Wave-Like Dose-Dependence of the Stimulating Effects of Dimebon on Cognition in a Wide Dose Range.

Comparison of the cognition-stimulating effects of Dimebon in a wide dose range revealed a non-monotonic and nontrivial wave-like dose-dependence of its activity. Positive results were obtained at low (0.02-0.05 mg/kg) or high (5-10 mg/kg) doses of Dimebon, while intermediate doses were ineffective. This type of the dose dependence of the pharmacological effect can indicate that the substance has several targets. This fact should be taken into consideration when selecting the doses and concentrations of the substance and its analogues for further studies, and for planning treatment schemes and administration doses in clinical studies.

The effects of estrogens on learning in rats with chronic brain cholinergic deficiency in a Morris water test. Identification of the "passive swimming" component.

Chronic decreases in brain cholinergic functions due to intraventricular administration of the neurotoxin AF64A were accompanied by increases in the latent period of locating an invisible platform during training of rats in a Morris water test, as compared with control sham-operated animals. Recordings of the animals' movement trajectories using a video camera along with an original computer program (Behavioral Vision) showed that administration of 17beta-estradiol and its synthetic analog J-861 (0.2 mg/kg p.o. daily for seven days before and 10 days after single intraventricular injections of AF64A) improved learning. The directivity of platform search trajectories was assessed quantitatively using a new parameter--trajectory straightness. Introduction of the "passive swimming" parameter allowed periods of immobility in water to be identified within the total latent period in animals after administration of AF64A; 17beta-estradiol but not J-861 "eliminated" these periods. The new parameters (especially trajectory straightness) allowed the ability to learn to be discriminated from decreases in mobility, including mobility losses due to study agents, in the Morris water test.

Content of autoantibodies to bradykinin and beta-amyloid(1-42) as a criterion for biochemical differences between Alzheimer's dementias.

We measured serum content of autoantibodies to beta-amyloid protein Abeta(1-42), its neurotoxic fragment Abeta(25-35), vasopressin, bradykinin, thrombin, antithrombin III, alpha(2)-macroglobulin, and angiotensin II in patients with various forms of Alzheimer's dementias, including presenile and senile dementias of the Alzheimer type. The ratio of antibradykinin and anti-Abeta(1-42) autoantibody contents differed by 39% in these patients. Our results can be used for the development of a new biochemical method for differential diagnostics of dementias of the Alzheimer type.

[Effects of estrogens on learning of rats with chronic brain cholinergic deficit in Morris water maze]. / Vliianie éstrogenov na obuchenie krys s khronicheskim kholinergicheskim defitsitov v mozge v vodnom teste Morrisa. Vydelenie komponenta "passivnogo plavaniia".

A chronic deprivation of brain cholinergic functions in rats caused by intracerebroventricular injection of neurotoxin AF64A increases the escape latency in Morris water maze test as compared to control sham-operated animals. Measurements and analysis of rat movement tracks using an original computerized "Behavioral Vision" system revealed the ability of 17 beta-Estradiol and its synthetic isomer J-861 (both administered daily in per os dose 0.2 mg/kg during 7 days before and 10 days after a single intracerebroventricular injection of AF64A) to improve learning of the animals. Directivity of search trajectories was estimated by a novel index of track straightness. The introduction of an index of "passive swimming" made it possible to reveal episodes of immobility in water-maze behavior of AF64A-injected animals. Unlike J-861, 17 beta-Estradiol almost completely eliminated these episodes. The newly developed indices (especially straightness) seem to be very useful in differentiating learning ability of rats from a decrease in their mobility in the Morris water-maze test, in particular, in case of the estrogens under study.

Comparison of the effect of NT-0409 and antidementia drugs on learning and memory in rats with chronic cerebral cholinergic deficiency.

Systemic oral administration of NT-0409, a new synthetic agonist of AMPA subtype glutamate receptor, to rats with chronic partial AF64A-induced deprivation of cholinergic functions improved their learning in a Morris water maze. NT-0409 is close to memantine by the effect on learning and, in contrast to cholinomimetic arisept, ensures longer retention of the developed habit.

Development of neuronal ganglion xenografts from gastropoda in rat brain.

Survival of neuronal ganglia from newborn snail (Helix aspera L.) in the brain of adult rats was studied. Snail ganglion survived in the brain of warm-blooded animals for 6 months without inducing immune conflict. At early stages (5 days) after transplantation, xenografts increased in size and were several times larger than native ganglia from 10-day-old snails, thereafter (on days 28 and 180) they became smaller still surpassing the sizes of ganglia from snail of the corresponding age. Rapid enlargement of the xenograft was due to cell reactive processes in the ganglion. Deep penetration of large vessels from xenografts to rat brain was observed.

Versatile computerized system for tracking and analysis of water maze tests.

A crucial step in the estimation of properties of compounds in behavioral experiments is the quantification and description of the different effects observed. The goal of the present work was the automation of the Morris water maze test, one of the most popular behavioral methods for the study of animal memory. An original system was developed that provides fast and accurate tracking of animals, storage of the results in the database and video archive and a means of analyzing the results. This computerized version of the Morris water maze test permits the quantification of such vague characteristics of cognitive function as the "directionality" of search of the hidden platform after a standard training series. The suggested parameters made it possible to discriminate cognitive properties of the novel compounds from other behavioral effects affecting escape latency. The effectiveness of this system was demonstrated in two experiments with neurochemically lesioned and drug-treated rats.

