Low-molecular mimetics of nerve growth factor and brain-derived neurotrophic factor: Design and pharmacological properties.

To overcome the limitations of the clinical use of neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), scientists have been trying to create their low-molecular-weight mimetics having improved pharmacokinetic properties and lacking side effects of full-sized proteins since the 90s of the last century. The efforts of various research groups have led to the production of peptide and nonpeptide mimetics, being agonists or modulators of the corresponding Trk or p75 receptors that reproduced the therapeutic effects of full-sized proteins. This review discusses different strategies and approaches to the design of such compounds.

Effect of Neuropeptide Cyclo-L-Prolylglycine on Cell Proliferative Activity.

Endogenous neuropeptide cyclo-L-prolylglycine possesses mnemotropic and neuroprotective properties, which can result from its positive effect on the level of brain-derived neurotrophic factor and modulation of activity of insulin-like growth factor-1 and AMPA receptors. For detection of possible mitogenic action of cyclo-L-prolylglycine, we analyzed its effect on proliferative activity of HEK293 and SH-SY5Y cells assessed by expression of Ki-67 proliferation marker, cell cycle examination, and incorporation of modified nucleotide analog EdU into DNA. Cyclo-L-prolylglycine did not affect the level of Ki-67 in examined cell lines and distribution of the cells over G1 and G2 phases of the cell cycle, although it insignificantly reduced the percentage of S phase cells, which attested to the absence of intrinsic mitogenic activity of the peptide.

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.

Effects of 5-Hydroxypyrimidine Derivatives on Tumor Growth and Lifespan of C57BL/6 Mice with Epidermoid Lung Carcinoma.

The effects of 5-hydroxypyrimidine derivatives SNK-411 (2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine) and SNK-578 (2-isobutyl-4,6-dimethyl-5-hydroxypyrimidine chlorohydrate) on the tumor growth and survival of male C57BL/6 mice with transplanted Lewis lung epidermoid carcinoma (LLC) were studied in animals receiving intraperitoneal treatment on days 2-15 of tumor development. Compound SNK-578 in a dose of 10 mg/kg significantly inhibited tumor growth (by 3.6 times; 72.

Antibodies to Glutamate Facilitate Spatial Memory Formation in the Morris Water Maze in Aging C57BL/6 mice.

Intranasal administration of antibodies to glutamate in a dose of 250 μg/kg for two weeks facilitated spatial learning and memory formation in the Morris water maze in aging C57BL/6 mice. In animals treated with glutamate antibodies, the content of serotonin and dopamine metabolites 3-MT and HVA in the hippocampus decreased, but no changes in the metabolism of neurotransmitter acids were revealed. In the prefrontal cortex, dopamine level decreased and the content of its metabolite DOPAC increased; in parallel, an increase in excitatory and inhibitory amino acids (aspartic acid, glutamate, glycine, taurine, and GABA) was observed.

The Levels of Monoamines and Their Metabolites in the Brain Structures of Rats Subjected to Two- and Three-Month-Long Social Isolation.

The levels of monoamines and their metabolites in the brain structures of adult Wistar rats subjected to post-weaning social isolation for 2 and 3 months were analyzed by HPLC with electrochemical detection. We have previously shown that these rats consistently demonstrate increased aggressiveness and, as a rule, impairment of short-term habituation. Two-monthlong social isolation was accompanied by a reduction in serotonin content and its increased turnover judging from the 5-HIAA/5-HT ratio in the hippocampus; three-month-long isolation was associated with increased levels of serotonin and reduction in its turnover in the amygdala.

Cardioprotective Effects of Metalloproteinase Inhibitor 1-({4-[(4-Chlorobenzoyl)amino]phenyl}sulfonyl-L-Proline in Modeled Acute Myocardial Infarction.

Cardioprotective effect of 1-({4 [(4 chlorobenzoyl)amino]phenyl}sulfonyl-L-proline (compound AL-828) was studied in rats with modeled acute myocardial infarction. The test compound was administered intragastrically in a dose of 30 mg/kg/day for 3 days prior to infarction modeling. Metalloproteinase inhibitor antibiotic doxycycline served as the reference drug and was administered in a dose of 40 mg/kg/day by the same schedule.

GK-2 Reduces Death of Cultured Granule Neurons in Cerebellum Induced by the Toxic Effects of Zinc Ions.

Peptide mimetic of nerve growth factor GK-2 in a dose of 1-2 mg/liter improves survival of cultured rat cerebellar granule neurons exposed to the cytotoxic effect of zinc ions, but has no protective effect against copper ion cytotoxicity. Experiments on cultured rat hippocampal slices demonstrated that GK-2 did not affect reactivity of pyramidal neurons and long-term potentiation in the hippocampal field CA1 and the probability of glutamate release from presynaptic terminals in the synapses of the CA3-CA1 fields. The results suggest that GK-2 does not affect the functional properties of synaptic transmission under normal conditions, but protects neurons from the toxic effects of zinc, which creates prerequisites for GK-12 use in the treatment of neurodegenerative diseases.

