[The effect of neurotoxin MPTP administration to mice on the proteomic profile of brain isatin-binding proteins]. / Vliianie neirotoksina MFTP na proteomnyi profil' izatin-sviazyvaiushchikh belkov mozga myshei.

Isatin (indole-2,3-dione) is an endogenous indole found in the mammalian brain, peripheral organs and body fluids. It acts as a neuroprotector, which decreases manifestation of locomotor impairments in animal models of Parkinson's disease. A wide range of biological activity of isatin is associated with interaction of this regulator with numerous isatin-binding proteins. The aim of this study was to investigate the profile of brain isatin-binding proteins in mice with MPTP-induced Parkinsonism (90 min and seven days after administration of this neurotoxin). A single dose administration of MPTP (30 mg/kg, ip.) was accompanied by locomotor impairments in the open field test 90 min after administration; seven days after MPTP administration locomotor activity of mice significantly improved but did not reach the control level. Five independent experiments on proteomic profiling of isatin-binding proteins resulted in confident identification of 96±12 proteins. Development of MPTP-induced locomotor impairments was accompanied by a significant decrease in the number of isatin-binding proteins (63±6; n=5; p<0.01). Seven days after MPTP administration the total number of identified proteins increased and reached the control level (132±34; n=4). The profiles of isatin-binding proteins were rather specific for each group of mice: in the control group these proteins (which were not found in both groups of MPTP-treated mice) represented more than 70% of total proteins. In the case of MPTP treated mice this parameter was 60% (90 min after MPTP administration) and >82% (seven days after MPTP administration). The major changes were found in the groups of isatin-binding proteins involved into cytoskeleton formation and exocytosis, regulation of gene expression, cell division and differentiation and also proteins involved in signal transduction.

Brain Mitochondrial Subproteome of Rpn10-Binding Proteins and Its Changes Induced by the Neurotoxin MPTP and the Neuroprotector Isatin.

Mitochondria play an important role in molecular mechanisms of neuroplasticity, adaptive changes of the brain that occur in the structure and function of its cells in response to altered physiological conditions or development of pathological disorders. Mitochondria are a crucial target for actions of neurotoxins, causing symptoms of Parkinson's disease in various experimental animal models, and also neuroprotectors. Good evidence exists in the literature that mitochondrial dysfunction induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) influences functioning of the ubiquitin-proteasomal system (UPS) responsible for selective proteolytic degradation of proteins from various intracellular compartments (including mitochondria), and neuroprotective effects of certain antiparkinsonian agents (monoamine oxidase inhibitors) may be associated with their effects on UPS. The 19S proteasomal Rpn10 subunit is considered as a ubiquitin receptor responsible for delivery of ubiquitinated proteins to the proteasome proteolytic machinery. In this study, we investigated proteomic profiles of mouse brain mitochondrial Rpn10-binding proteins, brain monoamine oxidase B (MAO B) activity, and their changes induced by a single-dose administration of the neurotoxin MPTP and the neuroprotector isatin. Administration of isatin to mice prevented MPTP-induced inactivation of MAO B and influenced the profile of brain mitochondrial Rpn10-binding proteins, in which two pools of proteins were clearly recognized. The constitutive pool was insensitive to neurotoxic/neuroprotective treatments, while the variable pool was specifically influenced by MPTP and the neuroprotector isatin. Taking into consideration that the neuroprotective dose of isatin used in this study can result in brain isatin concentrations that are proapoptotic for cells in vitro, the altered repertoire of mitochondrial Rpn10-binding proteins may thus represent a part of a switch mechanism from targeted elimination of individual (damaged) proteins to more efficient ("global") elimination of damaged organelles and whole damaged cells.

[Peculiarities of hypnotic effect and pharmacokinetics of hemisuccinate 3-hydroxyphenazepam (levana)].

