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.     

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.     

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.     

Influence of testosterone on morphine analgesia in albino rats

Pain threshold for thermal stimulus after morphine, naloxone alone and naloxone in combination with morphine was studied in male rats before and after three days treatment with testosterone. It was also determined 15 days after gonadectomy and administration of testosterone in such rats. There was significant reduction in morphine analgesia after administration of testosterone and also after gonadectomy. Naloxone increased the pain threshold in gonadectomised rats and it enhanced morphine induced analgesia instead of antagonising it. Naloxone, however, had no effect on morphine analgesia in testosterone treated control rats and gonadectomised rats.     

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.     

Platelet hyperreactivity and antiaggregatory properties of nootropic drugs under conditions of alloxan-induced diabetes in rats

The effects of nootropic drugs (noopept, pentoxifylline, piracetam, pramiracetam, Ginkgo biloba extract, entrop, cerebrocurin and citicoline) on platelet aggregation in rats with experimental diabetes have been studied. It is established that all these drugs exhibit an inhibitory action of various degrees against platelet hyperreactivity under conditions of chronic hyperglycemia. The maximum universality of the antiaggregatory action is characteristic of pramiracetam, entrop and Ginkgo biloba extract.     

Influence of dietary fats on weight gain in albino rats

Carbon-chain length and degree of saturation of dietary fat may influence weight gain. To examine this hypothesis we randomly allotted 100 male, 30-day old, albino rats to each of four groups. Each group was fed, ad libitum, a diet containing, as the only source of fat, either lard (L) or safflower oil (SO) (representing saturated and polyunsaturated fat respectively) or groundnut oil (GO) or coconut oil (CO) (representing long-chain and medium-chain triglycerides respectively). At the end of 90 days it was found that rats fed SO consumed more food than those fed L enriched diet (P < 0.001) but the weight gain was similar in the two groups. Similarly rats fed GO-containing diet ate more than those fed diet containing CO (P < 0.001), yet weight gain was similar. Thus it appears that carbon-chain length and degree of saturation of dietary fat does not influence weight gain in rats fed an ad libitum diet.     

Hepatotoxicity of diethyldithiocarbamate in rats

Hepatotoxicity of diethyldithiocarbamate (DDC) was investigated in rats. Plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were markedly elevated 24 hr after subcutaneous administration of DDC and histologically, the liver showed submassive necrosis. A sustained inhibition in the liver of Cu,Zn-superoxide dismutase (Cu-SOD) activity was observed following DDC treatment. DDC produced a significant loss in liver reduced glutathione (GSH) level after 1 hr, but the nadir was observed later than that of Cu-SOD. Catalase activity decreased gradually from 7 hr. Thiobarbituric acid reactive substances (TBARS) in the liver were significantly increased from 15 hr. Hepatic haemodynamics were scarcely changed up to 15 hr. Desferrioxamine (a chelator of iron) and piperonyl butoxide (an inhibitor of cytochrome P-450) prevented DDC-induced increases of both ALT and TBARS, but GSH did not, DDC hepatotoxicity was not changed by phenobarbital induction. Thus, we have shown that subcutaneous dose of DDC caused hepatotoxicity in rats. Although the exact sequence of its hepatotoxic factors is unproven, it seems likely that lipid peroxidation through the dysfunction of antioxidant defence factors and a toxic metabolite contribute to the formation of this liver injury.     

Antitesticular effect of copper chloride in albino rats

Copper chloride treatment adversely affects testicular activity in albino rats. To investigate its antitesticular effects mature (120 days) Wistar strain albino rats were treated intraperitoneally (i.p.) with copper chloride at doses of 1000, 2000 and 3000 micrograms/kg body weight/day for 26 days. Significant reduction of testicular and accessory sex organs (seminal vesicle, ventral prostate) weight, along with inhibition of testicular delta 5-3 beta-hydroxysteroid dehydrogenase (delta 5-3 beta-HSD) and 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity and reduction in plasma testosterone level, were observed at the doses of 2000 and 3000 micrograms/kg body weight/day. The degree of inhibition in all the parameters were increased with the increase of dosage. But no significant change was observed in the above parameters when the animals were treated with 1000 micrograms/kg body weight/day dose. This suggests that copper produces a suppressive influence on male reproductive activity, mainly on testicular weight and steroidogenesis and accessory sex organ weight in a dose-dependent manner.     

Influence of diethyldithiocarbamate on the activity of ecto-ATPase in lymphocytes of rats: ex vivo studies

Influence of diethyldithiocarbamate (DTC) on the activity of ecto-ATPase (plasma membrane-bound enzyme participating in a cascade of reactions leading to the formation of adenosine--a modulator of inflammation) was examined on the lymphocytes isolated from the spleen of rats with inflammation. DTC was administered at doses of 4 mg/kg and 290 mg/kg using two modes of administration. It has been observed that: a) an inflammation caused an increase in ecto-ATPase activity in both subpopulations of lymphocytes; in the case of B-lymphocytes, the maximum of activity occurred 48 h and in the case of T-lymophocytes, 72 h after the injection of carrageenin; b) a single injection of DTC at both doses, 24 h before or 24 h after carrageenin injection caused a decrease in ecto-ATPase activity in B-lymphocytes and its increase in T-lymphocytes throughout the whole measurement period, which was not observed when DTG was administered only after provocation of inflammation; c) administration of a high dose of DTC together with equimolar doses of disulfiram and CS2 led to a decrease in ecto-ATPase activity and 5 '-nucleotidase level in B-lymphocytes, which is bound to the former enzyme; d) in in vitro studies, both populations of lymphocytes isolated from the rats treated with a four-fold dose of DTC showed higher resistance of ecto-ATPase to inhibitors of the enzyme and antagonists of type P2 purinoceptors.     

