A comparative study of the nootropic properties of piracetam and oxiracetam]

The behavioral activities of piracetam and oxiracetam were studied during the learning tests (active avoidance, passive avoidance, T-maize). The levels of the orientation reaction and emotionality of the animals were determined by the "open field" method. To achieve similar effects, injections of 10 mg/kg of oxiracetam and 100 mg/kg of piracetam intraperitoneally were required. Both nootropics facilitated the learning of the animals but failed to change their behavior in the open field. Piracetam was more effective in the active avoidance test and oxiracetam in the T-maize test. The data indicate some differences in the activities of piracetam and oxiracetam.     

The nootropic and anxiolytic properties of different doses of piracetam

The effect of piracetam at various doses on the behavioral and electrophysiological characteristics was studied, including the development of passive and active avoidance conditional reflexes in rats, their behavior in conflict situations, and the transcallosal evoked response (TER) in rabbit brain. In the dose range from 50 to 300 mg/kg, piracetam improved the avoidance performance of both types and produced a dose-dependent increase in the TER amplitude, but did not affect the behavior of rats in conflict situations. As the drug dose was increased to 400-1000 mg/kg, the positive learning influence disappeared (sometimes the effect was even negative) and the TER increase changed to decrease. In contrast, the conflict situation tests revealed pronounced anxiolytic activity of piracetam at elevated doses. Thus, the nootropic and anxiolytic effects of piracetam (and, probably, of the other tranquilizers as well) do not coexist and are significantly shifted relative to one another on the dose scale, being probably realized via different mechanisms.     

The use of a scopolamine model to study the potential nootropic effects of aniracetam and piracetam in healthy volunteers

In this study 26 healthy volunteers received scopolamine 0.7 mg subcutaneously on seven occasions at least a week apart. Cognitive efficiency was measured with a test battery before and 60 min following scopolamine on each occasion. Following this, over the seven occasions, a range of oral and intravenous dose regimens were administered including aniracetam 2 mg intravenously, 100 mg intravenously, 200 mg intravenously, 1500 mg per os and piracetam 2400 mg per os. On each session the test battery was then performed again at 120 and 200 min following scopolamine. The seven treatments were administered double- blind and the order was counterbalanced between volunteers over visits using a Latin Square design. At 60 min, scopolamine produced marked and significant decrements in all of the measures of memory and information processing. Aniracetam 1500 mg was able to sig nificantly antagonize decrements on both memory and information processing tasks. The other active treatments also produced significant effects, but for two these were equal to, and for two slightly above, the number which may have occurred by chance, and thus were questionable. Overall, the findings demonstrate that aniracetam 1500 mg can antagonize cognitive decrements produced by cholinergic blockade in healthy volunteers, and suggest that the drug possesses nootropic properties.     

Comparative study of the indices of the antidepressive activity of potassium orotate and piracetam

It has been established in mouse experiments that potassium orotate (100 mg/kg) and piracetam (500 mg/kg) given in chronic oral doses have an antidepressant activity according to the "behavioral despair" test. It has been demonstrated that antidepressant activity of potassium orotate (20 and 50 mg/kg) and piracetam (50 and 100 mg/kg) is associated with a psychostimulant effect.     

Effect of centrophenoxine, piracetam and aniracetam on the monoamine oxidase activity in different brain structures of rats

In vitro studies of effects of some nootropic drugs (centrophenoxine, piracetam and aniracetam) on monoamine oxidase (MAO) activity in the rat striatum and hypothalamus, using tyramine, serotonin and beta-phenylethylamine as substrates, were carried out. At all concentrations used (5.10(-5)-1.10(-3) M) centrophenoxine inhibited total MAO, MAO A and MAO B in both brain structures. Piracetam activated striatal and hypothalamic total MAO, hypothalamic MAO A and MAO B but exerted a pronounced inhibitory effect on MAO A and MAO B activity in the striatum. Aniracetam inhibited total MAO and MAO A in both brain structures but activated striatal and hypothalamic MAO B. The different effects of centrophenoxine, piracetam and aniracetam on MAO activity in the brain structures support the view for the independent mode of action of nootropic drugs in spite of their similar molecular and metabolic activity.     

Modulating effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin secretion in male rats.

