Benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine, a prolyl endopeptidase inhibitor, modulates depression-like behavior of rats in forced swimming test and activities of proline-specific peptidases in the brain structures.

High activities of prolyl endopeptidase and dipeptidylpeptidase IV in the striatum and of prolyl endopeptidase in the frontal cortex were recorded in rats with stress-induced depression-like state (behavioral despair) developed in the Porsolt forced swimming test. Acute injection of benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine (prolyl endopeptidase noncompetitive synthetic inhibitor) in a dose of 1 mg/kg prevented the development of behavioral despair and the increase of prolyl endopeptidase and dipeptidylpeptidase IV activities in the brain structures. In a dose of 2 mg/kg prolyl endopeptidase inhibitor did not modify the development of behavioral despair, but prevented the increase of prolyl endopeptidase and dipeptidylpeptidase IV activities in the striatum.

Effect of imipramine and prolyl endopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine on activity of proline-specific peptidases in the brain of rats with experimental anxious-depressive syndrome.

Activities of prolyl endopeptidase and dipeptidyl peptidase IV in the frontal cortex, hypothalamus, nucleus accumbens, striatum, and hippocampus were measured in rats with the experimental anxious-depressive syndrome induced by treatment with a dipeptidyl peptidase IV inhibitor during the early postnatal period (days 5-18). Prolyl endopeptidase activity was elevated in the frontal cortex, hypothalamus, and nucleus accumbens. Increased activity of dipeptidyl peptidase IV was observed in the hypothalamus and striatum. Norepinephrine/serotonin reuptake inhibitor, imipramine, and noncompetitive prolyl endopeptidase inhibitor, benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine, were shown to abolish depression-like behavior of animals in the forced swimming test. These compounds had a normalizing effect on activities of prolyl endopeptidase and dipeptidyl peptidase IV in brain structures of rats.

Activities of proline-specific peptidases in brain structures of rats with experimental anxiety-depressive state caused by administration of dipeptidyl peptidase IV inhibitor in the early postnatal period.

We studied the dynamics of activity of dipeptidyl peptidase IV (DP-IV) and prolyl endopeptidase (PEP) in the frontal cortex, hypothalamus, striatum, nucleus accumbens, and hippocampus of rats with experimental anxiety-depression state induced by administration of methionyl-2(s)-cyano-pyrrolidine, an inhibitor of DPP-IV, in the early postnatal period. In 1-month-old experimental males, PEP and DP-IV activities increased in the frontal cortex and hypothalamus, while in 1-month-old experimental females PEP activity increased in the hippocampus and DP-IV activity increased in all studied brain structures. At the age of 3 months, increased PEP activity in the hypothalamus and nucleus accumbens was detected in males and decreased DP-IV activity in the nucleus accumbens and decreased PEP activity in the hippocampus were detected in females. At the age of 7 months, PEP activity increased in the frontal cortex and striatum and DP-IV activity increased in all studied brain structures in males; in 7-months-old females, activity of both enzymes increased in the striatum.

[Modeling of preclinical and early clinical stages of Parkinson's disease].

The first symptoms of Parkinson's disease manifest 20-30 years after the disease onset when the most dopaminergic neurons degenerated. Therefore, it is necessary to work out preclinical diagnostics and preventive treatment of this disease. Modeling of preclinical and early stages of Parkinson's disease was conducted in mice using 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP). The changes in motor behavior were not observed in mice by 14 day after MPTP injections in dose 12 mg/kg two times with interval of two hours. In the striatum, the region of dopaminergic axon projection, the content of dopamine and number of dopaminergic axons decreased by 57% and 59%, respectively, i.e. there were no changes in dopamine in single axons. In the substantia nigra, the region of dopamine neuron localization, the content of dopamine did not change though the total number of neurons decreased by 28%. However the dopamine content in remained neurons was higher by 77% compared to the control that indirectly indicated the compensatory enhancement of dopamine synthesis. After the MPTP injections in dose 4x12 mg/kg, there were changes in motor behavior of mice in the most sensitive tests. In the striatum, the dopamine content and number of dopaminergic axons decreased by 75% and 68%, respectively. In the substantia nigra, there were no changes in dopamine content but the number of dopaminergic neurons decreased by 43%. The intraneuronal dopamine content increased by more than 70%. In conclusion, we constructed the models of preclinical stage (two-time MPTP injections) and transition phase from presymptomatic to symptomatic stage (four times of MPTP injections) of Parkinson's disease.

