Neuropeptide cycloprolylglycine increases the levels of brain-derived neurotrophic factor in neuronal cells.

It was shown for the first time that the endogenous cyclic dipeptide cycloprolylglycine (CPG) at concentrations of 10(-7) and 10(-3) M and piracetam at a concentration of 10(-3) M increased the content of brainderived neurotrophic factor (BDNF) in the culture of neuronal cells in normal state and under conditions of glutamate and 6-oxydopamine neurotoxicity. This may indicate the possible involvement of BDNF in the mechanism of action of neuropeptide CPG and piracetam.

The first dipeptide ligand of translocator protein: Design and anxiolytic activity.

On the basis of the structure of Alpidem, a pyrazolopyrimidine ligand of the translocator protein (TSPO), a dipeptide TSPO ligand, N-carbobenzoxy-L-tryptophanyl-L-isoleucine amide (GD-23), was designed and synthesized using our own original peptide design strategy. This compound exhibited anxiolytic activity in BALB/cAnN mice in the "open-field" test and in outbred CD1 mice in the "elevated plus maze" test. The stereoselectivity of the anxiolytic effect of GD-23 is demonstrated. The results of this study suggest that GD-23 is a ligand of the translocator protein, and its structure can become the basis for creating anxiolytics with a fundamentally new mechanism of action.

Effectiveness of GK-2, a Nerve Growth Factor Mimetic, in Preventing Post-Resuscitation Changes in the Brain.

Neurological status was assessed and the numbers of neurons per 1 mm in pyramidal neuronal layer length in CA1 and CA4 hippocampal fields and cerebellar Purkinje cells were evaluated in albino male rats on post-resuscitation day 14 after 12-min cardiac arrest. Intraperitoneal administration of GK-2 (1 mg/kg 30 min after resuscitation and within the next 3 days with an interval of 24 h) accelerated neurological recovery of the animals, sharply reduced the intensity of cerebellar Purkinje cell death, and prevented loss of pyramidal neurons in the hippocampus. These results show the effectiveness of systemic administration of the nerve growth factor mimetic GK-2 in improving structural and functional state of the brain in the post-resuscitation period. This opens new prospects of its use for prevention and correction of post-hypoxic encephalopathy.

Noopept normalizes parameters of the incretin system in rats with experimental diabetes.

Experiments on adult Wistar rats with streptozotocin-induced diabetes showed that antihyperglycemic activity of an original nootropic and neuroprotective drug Noopept (N-phenylacetyl-L-prolylglycine ethyl ester) is more pronounced under conditions of oral application than after intraperitoneal injection. These data provided a basis for studying the effect of Noopept on major indexes of the incretin system. Streptozotocin was shown to decrease the concentrations of incretin GLP-1 and insulin in the blood. Noopept had a normalizing effect on these parameters. This influence of Noopept was not related to the inhibition of a major enzyme metabolizing incretins (dipeptidyl peptidase IV). A reference drug sitagliptin also increased the contents of incretins and insulin, which was associated with the inhibition of dipeptidyl peptidase IV. It is known that GLP-1 increases NGF expression in the insular system. Our results suggest that the increase in incretin activity contributes to the antiapoptotic effect of Noopept on pancreatic ß cells. The mechanism for an increase in blood GLP-1 level after oral application of Noopept requires further investigations.

[Neurotensin NT (8- 13) dipeptide analog dilept increases the pain threshold and decreases the severity of morphine withdrawal syndrome in rats].

The pain threshold effects of a neurotensin NT (8 - 13) dipeptide analog (dilept), morphine, and their combination have been studied using the tail flick test in rats. The animals of another experimental group were administered with morphine in increasing doses (10 - 20 mg/kg, i.p.) for 5 days in order to induce the state of dependence. The physical dependence on morphine was evaluated in the open-field test by monitoring 16 specific behavioral signs of withdrawal syndrome (WS) induced by the opioid receptor antagonist naloxone, after which the WS total index was calculated. It was established, that dilept (1.6 mg/kg, i.p.) produced a mild analgesic effect via increasing the pain threshold by 34% (p < 0.01), did not effect on the morphine analgesic effect, and decreased the expression of morphine WS by 29.1 and 37.5% (p < 0.01) after a single or subchronic administration, respectively. These behavioral effects of dilept were accompanied by normalization of dopamine and serotonin turnover in the hypothalamus, frontal cortex, and striatum of experimental animals.

[The new tripeptoid neurotensin analog dilept selectively affects dopamine turnover in nucleus accumbens and hypothalamus].