1. The effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin (PRL) secretion was investigated in vivo in male rats, by use of a stress-free blood sampling and drug administration method by means of a permanent indwelling catheter in the right jugular vein. 2. Four doses of piracetam were tested (20, 100, 200 and 400 mg kg-1), being given intraperitoneally 1 h before blood sampling; control rats received saline instead. After a first blood sample, rats were subjected to immobilization stress and received morphine, 6 mg kg-1, 90 min later. 3. Piracetam had no effect on basal plasma PRL concentration. 4. While in the non-piracetam-treated rats, stress produced a significant rise in plasma PRL concentration, in the piracetam-pretreated rats PRL peaks were attenuated, especially in the group given 100 mg kg-1 piracetam, where plasma PRL concentration was not significantly different from basal values. The dose-response relationship showed a U-shaped curve; the smallest dose had a minor inhibitory effect and the highest dose had no further effect on the PRL rise. 5. In unrestrained rats, morphine led to a significant elevation of plasma PRL concentration. After the application of immobilization stress it lost its ability to raise plasma PRL concentration in the control rats, but not in the piracetam-treated rats. This tolerance was overcome by piracetam in a significant manner but with a reversed dose-response curve; i.e. the smaller the dose of piracetam, the higher the subsequent morphine-induced PRL peak. 6. There is no simple explanation for the mechanism by which piracetam induces these contradictory effects. Interference with the excitatory amino acid system, which is also involved in opiate action, is proposed speculatively as a possible mediator of the effects of piracetam.     

Effects of nootropic drugs on dopaminergic systems in the CNS

The effect of 3 nootropic drugs, meclofenoxat (MEC), piracetam (PIR) and orotic acid (methylglucamine orotate, MGO), on locomotor activity and on rotational behavior after intracerebral injection of dopamine was tested in female Wistar rats. Whereas MGO-pretreatment increased the dopaminergic supersensitivity following repeated haloperidol in both behavioral tests, the other nootropics were without influence on intensity and duration of supersensitivity. Stimulating and sedative action of apomorphine on locomotion (following 2 mg/kg and 40 micrograms/kg apomorphine sc, respectively) was found to be unchanged after single doses of nootropics (300 mg/kg PIR or MEC, 225 mg/kg MGO, 30 min before apomorphine). Preceding systemic application of nootropics did not change the rotational behavior following application of dopamine (200 micrograms/2 microliters) into nucleus accumbens or nucleus caudatoputamen. The results show that nootropic drugs are without influence on spontaneous and dopaminergically stimulated locomotor activity but in contrast to PIR and MEC, MGO is able to facilitate the dopaminergic supersensitivity.     

Molecular modeling of beta-cyclodextrin complexes with nootropic drugs.

The geometry and structural features of the inclusion complexes of beta-cyclodextrin (beta-CD) with the chiral antiamnesic drugs (+/-)-1-benzyl-4-hydroxymethylpyrrolidin-2-one (WEB-1868). (+/-)-1-benzenesulfonyl-5-ethoxypyrrolidin-2-one (RU-35929), and (+/-)-1-(3-pyridinlysulfonyl)-5-ethoxypyrrolidin-2-one (RU-47010) were studied by the molecular modeling method (MacroModel interactive computer program). Docking procedures yielded the most stable complexes, which showed the aromatic ring of the guests inside the cavity and the pyrrolidinone ring out from the side of the beta-CD secondary hydroxyl groups. The binding energies were essentially due to hydrogen-bonded structures involving the C=O group of the guests. Selective interactions allowed chiral discrimination, and accordingly, separate beta-CD complexes of the R and S enantiomers of each guest compound were studied. The almost round beta-CD structure, in all the cases, assumed an elliptic shape on passing from the isolated molecule to the docked complex. The optimized structures and conformations of beta-CD and its inclusion compounds showed acceptable general agreement with information from proton nuclear magnetic resonance studies.     

Action of nootropic drugs on transcallosal responses in rats

The effects of nootropic drugs and related compounds on transcallosal responses were examined in urethane-anesthetized rats. The transcallosal response was recorded from the surface of the anterior neocortex following electrical stimulation of the contralateral corpus callosum. The transcallosal response consisted of a biphasic positive-negative waveform. Hopantenate increased the amplitude of the positive- and negative-waves, without affecting the latency. Aniracetam, idebenone, bifemelane hydrochloride, TRH and meclofenoxate increased the amplitude of the negative-wave, without affecting the latencies. Vinpocetine and eburunamonine had no effect on the transcallosal response. Muscimol, amino-oxyacetic acid, diazepam and pentobarbital increased the amplitude of the positive-wave and decreased the amplitude of the negative-wave, without affecting the latencies. Bicuculline and picrotoxin increased the amplitude of the negative-wave, without affecting the latencies. Physostigmine decreased the amplitude of the negative-wave, without affecting the latency. Atropine was without effect. The pharmacological nature of the transcallosal response is discussed, based on findings with 16 different pharmacological agents.     