[Experimental modeling of functional deficiency of the nigrostriatal dopaminergic system in mice].

The dopaminergic nigrostriatal system is a key component of regulation of the motor behaviour. Cell bodies of dopaminergic DA-ergic neurons are located in the compact zone of the substantia nigra, and their axons are projected along the nigrostriatal tract to the striatum. This study was aimed to develop an experimental model of the functional insufficiency of the DA-ergic neurons of the nigrostriatal system without any manifestation of movement disorders, i.e., a model of presymptomatic stage of parkinsonism. This model has been developed with a single subcutaneous injection of a low dose of MPTP (12 mg/kg) which is converted in the brain into the MPP+, a neurotoxin of DA-ergic neurons. It has been shown that the MPTP injection on the 14th day is followed by: (a) absence of any sign of movement disorders; (b) no change in the DA content and the number of DA-ergic neurons in the substantia nigra; (c) substantial loss of DA in the striatum as a result of the degeneration of about 50% of DA-ergic axons. The absence of movement disorders under the substantial DA depletion and degradation of DA-ergic axons in the striatum is supposed to be a consequence of the turning on of the compensatory processes in the brain. Thus, we have developed the experimental model of presymptomatic stage of parkinsonism which is characterized by the degeneration of DA-ergic axons in the striatum without degradation of the neuron cell bodes in the substantia nigra.

[Composite phytoadaptogens in oncology and gerontology].

The article describes results of research devoted to Phytomix-40, a mixture of plant adaptogens. It focuses on immunobiological criteria for its formulation, chemical composition and manufacture procedures, biological standartization tests, in vitro and in vivo preclinical studies, clinical trials in patients with non-malignant tumours (benign prostatic hyperplasia), precancer (oral leukoplakia), advanced cancer (malignant gastric cancer), and age-related neurodegenerative disease (parkinsonism). Prospects for the development of other plant preparations for non-toxic prevention and treatment of cancer and prolongation of life span of the affected subjects are discussed.

[Experimental model of anxiety-depression state in rats exposed to inhibitor of dipeptidyl peptidase IV methionyl-2(S)-cyano-pyrrolidine in early postnatal period].

The effects of irreversible synthetic inhibitor of dipeptidyl peptidase IV (DPPIV) methionyl-2(S)-cyano-pyrrolidine on behavior of adolescent and adult rats were studied. The inhibitor was administered in early postnatal period from day 5 to day 19 (1 mg/kg, i.p.) in rat pups (males and females). In 1-2-month-old males treated with inhibitor of DPPIV, increased anxiety was revealed in the elevated plus maze and in the open field, 2- and 7-month-old males demonstrated the increased anxiety in a special battery of tests for evaluating anxiety-phobic states, whereas in female 1-3 months-old rats, the increased anxiety was observed in the elevated plus-maze. The depression-like behavior in the forced swimming test was revealed in 2-3 month-old males and in 2- and 7-month-old females. Adolescent and adult (1-2-month-old) rats of both genders and 7-month-old females demonstrated anhedonia in sucrose consumption/preference test. The findings prove the development of anxiety-depression-like state in rats postnatally exposed to inhibitor of DPPIV and suggest the DPPIV involvement in the development of anxiety and depression.

Effects of prolylendopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine on experimental depressive syndrome development in rats.

Model of experimental depressive syndrome in rats induced by repeated systemic injection of proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine showed that chronic injection of prolylendopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine 30 min before pro-neurotoxin injection prevents the development of a number of depressive syndrome symptoms such as behavioral despair and biorhythmic disorders in forced swimming test, precludes the increase in anxiety-phobic level, prevents reduction of relative thymus mass. These results indicate that benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine possesses antidepressant, anxiolytic, and/antistress properties.