The pharmacodynamics and pharmacokinetics of hemisuccinate 3-hydroxyphenazepam (HS-3-HPh, levana)--a new hypnotic 1,4-benzodiazepine derivative--have been studied. It is established that HS-3-HPh in doses of 0.05, 0.1 and 2 mg/kg produces reliable hypnotic action (shortens the period of falling asleep, reduces the number of awakenings at night-time, and increases sleep duration) in the hexenal sleep potentiation test on mice. After a 7-day drug administration, no withdrawal syndrome has been observed. The concentration of 3-oxyphenazepam (3-OP, the main metabolite of HS-3-HPh) in brain after drug administration is significantly higher than the content of 3-OP upon its introduction. The content of 3-OP upon its introduction rapidly decreases, while that upon the administration of HS-3-HPh is retained on a stationary level for a rather long time (about 6 h). It can be suggested that a specific character of HS-3-HPh hypnotic action is determined by peculiarities of its pharmacokinetics, namely, easier entering the brain and subsequent hydrolysis with release of the active metabolite (3-OP).

[Effect of hemantane on bioelectric activity of brain in mice with MPTP-induced Parkinson syndrome].

A single intraperitoneal injection of MPTP neurotoxin (30 mg/kg) in C57BL/6 mice causes desynchronization of EEG with a decrease of theta-1 activity and a growth of beta activity in the interval of 15-30 Hz. Subchronic administration of the new antiparkinsonian drug hemantane (injection form) in a dose of 10 mg/kg makes the power of MPTP-induced beta oscillations less pronounced and leads to its reliable decrease within 24 h. This effect of hemantane administration was manifested during the entire period of observations.

Changes in the levels of inhibitory and excitatory amino acids in the brain structures of female rats with cobalt epileptogenic focus during different phases of the estrous cycle.

We studied changes in the levels of inhibitory and excitatory neurotransmitters in female rat brain structures during different phases of the estrous cycle in health and after creation of a cobalt epileptogenic focus at stage I of epileptogenic system development. The most pronounced shifts were found in the contralateral cortex, where the levels of GABA and glycine decreased significantly during the diestrus-2 phase (corresponding to menstruation), which attests to a convulsive threshold decrease during this period.

Antiparkinsonian effect of nerve growth factor adsorbed on polybutylcyanoacrylate nanoparticles coated with polysorbate-80.

The study examined the antiparkinsonian effect of nerve growth factor adsorbed on the surface of polybutylcyanoacrylate nanoparticles coated with polysorbate-80 surfactant. The parkinsonian syndrome in C57B1/6 mice was provoked by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The basic symptoms of the parkinsonian syndrome decreased under the action of the nerve growth factor adsorbed on nanoparticles coated with polysorbate-80, which was seen from decreased rigidity and increased locomotor activity compared to control mice receiving with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine alone. This effect of nerve growth factor on nanoparticles persisted after 7 and 21 days after single injection of the neurotoxin. These data attest to the possibility of using nanoparticles prepared from amphiphilic polymers and coated with polysorbate-80 for the delivery of nerve growth factor into the brain during systemic treatment.

[The possibilities of using himantane in the treatment of Parkinson's disease].

The domestic drug himantane has been used as a monotherapy in dosage 25 mg daily during 12 weeks in patients with Parkinson's disease. Patient's state has been assessed using clinical, electromyographic, electroneuromyographic, EEG and psychometric (UPDRS and other scales) methods. The preparation used is well tolerated, induces the significant decrease of movement disorders, i.e. tremor, and exerts a positive effect on emotional and personality disturbances. The clinical changes have been confirmed by electroneuromyographic data and EEG.

Relationship between the severity of hypokinesia induced by neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and neurochemical changes in brain structures of C57Bl/6 mice.

