Pro-Cognitive Effects of Non-Peptide Analogues of Soluble Amyloid Peptide Precursor Fragment sAPP.

We studied pro-cognitive effect of two heterocyclic low-molecular-weight compounds that serve as non-peptide analogues of soluble fragment of amyloid peptide precursor (sAPP). Intracerebroventricular and systemic administration of peptide mimetics P2 and P5 improved weak memory on the model of passive avoidance in chicks and in the object location task in mice. Both compounds were effective if administered close to the moment of training or 4 h after it. The time windows and dose range for the pro-cognitive effects of the mimetics were similar to those observed in previous studies with sAPP peptide fragments.

[Simultaneous AMPA receptor potentiation and NMDA receptor blockade as strategy for creating effective stimulants for cognitive functions].

New compounds representing derivatives of acyclic isothioureas have been synthesized, which are capable of simultaneously activating AMPA receptors and blocking NMDA receptors. In order to produce cognitive-stimulating effect, of principal importance is the pathway of NMDA receptor blockade produced by the drug. Positive influence is due to the blockade of NMDA receptors either by mechanism of rapid dissociation of intrachannel site or by inhibition of NR2B subunit of NMDA receptor. Substances that only potentiate AMPA receptor currents or only block NMDA receptors have less pronounced effect on memory than substances with ability to simultaneously potentiate AMPA receptor currents and block NMDA receptor currents. Based on these results, it is concluded that the simultaneous potentiation of AMPA receptors and blockade of NMDA receptors may be a new approach to the stimulation of cognitive functions.

[Influence of derivatives of arachidonic and docosohexaenic acids on AMPA receptors in Purkinje neurons and cognitive functions in mice].

The effect of derivatives of arachidonic and docosahexaenoic acids on AMPA receptors in Purkinje cells from the rat cerebellum was studied using the patch-clamp electrophysiological method. It was shown that derivatives of arachidonic acid-arachidonoyl dopamine and docosahexaenoic acid-docosahexaenoyl dopamine and ester of docosahexaenoic acid with ethylene glycol in nanomolar concentrations effectively potentiated the ionic currents caused by activation of AMPA receptors of kainic acid. Ester of docosahexaenoic acid with nitroethylene glycol blocked AMPA receptors, and anandamide (ethanolamide of arachidonic acid) was not effective. A behavioral test showed that docosahexaenoyl dopamine in doses of 0.1-20 mg/kg had no effect on the learning and memory abilities of the animals tested.

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.

[Importance of the components of the complex ester group for the action of acetylcholine and dicarboxylic acid dicholine esters]. / Znachenie komponentov slozhnoefirnoi gruppy dlia deistviia atsetilkholina i dikholinovykh efirov dikarbonovykh kislot.

The substitution of ether oxygen by a methylene group in the acetylcholine molecule sharply decreases the muscarinic action, while the substitution of the carbonyl group by a methylene one reduces the nicotinic properties. Sebacoyldicholine possesses only nicotinic properties. The replacement of its ether oxygens by methylene groups lowers the stimulant action on the frog rectus abdominis muscle by two orders of magnitude, whereas the stimulant action on the cat sympathetic ganglion is 30-fold as decreased. The blocking action on the isolated rat diaphragm becomes 30-fold less potent, but the blocking action on the cat skeletal muscle remains as strong as that of sebacoyldicholine after cholinesterase inhibition. The replacement of sebacoyldicholine carbonyl groups makes the compound elicit a noncompetitive cholinolytic action on the frog muscle, while the blocking action on the cat skeletal muscle becomes as weak as that exerted by hexadecamethylene-bis-trimethyammonium.

[Central action of a new cholinesterase reactivator, diethyxime]. / O tsentral'nom deistvii novogo reaktivatora kholinésteraz diétiksima.

In anesthetized cats, whose peripheral muscarinic-cholinorecptors are blocked by m-cholinolytics (benzilyl choline) failing to penetrate into the brain, the cholinesterases reactivator diethyxime debars the centrally caused fall of the arterial pressure produced by armine, an inhibitor of cholinesterases readily gaining access into the brain. Diethyxime is also capable of abolishing the depression of the phrenic nerve action potentials produced by armine. Dipyroxime-a quaternary diethyxime analogue and also a quaternary cholinesterase reactivator fails to produce such an effect.