[Effect of the novel nootropic and neuroprotective dipeptide noopept on the streptozotocin-induced model of sporadic Alzheimer disease in rats].

R U Ostrovskaia, A P Tsaplina, Iu V Vakhitova +2 more

Streptozotocin-intracerebroventricularly treated rats are proposed as an experimental model of sporadic Alzheimer disease (AD). Diabetogenic toxin streptozotocin (STZ) administered in both cerebral ventricles in a dose of 3 mg/kg decreases the expression of NGF and BDNF mainly in the hippocampus and increases the content of malonic dialdehyde (MDA)--a product of lipid peroxidation--in the brain tissues. These metabolic changes are accompanied by a pronounced cognitive deficiency, which is manifested by long-term memory deterioration in the passive avoidance test. These manifestations of pathology are not accompanied by hyperglycemia in the case of intraventricular STZ administration, in contrast to the systemic (in particular, intraperitoneal) route of introduction that causes a pronounced increase in the blood glucose level. These results are consistent with the existing notions that (i) STZ administered intraventricularly provokes a complex of changes imitating the sporadic AD and (ii) this disease can be considered as a manifestation of type-III diabetes. The new original cognition enhancing and neuroprotective dipeptide noopept decreases the aforementioned metabolic changes and the accompanying long-term deterioration of the memory. Previously, this systemically active dipeptide was shown to be capable of increasing expression of NGF and BDNF in the hippocampus, stimulating the antibody production to beta-amyloid, inhibiting the lipid peroxidation, activating the endogenous antioxidant systems, and decreasing the rate of glutamate release (cholinopositive effect). Taken together, these data indicate that noopept can be considered as a multipotent substance acting upon several important pathogenic chainsof the sporadic AD.

[The original nootropic and neuroprotective drug noopept potentiates the anticonvulsant activity of valproate in mice].

E V Kravchenko, I V Ponteleeva, S S Trofimov +3 more

The influence of the original dipeptide drug noopept, known to possess nootrope, neuroprotector, and anxiolytic properties, on the anticonvulsant activity of the antiepileptic drug valproate has been studied on the model of corazole-induced convulsions in mice. Neither a single administration of noopept (0.5 mg/kg, i.p.) nor its repeated introduction in 10 or 35 days enhanced the convulsant effect of corazole, which is evidence that noopept alone does not possess anticonvulsant properties. Prolonged (five weeks) preliminary administration of noopept enhanced the anticonvulsant activity of valproate. This result justifies the joint chronic administration of noopept in combination with valproate in order to potentiate the anticonvulsant effect of the latter drug. In addition, the administration of noopept favorably influences the cognitive functions and suppresses the development of neurodegenerative processes.

Comparative studies of Noopept and piracetam in the treatment of patients with mild cognitive disorders in organic brain diseases of vascular and traumatic origin.

G G Neznamov, E S Teleshova

Noopept stimulates the expression of NGF and BDNF in rat hippocampus.

R U Ostrovskaya, T A Gudasheva, A P Zaplina +4 more

We studied the effect of original dipeptide preparation Noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111) with nootropic and neuroprotective properties on the expression of mRNA for neurotropic factors NGF and BDNF in rat hippocampus. Expression of NGF and BDNF mRNA in the cerebral cortex and hippocampus was studied by Northern blot analysis. Taking into account the fact that pharmacological activity of Noopept is realized after both acute and chronic treatment, we studied the effect of single and long-term treatment (28 days) with this drug. Expression of the studied neurotropic factors in the cerebral cortex was below the control after single administration of Noopept, while chronic administration caused a slight increase in BDNF expression. In the hippocampus, expression of mRNA for both neurotrophins increased after acute administration of Noopept. Chronic treatment with Noopept was not followed by the development of tolerance, but even potentiated the neurotrophic effect. These changes probably play a role in neuronal restoration. We showed that the nootropic drug increases expression of neurotrophic factors in the hippocampus. Our results are consistent with the hypothesis that neurotrophin synthesis in the hippocampus determines cognitive function, particularly in consolidation and delayed memory retrieval. Published data show that neurotrophic factor deficiency in the hippocampus is observed not only in advanced Alzheimer's disease, but also at the stage of mild cognitive impairment (pre-disease state). In light of this our findings suggest that Noopept holds much promise to prevent the development of Alzheimer's disease in patients with mild cognitive impairment. Moreover, therapeutic effectiveness of Noopept should be evaluated at the initial stage of Alzheimer's disease.