The dynamics of hypokinesia in male C57Bl/6 mice induced by single administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was studied on the model of parkinsonian syndrome. The neurochemical effect of this neurotoxin was evaluated at the peak of locomotor disorders. Severe hypokinesia was accompanied by an increase in serotonin content and decrease in the rate of serotonin biodegradation in the striatum, hippocampus, and frontal cortex. The content of dopamine metabolite 3,4-dihydroxyphenylacetic acid and dopamine turnover decreased in the striatum, but increased in the hippocampus and frontal cortex. Norepinephrine content decreased in the hypothalamus and cortex. Aspartate content decreased in the hypothalamus and hippocampus.

[Antioxidants in complex treatment of Parkinson's disease].

Experimental and clinical study of mexidol efficacy in the complex therapy of Parkinson's disease has been carried out. It is shown that in a Parkinsonian animal model using oxotremorine, mexidol reduces Parkinsonian symptoms and decreases expression of neurophysiological changes caused by oxotremorine. Neurohistological study of substantia nigra neurons in a Parkinsonian model using MPTP revealed a neuroprotective effect of mexidol. An assignment of mexidol (4,0 ml intravenous in drops during 10 days) to patients with Parkinson's disease, receiving the basic therapy with antiparkinsonic drugs, reduced tremor, rigidity and bradykinesia. The most marked effect was observed in patients with prevalence of trembling symptoms at early stages of the disease. The results of clinical study have been confirmed by electromyographic and electroneuromyographic data.

Study of antiparkinsonic activity of panavir on a model of Parkinson syndrome induced by systemic administration of MPTP to outbred rats and C57Bl/6 mice.

The effect of panavir on Parkinson's syndrome induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine was studied in C57Bl/6 mice and outbred albino rats. Two injections of panavir significantly reduced the severity of oligokinesia and autonomic manifestations of experimentally induced Parkinson's syndrome.

[Functional brain activity in patients with Parkinson's disease during amantadin-sulfate therapy].

An investigation of bioelectrical brain activity in 32 patients with akinetic-rigid and trembling-rigid forms of Parkinson's disease was conducted before and after treatment with amantadin-sulfate on the basis of spectral-coherent EEG analysis. Comparing to controls, EEG deviations, mainly related to the main rhythm, were observed in 93.75% patients. Symptoms stabilization augmented EEG disorganization emerging in diffused spikes and sharp theta- and alpha-waves. The presence of paroxysmal activity in the form of synchronic bilateral groups of theta-waves and/or beta-waves was detected in 11 out of 32 patients, with paroxysmal activity of theta-waves being more evident in patients with a trembling PD form. In the group of patients with post treatment positive dynamics, EEG spectrum power increased in the range of alpha-beta-waves. Significant differences were mainly found in the range of beta-activity in frontal-parietal-occipital leads of the left hemisphere. The coherent analysis of EEG revealed that an amantadin-sulfate course resulted in normalization of space organization of biopotentials at the expense of a decrease of pathologically high indications of coherency for the majority of intra- and interhemisphere pairs of leads in alpha-, beta- and theta-ranges. In those regions, where the spectrum power increased in the same range, a significant decrease of the coherency indices was detected for inter hemispheric frontal-frontal, frontal-parietal and frontal-occipital leads and intracortical long connections of the left hemisphere. In amantadin-sulfate non-responders, the changes of EEG spectrum and coherency were insignificant.

[Clinico-neurophysiologic and experimental study of the peculiarities of adamantan-sulphate treatment in Parkinson's disease]. / Kliniko-neirofiziologicheskoe i éksperimental'noe izuchenie osobennostei primeneniia sul'fata adamantana pri bolezni Parkinsona.

An experimental investigation of parkinsonism in rats and patients with initial forms of Parkinson's disease was performed by using methods of electromyography and electroneuromyography. Neurophysiologic peculiarities of reorganization of peripheral neuromotor apparatus and criteria for treatment efficacy were detected. The results obtained in the study allowed evaluating of an adequacy of adamantan-sulphate therapy either in the animal experiments and in patients with Parkinson's disease.

[Comparative study of neurophysiological effects of adamantane derivatives in the experimental parkinsonism model]. / Sravnitel'noe izuchenie neirofiziologicheskikh éffektov gruppy aminoadamantana na éksperimental'noi modeli parkinsonizma.