Comparison of reactive processes in the rat brain elicited by xenotransplantation of nervous tissues of chicken or pulmonate snail.

It is known that a histocompatibility system is not developed to the same extent in lower invertebrates as in vertebrate animals. We assumed that the xenografts from the newborn invertebrate nervous system would not exert destructive effects on the brain of the vertebrate recipient even without immunosuppressive therapy. In search of brain xenografts (XG) capable to survive in the brain of a recipient without intensive immunosuppression, we transplanted ganglia of terrestrial snails into the rat brain. We compared effects of transplantation of the XG taken from anterior brain of the 18-day embryo chicken (XGC) and from ganglia of a newborn terrestrial pulmonate snail (Helix aspersa L., XGSn). Part of the XGSn were stained by vital fluorescent dyes Bisbenzimid or Fast Blue before grafting. The XGSn were implanted into the neocortex parenchyma in each hemisphere. Rat brains with the XGC were examined 5 days after, and brains with the XGSn - 5 and 28 days after the transplantation. Nonstained sections with the XGSn labeled with fluorescent dyes prior to transplantation were investigated in fluorescent microscope and stained later with tionin and cresyl-violet. Quantitative videoimage analysis of lymphocyte aggregations, reactive gliosis, morphology of the XG areas, and implantation trace was performed. It was found that the XGSn transplantation did not elicit in the rat brain an intensive immunological conflict 5 and 28 days after transplantation. In contrast, the XGC rapidly elicited a strong immune response resulting in massive obliterations in the rat brain and were rejected in 5 days. Labeled snail glia and vessels were observed in the stained XGSn 28 days after transplantation by fluorescence imaging. Putative snail vessels grew into the rat brain from the place of snail tissue transplantation serving the humoral integration of the XG and the host brain. Migration of molluscan glial cells was observed in the brain of recipients.

Autoantibodies to beta-amyloid and neurotransmitters in patients with Alzheimer's disease and senile dementia of the Alzheimer type.

The content of autoantibodies to beta-amyloid protein Abeta(1-42), its neurotoxic fragment Abeta(25-35), and neurotransmitters were studied in the blood of patients with presenile Alzheimer's disease and senile dementia of the Alzheimer type. Significant differences in the relative content of autoantibodies to Abeta(1-42)and autoantibodies to biogenic amines were demonstrated. These results can be used for the development of a biochemical method for differential diagnosis of Alzheimer dementias.

Dimebon and tacrine inhibit neurotoxic action of beta-amyloid in culture and block L-type Ca(2+) channels.

Dimebon, a Russian-made drug, inhibited toxic effects of beta -amyloid on cultured neurons. Excessive accumulation of beta-amyloid in the brain is characteristic of Alzheimer dementias. Antialzheimer preparations tacrine and dimebon improve survival of cerebellar granule cells during long-term incubation with Abeta25-35, the neurotoxic fragment of beta-amyloid. Both preparations can block potential-dependent Ca(2+) entry into neurons by about 20%, which is explained by their selective action on L-type Ca(2+) channels. It was assumed that the neuroprotective effect of dimebon and tacrine against Abeta25-35 partially depends on inhibition of potential-dependent Ca(2+) entry.

Dimebon improves learning in animals with experimental Alzheimer's disease.

Systemic administration of antihistamine drug dimebon improves active avoidance conditioning in rats with chronic partial deprivation of cerebral cholinergic functions caused by intracerebroventricular injections of AF64A. The effects of dimebon on learning are similar to those of tacrine used in the treatment of Alzheimer's disease.

Effects of 17 beta-estradiol and its isomer 17 alpha-estradiol on learning in rats with chronic cholinergic deficiency in the brain.

It was shown for the first time that estrogens 17 beta- and 17 alpha-estradiols compensate impaired cognitive functions in rats with partial chronic deprivation of cholinergic functions in the central nervous system induced by intracerebral administration of selective cholinergic neurotoxin AF64A. 17 beta-Estradiol produced strong dose-dependent changes in the weights of hormone-sensitive endocrine glands, while 17 alpha-estradiol did not affect the weight of the gonads and slightly influenced (in high concentration) the weights of the adrenal glands and thymus. The positive effects of exogenous 17 beta- and 17 alpha-estradiols on cognitive functions are due to their antioxidant properties, rather than due to specific action on hormone-sensitive endocrine glands.

The effect of dithiocarbamates on neurotoxic action of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) and on mitochondrial respiration chain.

