N. N. Lermontova

Dimebon and Tacrine Inhibit Neurotoxic Action of β-Amyloid in Culture and Block L-type Ca2+ 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 Ab25-35, the neurotoxic fragment of beta-amyloid. Both preparations can block potential-dependent Ca2+ entry into neurons by about 20%, which is explained by their selective action on L-type Ca2+ channels. It was assumed that the neuroprotective effect of dimebon and tacrine against Ab25-35 partially depends on inhibition of potential-dependent Ca2+ 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 Alzheimers disease.

Autoantibodies to β-Amyloid and Neurotransmitters in Patients with Alzheimer's Disease and Senile Dementia of the Alzheimer Type

The content of autoantibodies to β-amyloid protein Aβ1-42, its neurotoxic fragment Aβ25-35, and neurotransmitters were studied in the blood of patients with presenile Alzheimers disease and senile dementia of the Alzheimer type. Significant differences in the relative content of autoantibodies to Aβ1-42 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.

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 suggestedparameters 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.

Effects of tacrine on deficits in active avoidance performance induced by AF64A in rats

Effects of tacrine (1,2,3,4-tetrahydro-9-aminocridine) on memory deficits in rats treated with ethylcholine aziridinium ion (AF64A) were studied using active avoidance test in the two-way shuttle box. Neurotoxin AF64A injected at a dose of 6 nmol (i.c.v., bilaterally) causes nonspecific tissue damage in hippocampal fields CA2 and CA3. Two weeks after treatment with 6 nmol, AF64A active avoidance performance of toxin-treated rats was significantly deteriorated compared to vehicle-treated animals estimated in learning test (68 +/- 3.5 and 83 +/- 3.2% of correct responses, respectively; p < 0.01) and in retention test (53 +/- 5 and 76 +/- 3.6%, respectively; p < 0.01). Under these conditions, chronic treatment with tacrine at a daily dose of 1 mg/kg for 12-14 d reverses the effect of AF64A on the active avoidance performance both in learning (78 +/- 3.2%) and retention (72 +/- 4%) tests. It is supposed that behavioral effects of tacrine considerably depend on a severity of neurodegeneration in the hippocampus.

Content of Autoantibodies to Bradykinin and β-Amyloid1-42 as a Criterion for Biochemical Differences between Alzheimer's Dementias

We measured serum content of autoantibodies to β-amyloid protein Aβ1-42, its neurotoxic fragment Aβ25-35, vasopressin, bradykinin, thrombin, antithrombin III, α2-macroglobulin, and angiotensin II in patients with various forms of Alzheimers dementias, including presenile and senile dementias of the Alzheimer type. The ratio of antibradykinin and anti-Aβ1-42 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 17β-estradiol and its isomer 17α-estradiol on learning in rats with chronic cholinergic deficiency in the brain

It was shown for the first time that estrogens 17β- and 17α-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. 17β-Estradiol produced strong dose-dependent changes in the weights of hormone-sensitive endocrine glands, while 17α-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 17β- and 17α-estradiols on cognitive functions are due to their antioxidant properties, rather than due to specific action on hormone-sensitive endocrine glands.

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.

Kinetic characteristics of the action of biologically active compounds. II. Effect of the inhibition mechanism on the efficacy of reversible enzyme inhibition

Creation of highly effective and selective enzyme inhibitors is a widely used method for searching for new physiologically active substances for the needs of medicine and agriculture [8, 13]. Here it is customary to use the kinetic parameters of the inhibition process as the inhibition efficacy parameters, especially for construction of models quantitatively characterizing the structure--activity relation. In addition, the possibility of various inhibition mechanisms (even within a single inhibition type, reversible or irreversible) may substantially affect the efficacy of the generalphysiological effect, which generally is not connected with the action of the physiologically active substance itself [9] but rather with the change in the concentration of an endogenic compound metabolized under the action of the enzyme, inhibited by the physiologically active substance. This is clearly apparent in the example of enzymes for metabolism of mediators: their inhibition leads to a change in the concentration of the neuromediator and consequently to a substantial change in the physiological response. In this paper we give a kinetic assessment of the efficacy of various mechanisms for completely reversible inhibition of enzymes with respect to the concentration of the substrate of the reaction to be inhibited. Taking into account the results obtained, we have analyzed the kinetics of inhibition of acetylcholine esterase (ACE) by physiologically active phenylpyridinium derivatives and have investigated their effect on animals.