Comparative neurophysiological study of the nootropic drugs piracetam and centrophenoxine

Effects of nootropic drugs on transcallosal evoked potential (TEP) and EEG spectra of the animal brain cortex and hippocamp were studied. It was found that piracetam and centrophenoxine exert similar effects on the amplitude of the primary TEP components, produce its increase and also a rise and stabilization of the predominant peak in distribution of EEG power spectrum that corresponds to the improvement of theta rhythm organization. The drugs exert different effects on the secondary positive TEP component; centrophenoxine induces a change in non-basic rhythm of EEG in rats. Based on the results obtained, the authors consider possible neurophysiological mechanisms of the nootropic effect and make a comparative analysis of the actions of the drugs.     

Changes in brain biogenic monoamines induced by the nootropic drugs adafenoxate and meclofenoxate and by citicholine (experiments on rats)

1. The effects of Adafenoxate (Adf), meclofenoxate (Mf) and citicholine (CCh) administered at a daily dose of 100 mg/kg for 7 days on the levels of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the frontal cerebral cortex, striatum, hippocampus and hypothalamus of rats were studied. 2. Adafenoxate increased the NA level in the striatum and decreased it in the hypothalamus; it increased the DA level in the cerebral cortex and hypothalamus and decreased it in the striatum; it increased the 5-HT level in the cerebral cortex and decreased it in the hippocampus. 3. Meclofenoxate decreased the NA level in the cerebral cortex and hypothalamus; it increased the DA level in the hippocampus and hypothalamus and the 5-HT level in the cerebral cortex, striatum, hippocampus and hypothalamus. 4. Citicholine increased the NA level in the cerebral cortex and hypothalamus; it increased the DA level in the striatum and the 5-HT level in the cerebral cortex, striatum and hippocampus. 5. An attempt is made to explain some similarities and differences in the behavioral effects of the drugs tested (and those observed in other studies) by the changes they induce in brain biogenic monoamines.     

Effect of scopolamine and nootropic drugs on rewarded alternation in a T-maze.

The effects of different doses of scopolamine, and of the nootropic drugs oxiracetam and aniracetam, were investigated on the performance of male Wistar rats in a T-maze requiring a spatial discrimination in the stem (reference memory) and an alternate discrimination in the arms (working memory). Criterion (90% correct responses) was reached within 3 days of daily training for stem and 9 days for arm discrimination. Scopolamine (0.1, 0.2, 0.6, and 1.0 mg/kg, SC, 60 min before session) significantly impaired working memory, as shown by a decrease in the number of correct alternations, without affecting reference memory. Both nootropic drugs (25-50 and 100 mg/kg PO) 30 min before scopolamine) attenuated the working memory impairment induced by scopolamine.     

Studying specific effects of nootropic drugs on glutamate receptors in the rat brain

The influence of nootropic drugs of different groups (piracetam, phenotropil, nooglutil, noopept, semax, meclofenoxate, pantocalcine, and dimebon) on the binding of the corresponding ligands to AMPA, NMDA, and mGlu receptors of rat brain has been studied by the method of radio-ligand binding in vitro. It is established that nooglutil exhibits pharmacologically significant competition with a selective agonist of AMPA receptors ([G-3H]Ro 48-8587) for the receptor binding sites (with IC50 = 6.4 +/- 0.2 microM), while the competition of noopept for these receptor binding sites was lower by an order of magnitude (IC50 = 80 +/- 5.6 microM). The heptapeptide drug semax was moderately competitive with [G-3H]LY 354740 for mGlu receptor sites (IC50 = 33 +/- 2.4 microM). Dimebon moderately influenced the specific binding of the ligand of NMDA receptor channel ([G-3H]MK-801) at IC50 = 59 +/- 3.6 microM. Nootropic drugs of the pyrrolidone group (piracetam, phenotropil) as well as meclofenoxate, pantocalcine (pantogam) in a broad rage of concentrations (10(-4)-10(-10) M) did not affect the binding of the corresponding ligands to glutamate receptors (IC50 100 pM). Thus, the direct neurochemical investigation was used for the first time to qualitatively characterize the specific binding sites for nooglutil and (to a lower extent) noopept on AMPA receptors, for semax on metabotropic glutamate receptors, and for dimebon on the channel region of NMDA receptors. The results are indicative of a selective action of some nootropes on the glutamate family.     

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.     

Hypocholesterolemic effect of khellin and methoxsalen in male albino rats.

Khellin (CAS 82-02-0) and methoxsalen (CAS 298-81-7) were examined in male albino rats to evaluate their ability to modify serum lipoprotein cholesterol. Clinical chemistry parameters were also measured to obtain information indicative of possible drug toxicity. The drugs were evaluated in four-week double dose studies. After four weeks at 0.45 mg/100 mg b.wt. for khellin and 0.27 mg/100 g b.wt. for methoxsalen, per day, both drugs significantly lowered low density lipoprotein cholesterol, high density lipoprotein cholesterol and total cholesterol. Very low density lipoprotein cholesterol and triglycerides were not changed. No apparent toxicity was observed as clinical chemistry parameters and body weights were not different compared to control values. Similar results were observed with a lower dose of khellin (0.23 mg/100 g b.wt./d). A dose of 0.13 mg/100 g b.wt./d of methoxsalen had no observable effect in this study. Confirmation of the hypocholesterolemic activity of khellin and methoxsalen in this study enhances the therapeutic potential of these compounds against atherosclerosis.