Biomedical subjects
Publications and source records attributed to E A Val'dman.
The content of BDNF was measured in cerebral structures of intact C57Bl/6 and BALB/c mice in winter and spring. The level of cerebral neurotrophic factor in laboratory mice depended on genetic characteristics and chronobiological factors.
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.
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.
White laboratory male rats, inbred male C57BL/6 and Balb/c mice, and male Wistar rats, all previously divided on the basis of the type of emotional reactivity, were used to compare the effects of ten peptide compounds of the tuftsin family and Selank on the behavioral manifestations of emotional stress created by a conflict situation. Peptides were shown to have positive emotional effects and antistress actions. Individual physiologically significant effects were seen, due to the molecular structures of the study peptides and/or their degradation fragments. The results demonstrate the potential for the synthesis of peptide compounds with predictable directions of pharmacological actions and safe for wide use.
Effects of 10 peptides, tuftsin and Selank derivatives upon behavior during emotional stress induced by conflict situation, were studied in Balb/c and C57BL/6 male mice with genetically determined opposite types of emotional stress reaction, in white male mice and in Wistar male rats divided into different groups according to the type of emotional reactivity. Positive effects of some peptides upon the adaptive behavior of animals in stress situation were demonstrated. Individual physiologically important effects depending on molecular structure of the peptides under study and/or their fragments, possible products of degradation, were revealed. The results obtained confirm the perspectives of aimed synthesis of peptides with definite pharmacological activity, which are not ksenobiotics and will have no side effects.
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Hereditary variations in the effects of benzodiazepine tranquilizers depending on the phenotype of an emotional stress reaction (ESR) are described. The membrane-receptor relationship showed differences between C57B1/6 with an "active" ESR phenotype and Balb/c with a "passive" ESR at the GABA benzodiazepine receptor complex level. The pharmacological results evidenced the selective anxiolytic properties of the novel drug aphobazole (2-[2-morpholyno)ethylthio]-5-ethoxybenzimidazole dihydrochloride) which produced an activating anxiolytic action in Balb/c mice whereas no behavioral changes were observed in C57B1/6 mice.
Administration of Ca-entry blockers with different chemical structure before the braining sessions produced the reduction of memory retention in mice and rats in the one-trial passive avoidance tests. This effect was absent in animals treated immediately after training test. Nootropic drugs piracetam and oxiracetam corrected the retention of memory when injected just after training test. Chronic treatment of rats with increasing doses of the nootropic drugs produced about two-fold tissue-specific elevation in the density of DHP-receptors, associated with L-type Ca-channels in synaptosomal membranes of rat cerebral cortex. Maximal effect was observed in a dose of 10 mg/kg. Diltiazem, administrated in a dose of 10 mg/kg, produced about two-fold decrease in the receptors density measured 24 hrs after the first injection. Oxiracetam (10 mg/kg) completely antagonized the effect of Ca-entry blocker. These data imply that nootropic action of piracetam and oxiracetam is mediated by L-type Ca-channels.
The activity of the new original compound--hydrochloride N-2-(adamantyl) hexamethylenimine (code A-7) synthesized at the Institute of Pharmacology, Russian Academy of Medical Sciences, was studied on models of akinetic-rigid and tremor manifestations of the parkinsonian syndrome. A-7 completely relieves the akinetic-rigid manifestations of the syndrome and surpasses mydantan and L-dopa in antagonism with haloperidol and triftazine. Just as L-dopa, cyclodol, and mydantan, A-7 alleviates reserpine-induced oligokinesis and restores body temperature which is lowered by reserpine. A-7 possesses evident antitremor activity which advantageously distinguishes it from mydantan which failed to demonstrate antagonism with arecoline. A-7 is promising for further study as a potential agent for the treatment of parkinsonism.
Ondansetron (GR38032F, zofran)--a specific blocker of 5-HT3-receptors in a dose range of 0.05 to 0. mg/kg causes an anxiolytic effect in experiments on mice and rats on a model of elevated plus maze. The drug does not produce a sedative and myorelaxant effect. A 0.05 mg/kg dose of ondansetron reduces the level of anxiety and convulsive manifestations which are induced by discontinuation of long-term diazepam administration. The results of the study bear evidence of selectivity of the anxiolytic effect of ondansetron in intact animals and its effectiveness in rats with diazepam abstinence.
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).
The effect of a new potential antiparkinsonian drug, N-(2-adamantyl)hexamethyleneimine hydrochloride (A-7), upon some behavioral parameters was studied in rats after subchronic 14-day treatment. Also studied was the effect of abrupt termination of a prolonged (22-day) drug administration. The subchronic treatment with A-7 at a dose of 10, 20, or 40 mg/kg did not produce significant changes in coordination, explorative behavior, muscle tone, and aggression level. At the same time, the 14-day treatment with A-7 at a dose of 10 mg/kg increased the pain threshold; A-7 at a dose of 40 mg/kg (but not 10 or 20 mg/kg) increased the spontaneous motor activity. Upon abrupt termination of the drug administration after a prolonged treatment sensitivity of the test animals with respect to the MFTP neurotoxin as compared to that observed in the non-drug control group.