[Clinical and electroencephalographic characteristic of noopept in patients with mild cognitive impairment of posttraumatic and vascular origin].

V K Bochkarev, E S Teleshova, S A Siuniakov +2 more

An effect of a new nootropic drug noopept on the dynamics of main EEG rhythms and narrow-band spectral EEG characteristics in patients with cerebral asthenic and cognitive disturbances caused by traumas or vascular brain diseases has been studied. Noopept caused the EEG changes characteristic of the action of nootropics: the increase of alpha- and beta-rhythms power and reduction of delta-rhythms power. The reaction of alpha-rhythm was provided mostly by the dynamics of its low and medium frequencies (6,7-10,2 Hz), the changes of beta-rhythm were augmented in frontal and attenuated in occipital areas. The analysis of frequency and spatial structure of EEG changes reveals that noopept exerts a nonspecific activation and anxyolytic effect. The differences in EEG changes depending on the brain pathology were found. The EEG indices of nootropic effect of the drug were most obvious in cerebral vascular diseases. The EEG changes in posttraumatic brain lesion were less typical.

Noopept efficiency in experimental Alzheimer disease (cognitive deficiency caused by beta-amyloid25-35 injection into Meynert basal nuclei of rats).

R U Ostrovskaya, A P Belnik, Z I Storozheva

Experiments on adult Wistar rats showed that injection of beta-amyloid25-35 (2 microg) into Meynert basal nuclei caused long-term memory deficiency which was detected 24 days after this injection by the memory trace retrieval in conditioned passive avoidance reflex (CPAR). The effects of noopept, an original nootropic and neuroprotective dipeptide, on the severity of this cognitive deficiency were studied. Preventive (for 7 days before the injury) intraperitoneal injections of noopept in a dose of 0.5 mg/kg completely prevented mnestic disorders under conditions of this model. Noopept exhibited a significant normalizing effect, if the treatment was started 15 days after the injury, when neurodegenerative changes in the basal nuclei, cortex, and hippocampus were still acutely pronounced. The mechanisms of this effect of the drug are studied, including, in addition to the choline-positive effect, its multicomponent neuroprotective effect and stimulation of production of antibodies to beta-amyloid25-35. Noopept efficiency in many models of Alzheimer disease, its high bioavailability and low toxicity suggest this dipeptide for further studies as a potential agent for the treatment of this condition (initial and moderate phases).

Genotype-dependent characteristics of behavior in mice in cognitive tests. The effects of Noopept.

A P Bel'nik, R U Ostrovskaya, I I Poletaeva

Male C57BL/6J, BALB/c, and DBA/2J mice showed differences in their abilities to perform two cognitive tests. C57BL/6J mice had good learning ability and memory trace retention (at 10 days) in a simplified Morris maze, while BALB/c mice had low levels of memory trace retention and DBA/2J mice had low learning ability in this test. I.p. administration of the nootropic agent Noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) at a dose of 0.5 mg/kg 15 min before the start of the test induced significant improvements in long-term memory in this test in BALB/c mice but no further improvement in C57BL/6J mice, and had no effect in DBA/2J mice. On testing the ability to extrapolate the direction of movement of a stimulus, administration of Noopept increased the proportion of correct responses in C57BL/6J and BALB/c mice, but had no effect in DBA/2J mice.

[A comparative study of noopept and piracetam in the treatment of mild and moderate cognitive impairment in patients with organic brain diseases of vascular and traumatic origin].

G G Neznamov, E S Teleshova

[Genotype-dependent mice behavior in cognitive tasks. Effect of noopept].

A P Bel'nik, R U Ostrovskaia, I I Poletaeva

The interstrain differences in performance of C57BL/6J, BALB/c and DBA/2J male mice in two cognitive tasks were found. Mice C57BL/6J showed good learning ability and preservation of memory traces tested 10 days after performance in a simplified version of Morris water maze. Mice BALB/c learned the task but, virtually, no long-term memory traces were revealed, whereas DBA/2J demonstrated poor learning. The effect of nootropic drug Noopept (GVS-111, N-phenil-acetyl-L-prolylglycin ethyl ether) was shown to be genotype-dependent. Its administration (0.5 mg/kg i.p., 15 min before learning) improved the long-term memory in Morris test in BALB/c mice but failed to produce any improvement in C57BL/6J. The ability of mice for extrapolation of the direction of stimulus movement differently changed after Noopept injections: the proportion of correct task solutions increased in C57BL/6J and BALB/c mice, whereas the performance of DBA/2J did not change.