The activity of the adamantane derivative PK-Merz and the new aminoadamantane derivative hemantane was studied by methods of electromyography and electroneuromyography in rats with a model of Parkinson syndrome induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The toxin produced an increase in the pulse conduction velocity (PCV) in the motor fibers of peripheral nerves and a decrease in the amplitude and frequency of the maximum muscle stress curve. A singe administration of both PK-Merz and hemantane produced unidirectional changes in the neuromyographic parameters and reduced the PCV down to a level in the control group. These results give ground for the clinical investigation of hemantane.

[Estimation of the protective effect of the novel potential antiparkinsonian agent himantane against MPTP neurotoxicity]. / Otsenka zashchitnogo éffekta novogo potentsial'nogo protivoparkinsonicheskogo sredstva gimantana ot neirotoksicheskogo deistviia MFTP.

N-(Adamant-2-yl)hexamethyleneimine hydrochloride (hemantane) is a new potential antiparkinsonian drug with a complex mechanism of action. The drug exhibits the properties of a low-affinity blocker of the ion channels of NMDA receptors, increases the dopamine content in striatum, and inhibits monoamine oxidases (MAO-B). This combination of properties suggests that hemantane can also possess neuroprotector properties. In this context, the ability of hemantane to prevent from the development of MPTP neurotoxin action on the locomotor activity in mice and the EEG activity in rats has been studied. Preliminary single (and the more so, repeated over a period of 5 days) peroral administration of hemantane in a dose of 10 mg/kg significantly reduced the manifestations of MPTP-induced oligokinesia in C57BL/6 mice. Acute of subchronic (7-day) pretreatment with hemantane prevented the development of EEG changes typical of parkinsonism. The results of statistical EEG data processing showed that a systemic introduction of MPTP (30 mg/kg) on the background of hemantane pretreatment produced no reliable changes against control characteristics. Thus, hemantane is capable of protecting experimental animals from MPTP neurotoxicity.

[The effect of long-term administration of isatin and himantan to mice on sensitivity of brain monoamine oxidase B to inhibition by deprenyl in vivo and in vitro]. / Vliianie dlitel'nogo vvedeniia mysham izatina i gimantana na chuvstvitel'nost' monoaminoksidazy B mozga k ingibirovaniu deprenilom in vivo i in vitro.

Chronic administration of a low dose of reversible monoamine oxidase (MAO) B inhibitors isatin or himantane (20 mg/kg) to mice during 21 day did not influence the enzyme activity assayed in isolated brain mitochondria. However in vivo sensitivity of brain MAO B to irreversible mechanism-based inhibitor deprenyl injected to animals right after the last administration of the reversible inhibitor sharply decreased. This suggests accumulation of these compounds (or their metabolites?) in the brain accompanied by increased protection of active site of MAO B against specific irreversible inhibitor. deprenyl. In vitro inhibition of MAO B activity in mitochondria isolated from brain of mice treated with isatin or himantane was somewhat higher than in control mitochondria. The latter suggests that long-term treatment of animals with reversible easily dissociating inhibitors may influence regulatory properties of MAO B.

[Effect of carbamazepine on the structure-function relations in the development of the epileptic structure]. / Vliianie karbamazepina na strukturno-funktsional'nye sviazi v razvitii épilepticheskoi sistemy.

The experiments on white outbred male rats with cobalt-induced epileptogenic focus in the left sensomotor cortical region showed that the anticonvulsant effect of carbamazepine (20 mg/kg) depends on the functional state of the epileptic system (ES). In various stages of the ES development, the drug effect is related to the influence upon the determinant focus generating the epileptic activity. In the initial stage, carbamazepine primarily affects epileptic activity of the cortical foci (ipsi- and contralateral hemisphere). In the second (generalization) stage, the drug decreases the epileptic activity in all structures, but to a greater extent, in the dorsal hippocampus and lateral hypothalamus.