Psychotropic Effects of a New Pyrazolo[C]Pyridine Derivate GIZh-72 are Related to Functional Activity of Atp-Sensitive Potassium Channels.

We studied the influence of intraperitoneal injection of ATP-sensitive potassium channels inhibitor glibenclamide in doses of 0.01, 0.1, 1, and 10 mg/kg on the effects of a new pyrazolo[C]pyridine derivative GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1Hpyrazolo[ 4,3-C]pyridine-3-on, chloral hydrate; 20 mg/kg, intraperitoneally) in the marble burying and open-field tests in mice.

Antiexudative Effects of Finasteride and a New Pyrazolo[C]Pyridine Derivative GIZh-72 in Acetic Acid-Induced Experimental Peritonitis.

It was shown that finasteride, a 5α-reductase inhibitor (50 mg/kg, intraperitoneally) produced analgesic and antiexudative effects in experimental peritonitis induced by intraperitoneal injection of 1% acetic acid. These results agree with published data on its anti-inflammatory properties and ability to potentiate the analgesic effect of morphine in rodents. New pyrazolo[C] pyridine derivative GIZh-72 (4,6-dimethyl-2-(4-chlorphenyl)-2,3-dihydro-1H-pyrazolo[4,3-C]pyridine-3-on, chloral hydrate) injected intraperitoneally in doses of 20-80 mg/kg produced dose-dependent antiexudative effects, but exhibited no analgesic properties.

Role of GABA Receptors in the Mechanism of In Vivo Psychotropic Activity of Amitriptyline in Rats.

Standard water-reinforced drug discrimination model was employed to train Wistar rats to discriminate the intraperitoneal injections of tricyclic antidepressant amitriptyline (5.4 mg/kg) and physiological saline. To examine the role of GABA receptors in psychotropic action of amitriptyline, the substitution tests were performed with muscimol (0.

Neuroprotective Dipeptide Noopept Prevents DNA Damage in Mice with Modeled Prediabetes.

In experiments on BALB/c mice, prediabetes was modeled by administration of streptozotocin in a dose of 130 mg/kg. DNA damage was assessed by the method of DNA comets. Noopept (0.

Afobazole Alleviates Cognitive Rigidity in Experimental Model of Autism Spectrum Disorders.

Afobazole (10 mg/kg) alleviated cognitive rigidity in BALB/c mice, a phenotypic model of autism spectrum disorders. It improved spatial memory and retraining in T-maze with drinking reinforcement and restored the retrieval of acquired skill during reversal learning in Morris water maze.

Neuroprotective and Antiamnestic Effects of a New Drug Emopag in Rats.

Emopag, a new drug, preventively administered in doses of 10 and 30 mg/kg/day over 4 days produced a pronounced neuroprotective effect in the model of brain ischemia caused by gravitational overload and reduced animal mortality from 17 to 0%. The preparation more effectively corrected neurological deficit than the reference drugs Mexidol (in considerably larger doses of 30 and 90 mg/kg/day) and antihypoxic drug amtizol (30 mg/kg/day). Moreover, Emopag exhibited considerable antiamnestic activity comparable to that of Mexidol (in 3-fold higher doses); in a dose of 30 mg/kg/day Emopag was more effective than Mexidol and amtizol in the same dose.

Calcium Salt of N-(5-Hydroxynicotinoyl)-L-Glutamic Acid Weakens Depressive-Like Behavior and Parkinsonian Syndrome in Experiment on Rodents.

We studied antidepressant and antiparkinsonian properties of N-(5-hydroxynicotinoyl)-Lglutamic acid calcium salt (Ampasse) in rodents. It was found that Ampasse in a dose of 30 mg/kg exhibited antidepressant activity in the forced swimming test in mice and in a dose of 0.1 mg/kg maximally alleviates the symptoms of parkinsonian syndrome induced by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57Bl/6 mice, and haloperidol-induced catalepsy in rats.

Examination of Cardioprotective Effects of Fabomotizole Hydrochloride in Translational Rat Model of Chronic Heart Failure.

A translational rat model of chronic heart failure was employed to examine the cardioprotective effect of fabomotizole hydrochloride. Fabomotizole therapy for 28 days (15 mg/kg/day intraperitoneally) restored inotropic function of the left ventricle and increased ejection fraction from 54±3 to 65±3% (p=0.001).

Anti-Ischemic Activity of Fabomotizole Hydrochloride under Conditions of Endothelial Dysfunction.