The effects of dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester) - a new peptidomimetic of neurotensine - on the level of monoamines and their main metabolites in four functionally important brain structures has been studied upon single and subchronic administration in intact rats and in those pretreated with the NMDA receptor blocker ketamine. Repeated administration of dilept favors the accumulation of DOPAC and accelerates the dopamine (DA) turnover in nucleus accumbens, as manifested by an increase in the DOPAC/DA ratio. The opposite effect (decrease in the DOPAC/DA ratio) was observed in the hypothalamus, where the subchronic treatment with dilept completely inhibited the activating action of ketamine on the DA turnover. The selective influence of dilept on the dopaminergic system activity in nucleus accumbens (but not in striatum), together with the previously obtained behavioral data, suggest that dilept is a new atypical neuroleptic producing no extrapyramidal side effects.

Dipeptide analog of neurotensin active site prevents the development of experimental Parkinson's syndrome in mice.

Chronic administration of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (30 mg/kg) to C57BL/6 mice caused death of all animals within 7 days. Dipeptide analog of neurotensin active site injected with this neurotoxin protected the mice from death even after 2-week intoxication. When younger mice and lower dose of neurotoxin (25 mg/kg) were used, all animals survived, but after 2 weeks they developed parkinsonian syndrome with muscular rigidity, akinesia, decrease in motor and explorative activities. In mice treated with dipeptide analog of neurotensin active site these manifestations of oligokinesia caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine were less pronounced and the corresponding parameters approximated the control values. Possible mechanisms of neuroprotective action of neurotensin active site analog are discussed.

[Modulation of the long-term memory by delayed administration of the nootropic agent L-pyroglutamyl-D-alaninamide during spaced and massed training of rats]. / Moduliatsiia dolgovremennoi pamiati otsrochennym vvedeniem nootropa amida L-piroglutamil-D-alanina pri rasstavlennom i massirovannom obuchenii u krys.

L-pyroglutamyl-D-alanine amide significantly enhanced freezing response in the group of rats with massed training and reduced it in the group with spaced training. The control animals revealed a higher freezing response with the spaced training. No differences occurred between the groups in a cue test.

[The correction with nooglutil and L-pyroglutamyl-D-alanine amide of cognitive disorders in rats due to intrauterine hypoxia]. / Korrekstiia noogliutilom i amidom L-piroglutamil-D-alanina kognitivnykh narushenii u krys, vyzvannykh vnutriutrobnoi gipoksiei.

Novel nootropic compounds, nooglutyl (N-5-hydroxy(nicotinoyl)-L-glutamine acid, 25 mg/kg/day) and L-pyroglutamyl-D-alanine amide (1 mg/kg/day) administered intracutaneously from the 8th to 20th day of life prevent from movement hyperactivity in "open field", disturbances in ability to training and in memory in an alternate test and in tests of passive and active avoidance and normalize behavior of the adult mail rats (subjected to two-hour hypobaric hypoxia in on the 15-day of intrauterine life, vacuum corresponded to the height 8500 m) in-extrapolation avoidance test. Additionally, nooglutyl recovered the normal growth of rats in the first month of their life, prevented from deceleration of investigating behavior of adults animals and disturbances of the mink reflex in them.

[The comparative characteristics of the effect of piracetam peptide analogs on the recovery of conditioned reflex activity in animals following damage to the frontal cortex and the electrophysiological characteristics of the brain integrative activity]. / Sravnitel'naia kharakteristika vliianiia peptidnykh analogov piratsetama na vosstanovlenie uslovnoreflektornoi deiatel'nosti zhivotnykh posle povrezhdeniia frontal'noi kory i élektrofiziologicheskie kharakteristiki integrativnoi deiatel'nosti mozga.

The time course of recovery of a conditioned avoidance response (CAAR) after extirpation of brain frontal regions was examined in rat experiments. The reference nootropic drug piracetam given in a dose 200 mg/g for 9 days after surgery promoted CAAR recovery. The original peptide analogue of piracetam--pyroglutamyl-D-alanine amide (I)--produced the same effect when given in a dose of 1 mg/kg. Another peptide analogue of piracetam--pyroglutamyl-asparagine amide (II) showed no promoting effect on CAAR recovery after frontal lobectomy. Electrophysiological experiments have demonstrated that I promotes the transcallosal cortical responses to a greater extent than does II. It has been suggested that the most significant promoting effect on the compensatory and recovery process after frontal lobectomy is produced by the nootropic compounds which have a promoting effect on memory trace consolidation.

[Neuropharmacological properties of piracetam derivatives]. / Neirofarmakologicheskie svoistva proizvodnykh piratsetama.

Piracetam and its 8 derivatives were studied in experiments on mice and rats with the use of standard neurotropic tests and nootropic activity tools. The electrophysiological index of GABA-ergic inhibition (the recovery cycle of cortical evoked potentials) was also investigated. It was shown that piracetam derivatives as well as piracetam itself have a pronounced antihypoxic activity and prevent the amnestic effect of electroshock in experimental passive avoidance. Most of them were inactive according to the standard neurotropic test. Piracetam derivatives with a hydrazide grouping in the side chain combine nootropic activity and a specific stimulant effect, while the derivatives possessing a phenyl ring combine nootropic and depressant activity.