Behavioral Effects of Dimeric Dipeptide BDNF Mimetic GSB-106 in a Rat Model of Depressive-Like State.

The effects of GSB-106, a low-molecular mimetic of BDNF loop 4, that represents a substituted dimeric dipeptide bis (N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide, on cognitive and motor impairments in a model of a depressive-like state in rats caused by unavoidable electric foot-shock were studied using active avoidance and open-field tests. GSB-106 (0.5 mg/kg, per os, 10 days) completely restored the number of avoidance reactions that was reduced in rats exposed to foot-shock and the percentage of trained rats in active avoidance training. In the open-field test, the peptide restored reduced horizontal activity and the number of explored holes. Thus, GSB-106 corrected impaired learning and memory, as well as locomotor activity and exploratory behavior in a model of depression in rats.

New Positive Allosteric Modulator of AMPA Receptors: in vitro and in vivo Studies.

A new derivative of 3,7-diazabicyclo[3.3.1]nonane, which showed a high activity as a positive allosteric modulator of AMPA receptors of the CNS, was studied in electrophysiological experiments. At doses of 0.01 mg/kg, this compound significantly improved the memory of experimental animals disturbed by maximal electric shock. The results indicate that this compound is a promising candidate for preclinical trials and clinical studies as a drug for treatment of a number of psychoneurological diseases.

A New Component in the Mechanism of Regulation of Endogenous Depressive-Like States.

It was shown previously that cycloprolylglycine, an endogenous neuropeptide, is a positive AMPA receptor modulator and is able to increase the content of BDNF in neurons. In the present study, using the model of learned helplessness in rats, we showed that cycloprolylglycine at a dose of 1 mg/kg at subchronic intraperitoneal administration reduced the time of animal immobility to passive control values (from 167.6 to 83.6 s) on day 12 of the experiment. This indicates the presence of antidepressant-like activity. The results of the study allow us to consider cycloprolylglycine as a component in the physiological regulation of the depression-like state.

Antidepressant Effect of an Orally Administered Dipeptide Mimetic of the Brain-Derived Neurotrophic Factor.

Involvement of BDNF in the regulation of neuroplasticity and neurogenesis in the hippocampus, impairment of which underlies the pathophysiology of depression, makes this endogenous protein a promising object for the development of new-generation antidepressants with a neurophysiologically based mechanism of action. A low-molecular-weight BDNF mimetic, GSB-106 (a substituted dimeric dipeptide, bis-(N-monosuccinyl- L-seryl-L-lysine) hexamethylenediamide), was designed and synthesized at the Zakusov Institute of Pharmacology. GSB-106 was found to activate BDNF-specific TrkB receptors and their main post-receptor signaling pathways MAPK/ERK and PI3K/AKT. GSB-106 exhibited pronounced antidepressant activity in a rodent test battery at a dose of 0.1 to 1.0 mg/kg administered intraperitoneally. Because oral administration is preferable in the treatment of depression, which is associated with a prolonged duration and outpatient character of pharmacotherapy, we examined the antidepressant properties of GSB-106 administered orally as a pharmaceutical substance (PS) and in tablet dosage form (TDF). In the study, we used the Porsolt forced swim test in rats; a conventional antidepressant, Amitriptyline, was used as a reference drug. The antidepressant activity of GSB-106 was found to retain upon oral administration and to manifest at doses of 0.5-5.0 mg/kg for PS and 0.01-5.0 mg/kg for TDF. The effective dose of TDF was 50-fold lower than that of PS, and the efficacy of tableted GSB-106 exceeded that of Amitriptyline, the "gold standard" in antidepression care. Therefore, GSB-106, both as a substance and as a tablet dosage form, exhibits antidepressant activity when administered orally, which makes it a promising antidepressant agent, the first in the class of BDNF mimetics.

Involvement of BDNF and NGF in the mechanism of neuroprotective effect of human recombinant erythropoietin nanoforms.

Human recombinant erythropoietin adsorbed on poly(butyl)cyanoacrylate nanoparticles and administered intraperitoneally in a dose of 0.05 mg/kg exhibited a neuroprotective effect in experimental intracerebral posttraumatic hematomas (hemorrhagic stroke) and reduced animal mortality. Human recombinant erythropoietin, native and adsorbed on lactic and glycolic acid copolymer-based nanoparticles, exhibited no antistroke effect on this model. Analysis of reverse transcription PCR products showed that human recombinant erythropoietin adsorbed on poly(butyl)cyanoacrylate nanoparticles more than 2-fold increased the expression of BDNF and NGF neurotrophins in the rat brain frontal cortex and hippocampus.

Antidepressant Effect of Dimeric Dipeptide GSB-106, an Original Low-Molecular-Weight Mimetic of BDNF.