[Effect of phenytoin on neurotoxin homocysteine thiolactone-induced convulsions and epileptic status in rats with cobalt-induced epilepsy]. / Analiz vliianiia fenitoina na rasprostranenie sudorog i épilepticheskii status, vyzvannyi neirotoksinom gomotsisteinom tiolaktonom u krys s kobal'tovoi épilepsiei.

The administration of neurotoxin thiolactone homocysteine in rats with cobalt-induced epileptogenic focus in the sensomotor cortical region led to the development of secondary generalized convulsions and epileptic state. The pattern was analogous to the manifestation of convulsions in epileptic state in humans. Fenitoin (50 mg/kg) inhibited the development of convulsions, arrested the epileptic state, reduced the number and duration of the secondary generalized tonic--clonic attacks, decreased the behavioral manifestations (focal convulsions, lateral position etc.), normalized EEG, and prevented fatal outcome. An increase in the fenitoin dose to 100 mg/kg decreased the antiepileptic activity, enhanced side effects, and increased the lethality in test animals.

[Spatial organization of bioelectrical brain activity in epilepsy and amenorrhea of central genesis]. / Prostranstvennaia organizatsiia bioélektricheskoi aktivnosti golovnogo mozga pri épilepsii i amenoree tsentral'nogo geneza.

The study aimed at modification of co-herent analysis (CA), as a mathematical method for EEG data processing for objective evaluation of bioelectric brain activity spatial organization in women with epilepsy and secondary amenorrhea of central genesis. One hundred sixty one women (30 with epilepsy, 116 with amenorrhea and 115 controls aged 15 to 41 years) have been examined. Characteristic changes of cortico-cortical inter- and intra-hemisphere relations for patients with catamenial (CTM) and noncatamenial (NCTM) epilepsy in different menstrual cycle terms were found. The most distinct changes were detected in theta-activity analysis. In the beginning of menstrual cycle, the patients with CTM epilepsy exhibited higher CA indices in theta-rhythm range in all right hemisphere pairs studied. On the contrary, patients with NCTM epilepsy exhibited lower CA indices mainly in the right brain hemisphere. alpha-rhythm spatial organization analysis in the same patients showed similar correlations, but they were better expressed in alpha-rhythm generation zone: in the beginning of menstrual cycle CA indices were high in patients with CTM epilepsy and low in those with NCTM epilepsy. Comparing to controls, patients with secondary amenorrhea of central genesis showed most distinct changes in theta-activity towards the CA indices increase in the majority of the leads. In patients with epilepsy and amenorrhea, CA indices of right brain hemisphere and intra-central temporal lead pairs were lower than in patients with amenorrhea without epilepsy by both alpha- and theta-rhythms.

[Effect of the novel aminoadamantane derivative A-7 on Parkinsonian syndrome induced by systemic administration of neurotoxin MPTP]. / Vliianie novogo proizvodnogo aminoadamantana A-7 na proiavleniia parkinsonicheskogo sindroma, vyzvannogo sistemnym vvedeniem neirotoksina MFTP.

A new antiparkinsonian drug, N-(2-adamantyl)hexamethyleneimine hydrochloride (A-7), was studied on the model of parkinsonism syndrome (PS) induced by MPTP neurotoxin. A-7 (5-20 mg/kg) attenuated the MPTP induced akinesia and rigidity manifestations in C57B1/6 mice, the effect being more pronounced than that of cyclodol and levodopa and comparable to that of midantane (amantadine). A-7 also decreased the PS manifestations in rats: removed tremor, rigidity, and oligokinesia, normalized the MPTP-violated bioelectrical activity of nucleus caudatus, sensomotor cortex, and dorsal hippocamp, and eliminated pathologic slow activity, paroxysmal discharges, and high-frequency activity discharges. The activity of A-7 exceeded that of levodopa (enhancing tremor) and cyclodol (not eliminating the pathologic slow activity).