Interaction of a new potential antiparkinsonian drug, N-(2-adamantyl)hexamethyleneimine hydrochloride (A-7), with NMDA channels in acutely isolated rat hippocampal neuron culture was studied by the whole-cell patch-clamp technique. The currents through the NMDA channels were excited by aspartate (Asp) application in a magnesium-free glycine-containing (3 microM) medium. It was found that A-7 produced a concentration-dependent (IC50 = 11.8 +/- 0.6 microM) NMDA channel blocking. The blocking rate increased with the A-7 concentration, whereas the unblocking was concentration-independent. The degree of blocking was independent of the Asp concentration, but was markedly increased by hyperpolarization of the cell membrane. After Asp washout, A-7 remained trapped in the channel by the activation gate. The channel was unblocked upon the next Asp application. These data is evidence that the antiparkinsonian effect of A-7 is related to the NMDA-channel-blocking activity of the drug.
N-(Adamant-2-yl) hexamethyleneimine hydrochloride (A-7, himantane), a new potential antiparkinsonian drug belonging to the class of aminoadamantyl derivatives, exhibits pronounced immunomodulant activity in a therapeutic dose of 10 mg/kg. A single intraperitoneal injection of himantane stimulated a high B-lymphocyte activity in mice over a period of 21 days. The drug inhibited the reaction of delayed hypersensitivity with respect to the Freund adjuvant, while enhancing the immediate reaction with respect to horse serum in guinea pigs. Himantane increased the functional (absorption) activity of macrophages in the peritoneal exudate, while not affecting superoxide anion production by the macrophages. These results suggest that the immunomodulant activity of himantane may produce a positive neuroprotective and symptomatic effects in the course of parkinsonism.
The new aminoadamantane derivative N-(2-adamantyl)hexamethyleneimine hydrochloride (A-7, hemantane) exhibited a pronounced antiparkinsonian effect on various experimental models. Hemantane showed a broad activity spectrum, being superior to amantadine (midantane) in some tests. Administered in an effective antiparkinsonian dose, hemantane increased the extracellular dopamine content in the striatum. The drug also produced a dose-dependent decrease in the extracellular level of dihydroxyphenylacetic acid and homovanillic acid (DOPAC and HVA, the dopamine metabolites) and 5-hydroxyindoloacetic acid (5-HIAc, a serotonin metabolite) in the striatum, which may reflect inhibition of the monoamine oxidase activity in the brain. These results show that the dopaminergic and serotoninergic nigrostriatial systems are involved in the mechanism of hemantane action.
A prolonged immunotropic effect of himantane, a new potential antiparkinsonian drug with a multicomponent (including dopaminopositive) mechanism of action, upon the functional activity of splenic B-cells in mice was studied in comparison to the effect of a typical neuroleptic drug haloperidol. A single administration of himantane (10 mg/kg) stimulated the B-cell activity over a period of 21 days, while haloperidol (0.25 mg/kg) suppressed this activity for 14 days after administration. The results of experiments on the adjuvant arthritis (paw edema) model showed that a single administration of himantane in the same dose under these pathological conditions does not influence the immune response (B-cell activity) for 14 days and increases the number of antibody-forming cells only 21 day after injection. Himantane enhanced the model arthritis manifestations in the early stage and reduced them in the late stage. It was established that the pronounced effect of himantane on the activity of immunocompetent cells is probably related to the drug action upon the central mechanisms of immunoregulation (which is consistent with a prolonged effect observed upon a single administration). This immunotropic activity indicates that the drug may affect immunological mechanisms involved in the pathogenesis of Parkinson's disease.
The paper addresses evolution of the concept of individual sensitivity to drugs, based on the new pharmacogenetic and pharmacogenomic approaches. The possibility of geno- and phenotypy of the pharmacodynamic and pharmacokinetic processes, aimed at establishing the parameters ensuring reliable prediction of the individual response of a patient. The promising pharmacogenomic methods will allow to create preparations directly acting upon defective genes or the related products. Factors limiting the development of pharmacogenomic methods, related to the lack of data on the structure and physiological properties of protein products and their metabolites, are considered.
N-2(adamantyl)hexamethyleneimine hydrochloride (hemantane) is a new potential antiparkinsonian drug targeted at several neurochemical systems. The drug exhibits the properties of a low-affinity noncompetitive blocker of the ion channels of glutamate NMDA receptors. Hemantane increases the content of dopamine in the striatum, while decreasing the level of dopamine metabolite dioxyphenylacetic acid (DOPAC). Investigation of the drug interaction with monoamine oxidases (MAOs) of the A and B types in vitro showed that hemantane acts as a weak competitive inhibitor of MAO-B (Ki = 470 +/- 70 microM) and partly protected MAO-B from irreversible inhibition by selegiline (deprenyl), while virtually not influencing the activity of MAO-A. Administered to C57BL6 mice (20-100 mg/kg), hemantane did not influence the activity of MAO-B measured in isolated cerebral mitochondria. At the same time, hemantane administered in combination with deprenyl significantly reduced activity of the latter drug and caused pronounced irreversible inhibition of mitochondrial MAO-B (comparable with the effect of deprenyl introduced alone). Therefore, inhibition of MAO-B may contribute to the spectrum of neurochemical activity of hemantane.