Comparative study of neurophysiological effects of adamantane derivatives in the experimental parkinsonism model

The activity of the adamantane derivative PK-Merz and the new aminoadamantane derivative hemantane was studied by methods of electromyography and electroneuromyography in rats with a model of Parkinson syndrome induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The toxin produced an increase in the pulse conduction velocity (PCV) in the motor fibers of peripheral nerves and a decrease in the amplitude and frequency of the maximum muscle stress curve. A singe administration of both PK-Merz and hemantane produced unidirectional changes in the neuromyographic parameters and reduced the PCV down to a level in the control group. These results give ground for the clinical investigation of hemantane.     

Comparative study of the effect of picamilone and piracetam on learning in rats in a radial maze

During four weeks rats were learned to visit consequently 4 baited arms in the 8-armed radial maze. Picamilone (nicotinoyl-GABA) in a dose of 10 mg/kg daily accelerated rats to reach 80% level of learning (to 20-28 trials). After picamilone injections rats obtained the maximal level of short-term memory as just 3-5 trials. Piracetam in a dose of 200 mg/kg daily exerted no effects on long-term and short-term memory of rats in the radial maze.     

Effects of nootropic drugs in a scopolamine-induced amnesia model in mice

Scopolamine (3 mg/kg IP) given before an acquisition trial, reduced the retention of a one-trial passive avoidance step through response in mice. A single administration of cholinergic agonists such as oxotremorine, BM-5, or arecoline, antagonized this amnesic effect of scopolamine. A significant anti-amnesic effect was also found with nootropic drugs such as piracetam and ucb L059, whereas ucb L060 (the enantiomer of ucb L059), oxiracetam and rolziracetam were shown to be ineffective. Moreover, ucb L059, administered twice daily for 3 days, counteracted the amnesic effects of scopolamine completely, whereas ucb L060 was again inactive. The results demonstrate that: (a) this model of impaired cognition by scopolamine is able to discriminate between closely related chemical substances and even stereoisomers; and (b) nootropic drugs, such as ucb L059, are more effective after repeated rather than after acute administration.     

Influence of nootropic drugs on the learning- and memory-impairing effect of diethyldithiocarbamate in albino rats

The effects of four nootropic drugs (piracetam, aniracetam, meclofenoxate and fipexide) on the impaired cognitive functions by the dopamine-beta-hydroxylase inhibitor diethyldithiocarbamate (DDC) were investigated in albino rats. The changes in learning and memory were studied by the two-way active avoidance with punishment reinforcement (shuttle box). DDC injected intraperitoneally at a dose of 300 mg/kg in the course of the 5-day shuttle box training significantly impaired learning and retention. The 10-day treatment (5 days before and 5 days during training) with piracetam 600 mg/kg, aniracetam 50 mg/kg, meclofenoxate 100 mg/kg and fipexide 10 mg/kg completely abolished the learning- and memory-impairing effect of DDC. The role of the NA-ergic neurotransmitter system for the DDC-induced disturbances in cognition as well as for the protective effects of nootropic drugs was discussed.     

Influence of nootropic drugs on the memory-impairing effect of clonidine in albino rats

The effects of four nootropic drugs (piracetam, aniracetam, meclofenoxate and fipexide) on cognitive functions impaired by the antihypertensive drug clonidine were investigated in albino rats. The changes in learning and memory were studied by two-way active avoidance with punishment reinforcement (shuttle box). Clonidine injected intraperitoneally at a dose of 0.1 mg/kg immediately after a one-day shuttle box training significantly impaired retention. A 5-day treatment before the training session with piracetam 600 mg/kg, aniracetam 50 mg/kg, meclofenoxate 100 mg/kg and fipexide 10 mg/kg completely abolished the memory-impairing effect of clonidine. The role of the NAergic neurotransmitter system in the clonidine-induced disturbances of cognition, as well as in the protective effects of nootropic drugs, was discussed.     

Characterization of the transcallosal response in aged rats and its susceptibility to nootropic drugs.

The transcallosal response in aged rats was recorded and its susceptibility to certain nootropic drugs was compared with adult animals, under urethane-anesthesia. The transcallosal response in 24-month old rats was significantly reduced in the amplitude of both positive and negative waves, as compared with 5-month old animals. In adult rats, intravenous administration of 100 mg/kg of calcium hopantenate augmented the amplitude of both the positive and the negative waves. Intraperitoneal administration of 300 mg/kg of calcium hopantenate or 10-100 mg/kg of aniracetam increased the amplitude of the negative wave by 20-30% above the control level but had no effect on the positive one. In aged rats, these drugs, given intraperitoneally, also increased the negative wave without affecting the positive one and the degree of augmentation was more prominent; both drugs increased the amplitude of the negative wave by about 190% of the control. These results suggest that the susceptibility to the nootropic drugs became even more striking in older animals, the function in the brain of which are reduced by the natural ageing process.