Dipeptide preparation Noopept prevents scopolamine-induced deficit of spatial memory in BALB/c mice.

A P Belnik, R U Ostrovskaya, I I Poletaeva

The effect of original nootropic preparation Noopept on learning and long-term memory was studied with BALB/c mice. Scopolamine (1 mg/kg) impaired long-term memory trace, while Noopept (0.5 mg/kg) had no significant effect. Noopept completely prevented the development of cognitive disorders induced by scopolamine (blockade of muscarinic cholinergic receptors). Our results confirmed the presence of choline-positive effect in dipeptide piracetam analogue Noopept on retrieval of learned skill of finding a submerged platform (spatial memory). We conclude that the effectiveness of this drug should be evaluated in patients with Alzheimer's disease.

The nootropic and neuroprotective proline-containing dipeptide noopept restores spatial memory and increases immunoreactivity to amyloid in an Alzheimer's disease model.

Rita U Ostrovskaya, Marina A Gruden, Natalya A Bobkova +7 more

The effects of the novel proline-containing nootropic and neuroprotective dipeptide, noopept (GVS-111, N-phenylacetyl-L-prolylglycine ethyl ester) 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.

[Comparative study of the long-term behavioral effects of noopept and piracetam in adult male rats and female rats in postnatal period].

T A Voronina, L S Guzevatykh, S S Trofimov

Adult male and female rats were treated with the peptide nootrope drug noopept (daily dose, 0.1 mg/kg) and piracetam (200 mg/kg). In the period from 8th to 20th day, both drugs (cognitive enhancers) suppressed the horizontal and vertical activity and the anxiety in test animals as compared to the control group treated with 0.9 % aqueous NaCl solution. Early postnatal injections of the nootropes influenced neither the morphology development nor the behavior of adult female rats in the plus maze, extrapolational escape, passive avoidance, and pain sensitivity threshold tests. Animals in the "intact" group (having received neither drugs not physiological solution, that is, developing in a poor sensor environment), showed less pronounced habituation in the open field test as compared to the control and drug treated groups.

GVS-111 prevents oxidative damage and apoptosis in normal and Down's syndrome human cortical neurons.

Alejandra Pelsman, Carlos Hoyo-Vadillo, Tatiana A Gudasheva +3 more

The neuroprotective activity of a novel N-acylprolyl-containing dipeptide analog of the nootropic 2-oxo-1-pyrrolidine acetamide (Piracetam) designated as GVS-111 (DVD-111/Noopept) was tested in two in vitro models of neuronal degeneration mediated by oxidative stress: normal human cortical neurons treated with H(2)O(2), and Down's syndrome (DS) cortical neurons. Incubation of normal cortical neurons with 50 microM H(2)O(2) for 1h resulted in morphological and structural changes consistent with neuronal apoptosis and in the degeneration of more than 60% of the neurons present in the culture. GVS-111 significantly increased neuronal survival after H(2)O(2)-treatment displaying a dose-dependent neuroprotective activity from 10nM to 100 microM, and an IC(50) value of 1.21+/-0.07 microM. GVS-111 inhibited the accumulation of intracellular free radicals and lipid peroxidation damage in neurons treated with H(2)O(2) or FeSO(4), suggesting an antioxidant mechanism of action. GVS-111 exhibited significantly higher neuroprotection compared to the standard cognition enhancer Piracetam, or to the antioxidants Vitamin E, propyl gallate and N-tert-butyl-2-sulpho-phenylnitrone (s-PBN). In DS cortical cultures, chronic treatment with GVS-111 significantly reduced the appearance of degenerative changes and enhanced neuronal survival. The results suggest that the neuroprotective effect of GVS-111 against oxidative damage and its potential nootropic activity may present a valuable therapeutic combination for the treatment of mental retardation and chronic neurodegenerative disorders.

[The original novel nootropic and neuroprotective agent noopept].