A large amount of clinical and experimental data suggest the involvement of neurotrophins, in particular the brain-derived neurotrophic factor (BDNF), in depression pathogenesis. However, the therapeutic use of BDNF is limited because of its instability in biological fluids, poor blood-brain barrier (BBB) permeability, and the presence of side effects. A low-molecular-weight mimetic GSB-106, which is a substituted dimeric dipeptide bis(N-monosuccinyl-L-seryl-L-lysine)hexamethylenediamide, was designed and synthesized based on the BDNF fourth loop structure at the V.V. Zakusov Institute of Pharmacology (RAMS). GSB-106 was found to exhibit an antidepressant activity in various models of depressive-like state when administered intraperitoneally to outbred mice and rats. An effect for the substance, when administered daily for 4-5 days, was detected in the Porsolt forced swimming test (0.1 and 1.0 mg/kg) and in the tail suspension test in mice (1.0 and 1.5 mg/ kg). An effect for GSB-106 at doses of 0.1 and 0.5 mg/kg was observed after a single application in experiments on rats in the Nomura water wheel test. The obtained evidence supports the hypothesis on the involvement of BDNF in the pathogenesis of various depression conditions, thus opening prospects for searching for new original antidepressants.

[Comparative study of himantane and amantadine effects in experimental intracerebral posttraumatic hematoma].

Effects of the novel antiparkinsonian drug himantane and amantadin were studied in rats with intracerebral posttraumatic hematoma. Drugs were administered first at 3.5 hours after surgery and then for 4 consecutive days. Effects were registered on days 1, 3, 7 and 14 after surgery. It was shown that both drugs significantly decreased mortality and improved motor activity, exploratory behavior and memory. Amantadin was more effective in tests for motor activity and exploratory behavior. Himantane 5 mg/kg i.p demonstrated the more pronounced activity in restoring memory. The results obtained testify for neuroprotective properties of the novel antiparkinsonian drug himantane.

[Neuroprotective effect of recombinant human erythropoietin-loaded poly(lactic-co-glycolic) acid nanoparticles in rats with intracerebral posttraumatic hematoma].

The neuroprotective activity of recombinant human erythropoietin (rhEPO) loaded poly(lactic-co-glycolic) acid (PLGA) nanoparticles has been observed in rats with model intracerebral post-traumatic hematoma (hemorrhagic stroke). It is established that rhEPO-loaded PLGA nanoparticles produce a neuroprotective effect in rats with hemorrhagic stroke, which is manifested by reduced number of lethal outcomes and animals with neurological disorders. Treatment with rhEPO-loaded PLGA prevented amnesia of passive avoidance reflex (PAR), which was produced by the hemorrhagic stroke, and reduced the area of brain damage caused by the intracerebral hematoma. These effects were recorded during one-week observation period. Native rhEPO exhibited a similar, but much less pronounced effect on the major disorders caused by the model hemorrhagic stroke in rats.

[The absence of tolerance and withdrawal syndrome after the treatment with the new L-tryptophane-containing dipeptide anxiolytic GB-115].

Effects of GB-115, an anxiolytic L-triptophan-containing dipeptide, based on the endogenous tetrapeptide cholecystokinin, were evaluated during and after withdrawal of its long-term administration to rats in comparison with diazepam. It was shown using the "elevated plus-maze" test (EPM) that GB-115 retained its anxiolytic properties after i/p injections at a daily dose of 0.1 mg/kg fo r 30-days. Discontinuation of dipeptide administration 24h and 48 hours after the onset of the experiment did not lead to behavioral (increased anxiety, aggression) and convulsive (decreased corazol sensitivity) manifestations of withdrawal syndrome. In contrast, the withdrawal ofdiazepam (4.0 mg/kg/day, ip, 30 days) induced the anxiogenic response in EPM, reduction of the aggression threshold, and enhancement of convulsive readiness. Significant differences between GB-115 and diazepam effects on the levels of dopamine, norepinephrine, and their metabolites after chronic administration and withdrawal were restricted to striatum.

[Neuroprotector effect of human recombinant erythropoietin sorbed on polymer nanoparticles studied on model of intracerebral post-traumatic hematoma (hemorrhagic stroke)].

The neuroprotective activity of recombinant human erythropoietin (r-HuEpo) sorbed on poly(butyl)cyanoacrilate nanoparticles (EPO-PBCA) and on polylactic-co-glycolic acid nanoparticles (EPO-PLGA) has been studied on Wistar rats with intracerebral post-traumatic hematoma (model of hemorrhagic stroke) (IPH-HS) in comparison to native r-HuEpo. It is established that EPO-PBCA produced a protective effect in rats after IPH-HS that was manifested by a decrease in the number of animals with neurological disorders such as circus movement, paresis, and paralysis of hind limbs; the drug also improved coordination (rotating rod test), reduced the number of lost animals, and decreased the loss weight among survived rats. In addition, EPO-PBCA optimized the research behavior of rats with IPH-HS in the open field test and prevented amnesia of passive avoidance reflex (PAR), which was caused by the IPH-HS. These effects were manifested during a two-week observation period. EPO-PLGA has a similar but much less pronounced effect on the major disorders caused by IPH-HS. The efficiency of native r-HuEpo as a neuropotective agent was insignificant and only manifested by decrease in the number of lost animals with IPH-HS.