Behavioral changes in rats induced by a dipeptidyl peptidase IV inhibitor methionyl-2(S)-cyanopyrrolidine: experimental model of anxiety-depression disorder.

Administration of a synthetic dipeptidyl peptidase IV inhibitor methionyl-2(S)-cyanopyrrolidine (1 mg/kg) to rats during the early postnatal period was followed by the development of behavioral changes in young and adult animals. The degree of anxiety in the elevated plus maze increased in treated rats at the age of 1-2 months. Depressive behavior in the forced swimming test was typical of animals aging 2-3 months. Diazepam reduced the severity of anxiety in treated rats. Melipramine had a normalizing effect on swimming behavior. A novel prolyl endopeptidase inhibitor benzyloxycarbonyl-methionyl-2(S)-cyanopyrrolidine had the antidepressant properties.

Effect of a prolyl endopeptidase inhibitor benzyloxycarbonyl-alanyl-proline on the development of experimental depressive syndrome in rats.

The effects of a competitive prolyl endopeptidase inhibitor benzyloxycarbonyl-alanyl-proline were studied in rats with experimental dopamine deficiency-dependent depressive syndrome due to systemic administration of a proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine for 14 days. The inhibitor was injected intraperitoneally 30 min before treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2nd week of the study). This substance contributed to rapid disappearance of depressive symptoms during the recovery of behavioral activity. Our results indicate that benzyloxycarbonyl-alanyl-proline has the antidepressant properties.

Involvement of brain dopaminergic systems in the development of an MPTP-induced depressive state in rats.

A depressive state was induced in Wistar rats by repeated i.p. injections of the proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces the death of dopaminergic neurons in the brain. Signs of the development of the experimental depressive state were a reduction in body weight and an increase in the proportion of REM sleep during daytime sleep. The rearrangement of the spectral characteristics of electrical activity during the development of experimental depressive syndrome in rats was shown to occur in target structures of the nigrostriatal, mesocortical, and mesolimbic dopaminergic systems of the brain, as well as in the amygdala and hippocampus. The most marked changes were seen in the terminal field of the nigrostriatal dopaminergic system and hippocampus. Spectral rearrangements of electrical activity in the theta-1 and theta-2 ranges in the hippocampus and dopaminergic structures suggest the involvement of the hippocampus in mediating changes in the emotional status of the experimental animals during the development of the MPTP-induced depressive state.

[Involvement of the brain dopaminergic systems in the development of the MPTP-induced depressive state in rats].

Depressive state was produced in Wistar rats by repeated intraperitoneal administration of proneurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) inducing death of brain dopaminergic neurons. Weight loss and increase in REM-sleep rate during diurnal sleep were considered to be signs of the development of an experimental depressive state. During the development of the depressive state of rats, the MPTP-induced reorganization of the spectral power of electrical activity was observed in the terminal fields of the nigrostriatal, mesocortical, and mesolimbic dopaminergic systems, amygdala, and hippocampus. The most pronounced changes were revealed in the terminal field of the nigrostriatal system and hippocampus. The reorganization of the spectral power in the thetal and theta2 bands in the hippocampus and dopaminergic structures suggests the involvement of the hippocampus in producing changes in the emotional state during development of the MPTP-induced depressive syndrome.

[Mechanisms of development of secondary axonal failure in diffuse and local demyelinating neuropathies].

To estimate a qualitative and quantitative effects of axonal failure on the clinical and electromyographic (EMG) picture of diffuse and local demyelination, 24 patients with Guillain-Barre syndrome (GBS), 144 with chronic inflammatory demyelinating polyneuropathy (CIDP) and 27 patients with multifocal motor neuropathy (MMN) have been studied. All the patients underwent a complex clinical neurological and EMG examination. Along with significant association between muscular hypotrophies and weakness in the majority of patients (tau=0,51; p<0,001), in some cases weakness in extremities was found in the absence of amyotrophic syndrome specifying a "functional" axonopathy due to the disturbance of ionic transport and the blockade of potassium channels. The formation of persisting conduction block in 100% of MMN cases and in up to 75% of GBS and CIDP cases revealed the additional special mechanism of axonopathy. The primary autoimmune affection of axonal membrane in a case of acute motor axonal neuropathy is described. The data obtained suggest that secondary axonal pathology underlies formation of the pathological system manifesting with failure of neurotrophic influence of the affected axons in relation to muscles and leading to neurological plastic deficiency at a level of self-supporting dysregulation pathology.