R U Ostrovskaia, T A Gudasheva, T A Voronina +1 more

The paper describes pharmacological properties of the new nootropic drug noopept created using an original approach based on the imitation of a nonpeptide nootrope structure by means of the short-peptide design. In particular, the structure of pyracetam was designed using dipeptide nootropes. Experimental investigations of noopept (N-phenylacetyl-L-polyglycine ethyl ester) showed that the new drug exceeds pyracetam both with respect to the effective dose level (1000 times lower for noopept than for pyracetam) and in the spectrum of mnemotropic activity. In contrast to pyracetam facilitating only the early stages of the memory process, noopept positively influences the memory consolidation and retrieval steps as well. The new drug produces an additional selective anxiolytic action. The pronounced neuroprotective effect of noopept was demonstrated both in vivo (in cases of various forms of brain ischemia) and in vitro (on various neuronal models). The drug action is based on the antioxidant effect, the antiinflammatory action, and the ability to inhibit the neurotoxicity of excess calcium and glutamate, and to improve the blood rheology. It was established for the first time that the activity of noopept is retained both upon parenteral introduction and upon peroral administration, which is a principal advantage of this proline-containing dipeptide over other, more complex peptides. This property provided a basis for the development of a medicinal form of noopept for peroral usage. At present, noopept tablets (noopept 5 and 10 mg) are under clinical assessment as a means of treating cognitive deficiency of cerebrovascular and post-traumatic origin.

[Behavioral and electrophysiological analysis of the choline-positive effect of nootropic dipeptide acylproline (GVS-111)].

R U Ostrovskaia, T Kh Mirzoev, F A Firova +5 more

The behavioral experiments using a passive avoidance learning model showed that the new cognition-enhancing acyl-prolyn containing dipeptide GVS-111 promotes recovery of the test performance in animals with a long-term memory deficit caused by the M-cholinolytic scopolamine (1 mg/kg/day scopolamine for 20 days, followed by 0.5 mg/kg/day GVS-111 for 10 days). At the same time, GVS-111 increased the duration of tremor induced by the M-cholinomimetic arecoline. The results of electrophysicological experiments showed that GVS-111 in a concentration range from 10(-11) to 10(-9) M increased amplitude of the neural response to acetylcholine (Ach) microappications in 75% of the isolated neurons of Helix Pomatum and produced a predominantly facilitating effect upon the endoneuronal pacemaker activity. The effect of GVS-111 upon the Ach response in a part of neurons was attenuated or even blocked by scopolamine, and in the other neurons--by the N-cholinolytic d-tubocurarine. This fact indicates that both muscarinic and nicotinic receptors are involved in the mechanism of the cholino-sensitizing action of GVS-111 upon the neuronal activity.

Memory restoring and neuroprotective effects of the proline-containing dipeptide, GVS-111, in a photochemical stroke model.

R U Ostrovskaya, G A Romanova, I V Barskov +5 more

Local thrombosis of the frontal cortex (Fr1 and Fr3 fields), caused by combination of the intravenous photosensitive dye Rose Bengal administration with focused high-intensity illumination of the frontal bone, was shown to provoke a pronounced deficit in step-through passive avoidance performance in rats without concomitant motor disturbances. N-Phenylacetyl-L-prolylglycine ethyl ester (GVS-111) administered intravenously at a dose of 0.5 mg/kg/day, for the first time 1 h after ischaemic lesion and then for 9 post-operative days, with the last administration 15 min before testing, attenuated the deficit. This treatment significantly diminished the volume of the infarcted area. Thus, post-ischaemic injection of GVS-111 demonstrated both cognition-restoring and neuroprotective properties. The cognition-restoring effect is probably based on an increase in neocortical and hippocampal neuronal plasticity. Neuroprotective effects of GVS-111 combine antioxidant activity with the ability to attenuate glutamate-provoked neurotoxicity and block voltage-gated ionic channels, i.e. the compound mitigates the main metabolic shifts involved in pathogenesis of brain ischaemia.

The major metabolite of dipeptide piracetam analogue GVS-111 in rat brain and its similarity to endogenous neuropeptide cyclo-L-prolylglycine.

T A Gudasheva, S S Boyko, R U Ostrovskaya +7 more

The metabolism of a new piracetam analogue, the dipeptide cognitive enhancer N-phenylacetyl-L-prolylglycine ethyl ester (GVS-111) was studied in vivo. GVS-111 itself was not found in rat brain 1 h after 5 mg/kg i.p. administration up to limit of detection (LOD) under high performance liquid chromatography (HPLC) conditions. Three substances corresponding to the three possible GVS-111 metabolites, namely phenylacetic acid, prolylglycine and cyclo-prolylglycine, were found in experimental rat brain samples as well as in controls using HPLC, gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) methods. Only cyclo-prolylglycine concentration increased (2.5-fold) 1 h after GVS-111 administration. Cyclo-prolylglycine formation from GVS-111 in the presence of plasma and brain enzymes was shown in vitro. These data could be considered as evidence that GVS-111 is prodrug which converts in the body to cyclo-prolylglycine, and which is identical to the endogenous cyclopeptide that produces the nootropic activity.