[Effects of chronic administration of dimebon on behavior and memory of SAMP 10 mice].

SAMP 10 mice with genetically determined senescence (senescence-accelerated mouse prone 10) aged 16 months demonstrated (in comparison to 3-months old animals of the same strain) the following traits typical of old animal: behavior and memory deficiency, exploratory behavior impairment, and elevated level of anxiety. Dimebon administered for a long period of time with drinking water (1.5 mg/kg over 5 months) produced a positive action upon behavior and memory of 16-months-old SAMP 10 mice, optimized exploratory behavior in the open field test, diminished anxiety in elevated plus maze test, and improved retrieval of passive avoidance reaction.

[Features of memantine action profile in cholinergic deficit and intracerebral posttraumatic hematoma (hemorrhagic stroke) models in rats].

Memantine, a low-affinity non-competitive antagonist of glutamatergic NMDA-subtype receptors, was used at a daily dose of 1 mg/kg over 10 days for the treatment of rats with cholinergic deficit induced by the chronic administration of scopolamine (1 mg/kg, 20 days). The drug prevented violation of the learning of conditioned active and passive avoidance reflexes and produced no significant effect on the emotional state of animals in elevated plus maze (EPM) test. In animals with intracerebral posttraumatic hematoma (hemorrhagic stroke), memantine (2 mg/kg, for 3 days after operation) completely prevented the loss of animals, reduced the neurological deficit, improved conditioned passive avoidance reflex performance, and decreased emotional stress in the EPM test.

[Effect of nooglutyl on the behavior and memory of SAMP10 mice with genetically determined accelerated aging].

It is established that SAMP10 mice (senescence-accelerated mice prone 10) with genetically determined accelerated senescence at an age of 9-month exhibit (in comparison to 3-month animals of the same strain) the behavior and memory deficits typical of aged animals, namely, reduced locomotor activity elevated anxiety, and disturbances of memory trace retrieval. Nooglutyl in a dose of 20 mg/kg produces a positive effect on the behavior and memory of 9-month old SAMP10 mice. The observed improvements include optimization of the locomotor activity in the open field test, diminished anxiety in elevated plus maze test, and improved retrieval of passive avoidance reflex.

[Changes in proline-specific peptidase activity in experimental model of retrograde amnesia].

Changes in proline-specific peptidase activity in the frontal cortex and hippocampus were studied using the experimental model of retrograde amnesia in rats. In one group, the amnesia was produced by a single injection of M-cholinergic antagonist scopolamine and the other group received the maximal electroconvulsive stimulation (MES). The amnesic effect was evaluated in passive avoidance test. In the amnesia models under consideration, the activity of prolylendopeptidase was significantly increased in both frontal cortex and hippocampus. The activity of dipeptidyl peptidase IV was significantly decreased in the cortex, whereas in the hippocampus it remained unchanged. Pyracetam inhibited prolylendopeptidase in the cortex and hippocampus, whereas dipeptidyl peptidase IV activity remained unchanged.

Neuroprotective effects of afobazol in experimental cerebral hemorrhage.

The study of novel selective anxiolytic afobazol on rats with experimental intracerebral post-traumatic hematoma (cerebral hemorrhage) demonstrated its efficiency in a dose of 5 mg/kg applied by a single or repeated administration for 2 weeks. The preparation significantly decreased the incidence of neurological disturbances in most rats (pareses, paralyses, convulsive movements, lateral posture). The therapeutic course of afobazol improved survival rate. Afobazol improved learning and memory in rats with cerebral hemorrhage in the conditioned passive avoidance test and positively affected motor activity in the open field test, which was documented by significant increase in total motor activity indices. The effects of afobazol were more pronounced after course treatment.

[Effect of phenyl-tert-butylnitrone, mexidol and nooglutil on the ischemic lesion zone and memory in rats following middle cerebral artery occlusion]. / Vliianie fenil-t-butilnitrona, meksidola i noogliutila na zonu ishemicheskogo porazheniia mozga i pamiat' krys posle okkliuzii srednei mozgovoi arterii.