Effect of complex phytoadaptogen on MPTP-induced Parkinson's syndrome in mice.

Oral administration of 10% solution of Phytomix-40 (multicomponent plant phytoadaptogen) to C57Bl/6 mice with MPTP-induced Parkinson's syndrome alleviated symptoms (oligokinesia and muscle rigidity), compensated for the deficiency of dopamine and its metabolites (DOPAC and homovanillic acid), and reduced the level of lipid peroxides in the striatum. In vitro Phytomix-40 in a concentration of 3.3 x 10(-2) g/liter exhibited a pronounced antioxidant effect (5-fold decreased MDA level in mouse brain homogenate in Fe(2+)-ascorbate-dependent LPO).

[Therapeutic effect of dexalgin on disturbances of vertebrogenic and nonvertebrogenic mechanisms in back pain].

To evaluate the effect of Dexalgin on dysregulation mechanisms in the complex therapy of dorsalgia, 39 patients have been studied. They were divided into 2 groups: with vertebrogenic (23 patients) and without vertebrogenic (16 patients) pain syndrome. Dexalgin was prescribed in dosage 75 mg daily during 5 days. Its efficacy was measured using the Visual Analogue Scale (VAS), Mc Gill Pain Questionnaire, OBPDQ in case of low back pain. Electromyographic (EMG) and magnetic resonance imaging (MRI) examination was performed in radiculopathic patients receiving dexalgin. The results revealed a statistically significant decrease of the VAS values at the control examination in both groups of patients (p<0,001) with background RI values being 18,4 +/- 9,7 and 21,2 +/- 11,7, respectively. The considerable reduction of RI to 14,6 +/- 9,2 was observed in the second group (p=0,044) on day 5. Dynamic examination showed the predominant decrease of OBPDQ percentage values in patients with myofascial back pain (p=0,038). The EMG data demonstrated a tendency to reduction of spontaneous activity in muscular fibers and normalization of the H-reflex latency during the tibial nerve conduction study in patients with vertebrogenic dorsalgia (p=0,058 and p=0,064, respectively). Dexalgin is the new generation of nonsteroid analgesics possessing potential in treatment of both, acute and exacerbations of chronic dorsalgias. No significant between-group differences were found in the MRI study. The study revealed dexalgin efficacy in patients with myofascial low back syndrome.

Activities of prolyl endopeptidase and dipeptidyl peptidase IV in brain structures of rats with dopamine deficiency-dependent MPTP-induced depressive syndrome.

The development of MPTP-induced depressive syndrome in rats was accompanied by activation of prolyl endopeptidase and dipeptidyl peptidase IV in the brain frontal cortex. Prolyl endopeptidase activity in the striatum also increased under these conditions. Our results indicate that proline-specific peptidases in the target structures of the brain dopaminergic system are involved in the pathogenesis of dopamine deficiency-dependent depressive states.

[Some general pathological and biological categories: health, disease, homeostasis, sanogenesis, adaptation, immunity. New approaches and definitions]. / Nekotorye obshchepatologicheskie i biologicheskie kategorii: zdorov'e, bolezn', gomeostaz, sanogenez, adaptatsiia, immunitet. Novye podkhody i opredeleniia.

The article outlines new approaches to definition of categories of homeostasis, health, disease and sanogenesis in terms of relationships between human body and environment. According to these definitions, health is the state of the body with unaffected functional dynamic homeostasis securing optimal functioning for productive relations with the environment; disease is the state of the body with affected functional dynamic homeostasis and its inability to accomplish functions for productive relations with the environment. These formulations reflect biological and social aspects of the above categories.