The neurotoxin MPTP induces in human and in some laboratory animals parkinsonism-like neurological disorder, biochemically characterized by selective and irreversible decrease of dopamine content in striatum. The terminal step in the mechanism of neurotoxic action of MPTP is the inhibition of mitochondrial respiratory chain by pyridinium metabolite (MPP+) resulting in energy depletion and nervous cells death. Earlier it was shown that some chemical compounds, in particular diethyldithiocarbamate (DTC), can potentiate MPTP neurotoxicity. In the present work we have studied the influence of DTC derivatives on MPTP neurotoxic effect in vivo and on MPP+ inhibition of mitochondrial respiration (both on intact mitochondria and on submitochondrial particles) in vitro. It was revealed that DTC alone change mitochondrial membrane state by respiratory chain uncoupling and inhibition. DTC and MPP+ mutually potentiate inhibition of electron transport as well. The combined effect of DTC plus MPP+ action on mitochondria respiration reflects the sum of reciprocally leveling and potentiating factors and can explain the order of efficacy of MPTP-neurotoxicity potentiation in vivo in series of close DTC derivatives.

Molecular basis of discrepancies in neurotoxic properties among 1-methyl-4-aryl-1,2,3,6-tetrahydropyridines.

The relationship between structural specificity of the main stages of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) action and the display of parkinsonogenic properties among homologous structures in a number of 4-tolyl derivatives of MPTP has been studied. All the compounds are better substrates for monoamine oxidase (MAO) than MPTP. MAO is inactivated during the reaction according to a mechanism of irreversible inhibition by 2,3-dihydropyridinium metabolite. All the tolyl derivatives are stronger inhibitors of MAO than 1-methyl-2,3-dihydropyridinium (MPDP). A significant contribution of enzyme inhibition to the catalytic conversion of the substrate leads to the fact that substrates having equal (para isomer) or even higher (meta isomer) values of catalytic parameters are oxidized by MAO to a lesser extent than MPTP. It has been found that all 4-arylpyridiniums (final products of MATP bioconversion) competitively and reversibly inhibit [14C]dopamine (DA) uptake in mouse brain synaptosomes. Affinity toward DA transporter characterized by KI (microM) is 0.37 +/- 0.04, 0.7 +/- 0.1, 2.0 +/- 0.15, 2.0 +/- 0.35 for MPP, and its o-, m-, and p-tolyl derivatives, respectively. Joint calculation of specificity factors for the processes discussed define the following rank order for the bio-delivery of MATP's metabolic produces into DA nerve terminals: o-tolyl > MPTP >> m-tolyl > p-tolyl. The regularity revealed is in good agreement with the observed relative potency of these compounds to cause dopaminergic neurodegeneration.

Pyridine derivatives: structure-activity relationships causing parkinsonism-like symptoms.

In recent years, sufficient evidence has surfaced to implicate low-molecular-weight organic compounds in certain known neurological disorders. At this time, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is considered the compound capable of inducing conditions most similar to idiopathic parkinsonism in clinical, biochemical, and histopathological characteristics. Substances containing MPTP-like fragments are used as herbicides, drugs and intermediates in the synthesis of many heterocyclic compounds. The mechanistic study of toxic MPTP action has enabled development of criteria for appraising potential parkinsonogenic properties of similar chemical structures. Key features of MPTP action include the following: 1. Ability to pass through the blood-brain barrier (BBB). 2. Enzymatic biotransformation to the neuroactive form (pyridine metabolites). 3. Transfer to neurons via a neuromediator reuptake system. 4. Action on intracellular targets. This review discusses data concerning the effects of metabolite structure on the major steps in the neurotropic action mechanism of MPTP-like compounds. Special attention is focused on the key steps defining the selectivity of MPTP's neuronal action, i.e., the activation step caused by monoamine oxidase (MAO) and interaction with the dopamine (DA) reuptake system. Most structural MPTP analogs (including certain pesticide preparations) used in our experiments and described in the literature exhibit no degenerative MPTP-like properties. This is probably related to the fact that each consecutive stage in the MPTP neurotoxicity mechanism makes rather stringent demands on metabolite structure. The number of structures which concurrently meet the requirements of all the processes is finite. This, however, does not invalidate the hypotheses concerning the ecotoxic nature of idiopathic parkinsonism. Possible ecotoxins may have only a partial, presymptomatic effect which, however, promotes age-related neurodegenerative processes and accelerates development of parkinsonism. This concept necessitates designing special tests of the possible neurotoxic properties of compounds found in the environment which may be functional MPTP analogs.

[Clinical and biochemical parameters of parkinsonism induced by 1-methyl-4-phenyl-1,2,2,6-tetrahydropyridine and its methyl-phenyl and methoxy-phenyl derivatives in C57Bl/6 mice]. / Klinicheskie i biokhimicheskie pokazateli parkinsonizma, vyzvannogo 1-metil-4-fenil-1,2,3,6-tetragidropiridinom i ego metil-fenil- i metoksi-fenil-proizvodnymi u myshei C57Bl/6.

Possibility of ortho-, para-, meta-methylphenyl and methoxyphenyl-derivates of MPTP to produce parkinsonism was investigated. Only ortho-methylphenyl- and ortho-methoxyphenyl-derivates of MPTP cause a persistent loss in dopamine content in the brain and produced the clinical symptoms of parkinsonism. All substances produced Parkinsonian-like syndrome gives the symptoms of activation of nervous system during 0.5-1 h after injection and symptoms of depression in following 3 h of observations.