An ischemic cerebral affection zone amounting to 22.51 +/- 3.0% of the ipsilateral hemisphere volume was found on the frontal brain sections in the frontoparietal cortex of rats 72 h after occlusion of the distal branch of the medial cerebral artery. The new nootropic drug nooglutyl [N-(5-hydroxynicotinoyl)-L-glutamic acid] in a dose of 10 mg/kg, as well as mexidol or phenyl-tert-butylnitrone (PBN) in a dose of 100 mg/kg, introduced into the vein at the moment of occlusion and intraperitoneally for two days after operation, effectively restricted the affected zone: nooglutyl, up to 7.6 +/- 2.28%; mexidol, up to 9.55 +/- 1.9%; and PBN, up to 12.8 +/- 1.7% of the ipsilateral hemisphere volume. On the third day after operation, animals preliminarily learnt to the passive avoidance conditioned reflex exhibited violated memory retrieval. The retrieval was significantly improved in the test animals treated with mexidol and especially nooglutyl.

[Effect of nooglutil on rats with intracerebral posttraumatic hematoma (hemorrhagic stroke)]. / Effekt noogliutila u krys s intratserebral'noi postravmaticheskoi gematomoi (gemorragicheskim insul'tom).

The effect of the new nootropic drug nooglutyl, a positive modulator of AMPA-subtype glutamatergic receptors, was studied in rats with a model hemorrhagic stroke (HS)--posttraumatic hematoma induced by cerebral tissue destruction in the capsule interna region. Single intraperitoneal injections of nooglutyl (10 and 20 mg/kg) 3-4 h after operation decreased the HS-induced neurological deficiency, restored the coordination of movements, improved the passive avoidance reaction retrieval, and prevented the loss of experimental animals. The results show evidence of a pronounced neuroprotector action of nooglutyl in rats with the HS model.

[Pharmacokinetics and efficacy of phenazepam after transdermal and enteral administration in rats]. / Otsenka farmakokinetiki i éffektivnosti fenazepama u krys pri transdermal'nom i énteral'nom sposobakh vvedeniia.

The concentration of fenazepam in the blood plasma of rats upon application of the transdermal therapeutic system (TTS) fenapercuten was very low, incomparable to the drug concentration (recalculated to equal input doses) upon intravenous or enteral administration. Nevertheless, the TTS exhibited a pronounced anxiolytic and weak sedative action in the absence of any side myorelaxant effect. The agent responsible for adverse side effects (3-hydroxyfenazepam) was not determined in the blood plasma upon the TTS application. A steady-state concentration of fenazepam in the blood plasma of rats was observed between 2nd and 8th hours upon fenapercuten application, which agrees with the duration of anxiolytic action of the parent drug.

Effect of nooglutil on benzodiazepine withdrawal syndrome and binding of 3H-spiperone with D2 receptors in rat striatum.

A new nootropic preparation nooglutil (N-(5-oxynicotinoyl)-L-glutamic acid), a positive modulator of AMPA receptors for glutamate, administered intraperitoneally in a dose of 70 mg/kg reduced anxiety of rats in the Vogel conflict test after 24-h withdrawal from chronic diazepam treatment (4 mg/kg intraperitoneally for 45 days). Nooglutil (5 nM-750 microM) had no effect on in vitro binding of (3)H-spiperone in intact rats. Systemic administration of 50 mg/kg nooglutil in vivo increased the dissociation constant and density of D(2)receptors. Increasing the dose to 100 mg/kg abolished this effect. Our findings suggest that nooglutil produces an indirect effect on the brain dopaminergic system under normal and pathological conditions and this effect is probably mediated via the glutamatergic system.

Discriminative effects of phenazepam and gidazepam in rats: comparison with other GABA-related drugs.

The present study assessed the discriminative stimulus effects of phenazepam (PHZ) (2 mg/kg, i.p.), gidazepam (GDZ) (10 mg/kg, i.p.), pentobarbital (PB) (10 mg/kg, i.p.), and buspirone (B) (5 mg/kg, i.p.) by testing GABA-related drugs in the two-lever liquid reinforced operant discrimination procedure in rats. Diazepam (5-30 mg/kg, i.p.) dose dependently and completely substituted in GDZ-trained rats and in only 40% PHZ-trained rats. Following phenobarbital (40-100 mg/kg, i.p.) injections the mean percentages of PHZ- and GDZ-lever responding generally were a monotonically increasing function of dose, but peaked at 39.3 and 52.9%, respectively. The PB discriminative cue was generalized completely to PHZ, GDZ, and phenobarbital. Picrotoxin (2 mg/kg, s.c.) did not inhibit the PHZ and GDZ discriminations, while it antagonized the PB (10 mg/kg, i.p.) cue. Calcium valproate (200 mg/kg, i.p.) failed to produce PHZ effects, and partially substituted for GDZ. B failed to substitute for the discriminative effects of PHZ, GDZ, or PB, producing a maximum 9.3, 18.0, and 33.3% drug lever responding, respectively. These results suggest that the discriminative stimuli of PHZ and GDZ are similar to those of other benzodiazepine agonists. However, the PHZ cue is more selective than that of GDZ.