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.

Biological Activity of Spirocyclic Hydroxamic Acids.

Iron-chelating activity of synthesized spirocyclic hydroxamic acids, their toxicity, and effects on mitochondrial function were studied using primary culture of cerebral cortical neurons from newborn rats. All tested compounds effectively chelated Fe(II) ions. Activity of spirocyclic hydroxamic acids more strictly depended on the structure their piperidine, but not imidazolidine fragment. All compounds were non-toxic for normal neuronal culture.

N,N'-Substituted Selenoureas as Polyfunctional Antioxidants.

Analysis of antioxidant activity of synthesized selenourea derivatives showed that N,N'-substituted selenoureas inhibited Fe(III)-induced LPO in rat brain homogenate. On the other hand, oxygen- and sulfur-containing analogs exhibited no antioxidant activity or even slight prooxidant activity. Intramolecular alkylation of selenium atom also led to loss of antioxidant activity. Thus, antioxidant activity of the compounds was due to the presence of a nonalkylated selenium atom in N,N'-substituted selenourea analogs.

Effect of somatostatin on presynaptic and postsynaptic glutamate receptors and postsynaptic GABA receptors in the neurons of rat brain.

We studied the effect of somatostatin on presinaptic NMDA receptors and postsinaptic GABA, NMDA, and AMPA receptors in rat brain. It was shown that somatostatin inhibits NMDA-induced (45)Ca(2+) uptake into synaptosomes isolated from rat brain cortex (IC50=2.8×10(-11) M). Somatostatin potentiates AMPA receptors and inhibits hippocampal NMDA receptors in the entire range of examined concentrations (10(-14)-10(-7) M); it also potentiates or inhibits GABA receptor currents in a concentration-dependent manner. Our results suggest that somatostatin modulates the function of ionotropic glutamate and GABA receptors and is involved in cognitive and neurodegenerative processes in the mammalian brain.

Effect of corticotropin-like intermediate lobe peptide on presynaptic and postsynaptic glutamate receptors and postsynaptic GABA receptors in rat brain.

We studied the effect of corticotropin-like intermediate lobe peptide (CLIP) on presynaptic NMDA receptors and postsynaptic GABA, NMDA, and AMPA receptors in rat brain. CLIP inhibited presynaptic and postsynaptic NMDA receptors, but potentiated postsynaptic GABA and AMPA receptors. Our results indicate that CLIP modulates function of ionotropic receptors for glutamate and GABA.

Effects of delta sleep-inducing peptide on pre- and postsynaptic glutamate and postsynaptic GABA receptors in neurons of the cortex, hippocampus, and cerebellum in rats.

We studied the effect of delta sleep-inducing peptide on GABA receptors of hippocampal and cerebellar neurons in rats. It was shown that delta sleep-inducing peptide considerably and dose-dependently potentiates GABA-activated currents in these neurons and blocks NMDA-activated potentiation in cortical and hippocampal neurons. The peptide modulates activity of presynaptic NMDA receptors, which is seen from changes in (45)Ca(2+) uptake into synaptosomes of the brain cortex after uptake stimulation with glutamate and NMDA.

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.

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.

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.

[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.

[Evaluation of the capability of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and pyridine derivatives to evoke parkinsonism]. / Otsenka sposobnosti 1-metil-4-fenil-1,2,3,6-tetragidropiridina i nekotorykh proizvodnykh piridina vyzyvat' parkinsonizm.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produce an irreversible parkinsonian-like syndrome in humans, monkeys and mice C57BL/6. Experimental parkinsonism produced by MPTP on mice C57BL/6 were studied with the aim of working up the method for testing MPTP-like substances. It has been shown that intraperitoneal administration the maximal tolerated doses of MPTP cause significant decrease (by 40-60%) of dopamine content on the mice brain. Number of injections did not influence the results. The similar administration of 4-phenyl-pyridyl and 4,4'-dipyridyl derivates, including known herbicides paraquat and cyperquat, produce neither decrease of dopamine content in the brain, nor the development of parkinsonian-like behavioral syndrome.