Anti-ischemic activity of fabomotizole hydrochloride was studied on the model of subendocardial ischemia in rats with endothelial dysfunction. Endothelial dysfunction was modeled by intragastric administration of methionine (3 g/kg, once a day for 7 days). Acute subendocardial ischemia was induced in narcotized rats by intraperitoneal injection of isoproterenol (20 μg/kg/min over 5 min).

A Translational Model of Chronic Heart Failure.

We created a translational model of chronic heart failure in rats that developed in 3 months after reproducing experimental anterior transmural myocardial infarction. The model simulated the basic clinicodiagnostic criteria of this disease: impaired contractility and dilatation of heart ventricles, signs of venous congestion, elevated plasma content of biochemical markers, and abnormal overexpression of AT1aR and β-adrenoceptors.

Comparative Preclinical Pharmacokinetics and Bioavailability of Antidepressant GSB-106 Tablet Form.

Pharmacokinetics and relative bioavailability of antidepressant GSB-106 (hexamethylendiamide bis-(N-monosuccinyl-L-seryl-L-lysine) were determined in rabbits after single oral administration of the pharmaceutical substance and tablet mass. GSB-106 concentrations in the blood plasma were determined by HPLC-mass spectrometry. Relative bioavailability of GSB-106 tablet form was 160.

Selank, Peptide Analogue of Tuftsin, Protects Against Ethanol-Induced Memory Impairment by Regulating of BDNF Content in the Hippocampus and Prefrontal Cortex in Rats.

The effects of a peptide anxiolytic Selank synthesized on the basis of the endogenous peptide tuftsin on memory impairment and content of brain-derived neurotrophic factor (BDNF) in brain structures were analyzed in outbred rats receiving 10% ethanol as the only source of fluid for 30 weeks. In the object recognition test, Selank (0.3 mg/kg a day, 7 days, intraperitoneally) produced a cognitive-stimulating effect in 9 months rats not exposed to ethanol (p<0.

Changes in Monoamine Levels in BALB/c and 57Bl/6N Mice in Response to Acute Stress with Different Controllability.

The severity and specificity of CNS disturbances resulting from negative psychoemotional experience are determined by not only genetically determined stress sensitivity, but also epigenetic factors; among the latter, the context of stress exposure, e.g. stress controllability is considered.

Anti-Ischemic Activity of Triamine ALM-802 under Conditions of Endothelial Dysfunction.

Anti-ischemic activity of N1-(2,3,4-trimethoxybenzyl)-N2-{2-[(2,3,4-trimethoxybenzyl)amino] ethyl}-1,2-ethanediamine (ALM-802) based on the structure of standard p-FOX inhibitors trimetazidine and ranolazine was studied on the model of endocardial ischemia in intact rats and animals with endothelial dysfunction. Acute endocardial myocardial ischemia was caused by infusion of isoproterenol (20 μg/kg/min intravenously). Endothelial dysfunction in rats was modeled by inducing hyperhomocysteinemia (3 g/kg methionine intragastrically one a day over 7 days).

Effect of Endogenous Neuropeptide Cycloprolylglycine on GABA Receptors in Cerebellar Purkinje Cells.

Voltage clamp and concentration-jump methods were employed to examine the effects of endogenous neuropeptide cycloprolylglycine on GABA-activated ionic currents in isolated cerebellar Purkinje cells. In the concentration range of 0.1-10.

A Novel Dipeptide NGF Mimetic GK-2 Selectively Activating the PI3K/AKT Signaling Pathway Promotes the Survival of Pancreatic β-Cells in a Rat Model of Diabetes.

We investigated the cytoprotective effect of a novel low-molecular-weight NGF mimetic, GK-2 (hexamethylenediamide bis-N-monosuccinyl-L-glutamyl-L-lysine), on pancreatic β-cells. The neuroprotective effect of GK-2 had been previously shown to be associated with selective activation of the PI3K/Akt signaling pathway. In this study, rats with streptozotocin (STZ)-induced type 2 diabetes mellitus were used.

Comparative Assessment of the Effectiveness of Noncompetitive NMDA Receptor Antagonists Amantadine and Hemantane in Morphine Withdrawal Syndrome Model.

Activities of noncompetitive NMDA receptor antagonists (aminoadamantane derivatives) were assessed in random-bred rats with modeled morphine withdrawal syndrome. A single intraperitoneal injection of hemantane (10 or 20 mg/kg) significantly and dose-dependently moderated some behavioral symptoms (teeth-chattering, ptosis, and vocalization) and reduced total score of morphine withdrawal syndrome. In morphine-abstinent rats, hemantane partially prevented the decrease in the thresholds of tactile sensitivity, but had no effect on locomotor activity and body weight loss.