Contrasting effect of piracetam and proline on the release of 3H-D-aspartic acid from the cerebral cortical synaptosomes of rats

Piracetam (at concentrations of 10(-6) and 10(-5), but not 10(-4) and 5 X 10(-4) M) decreased K+-stimulated 3H-D-aspartate release. Proline enhanced K+-stimulated D-aspartate release, and its effect was antagonized by piracetam at a concentration that had no effect on K+-stimulated release. Quisqualic acid attenuated K+-stimulated D-aspartate release, with the effect antagonized by GDEE. GDEE also blocked the effect of piracetam, but not proline. The data are discussed in terms of the role of excitatory amino acid neurotransmission in the mechanisms of amnestic and antihypoxic piracetam action.     

Vasoactive intestinal peptide (VIP): an amnestic neuropeptide

Vasoactive intestinal peptide (VIP) is a neuropeptide present in high concentrations in the hippocampus. The studies reported here demonstrate that VIP administered into the third ventricle of the brain caused amnesia in mice trained on a left-right footshock avoidance task in a T-maze. VIP resulted in amnesia when administered directly into the rostral portion of the hippocampus at a 10-fold lower dose than was needed to produce amnesia when VIP was administered intracerebroventricularly. When VIP was administered 24 hr after training, it failed to impair retention measured a week later. VIP receptor antagonist ([4-Cl-D-Phe6,Leu17]VIP) enhanced retention when administered into the rostral portion of the hippocampus, suggesting that VIP plays a physiological role in memory modulation. VIP receptor antagonist administered 24 hr after training did not facilitate retention. To gain some insight as to how VIP may be affecting memory processing, we determined if some memory-improving compounds showed a selective ability to block amnesia induced by VIP. The amnestic effect of VIP was blocked by peripheral administration of the memory-enhancing agents, arecoline, naloxone and ST 587 (a noradrenergic receptor agonist) but not by cholecystokinin octapeptide. Central administration of arecoline, but not neuropeptide Y, blocked the amnestic effect of VIP. It is concluded that VIP is a potent amnestic peptide.     

Antagonism of RO 15-1788 with benzodiazepines in the effect on motivated aggression and the action of analgesics

The influence of Ro 15-1788 and bicuculline on the action of GABA-positive drugs (muscimol), GABA cethyl ester, piracetam and depakine and benzodiazepine tranquilizers (diazepam, phenazepam) on motivated aggression has been studied. It has been shown that Ro 15-1788 which has a weak antiaggressive effect selectively antagonizes the anti-aggressive effect of tranquilizers but not that of GABA-positive drugs. Bicuculline antagonizes antiaggressive activity of the drugs of both types. The action of these antagonists on the effect of the drugs under study as regards the analgetic activity of morphine was also studied. It has been shown that Ro 15-1788 antagonizes the potentiation of morphine analgesia caused by diazepam. At the same time Ro 15-1788 does not influence morphine analgesia potentiated by muscimol. Bicuculline removes the potentiation of morphine analgesia caused both by diazepam and muscimol it is concluded that bicuculline-sensitive GABA receptors modulate the antiaggressive effect of benzodiazepines and their influence on the analgetic action of opiates.     

Electroconvulsive shock and brain muscarinic receptors: relationship to anterograde amnesia

Rats were administered one electroconvulsive shock daily for 7 days (ECS X 7) and were killed 24 hours after the last treatment. Muscarinic cholinergic receptor number, as determined by [3H] quinuclidinyl benzilate [( 3H]QNB) binding, was significantly reduced in the cerebral cortex. A parallel group of rats was trained on a passive avoidance task 24 hours following the last ECS and tested for retention of the original avoidance response 24 hours later; these animals exhibited a profound amnesia. Animals tested 1 hour following training were not amnestic, indicating that learning was unimpaired. Animals trained 7 days following ECS X 7 were not amnestic and [3H] QNB binding changes were not demonstrable at this time. A single ECS which does not significantly affect cortical [3H] QNB binding, did not induce amnesia in rats trained 24 hours after the treatment and tested 24 hours later. The parallel, cumulative nature of ECS-induced muscarinic receptor down-regulation and ECS-induced anterograde amnesia suggests a possible causative relationship.     

Comparative influence of nootropic preparations on the emetic effect of morphine

The effect of electroshock (ECS) and piracetam, oxiracetam or N-acetylglycinamide on the passive avoidance conditioned response in rats was studied. The antiemetic effect of the compounds was examined in cats as well. The results obtained allowed us to distinct the nootropic and antiemetic action of the drugs. The substances possessed a similar ability to prevent ECS-induced amnesia. On the contrary, oxiracetam completely prevented the emetic response to morphine at doses 100 times lower and piracetam at doses 10 times higher then those of the opioid. N-Acetylglycinamide had no antiemetic activity. The results obtained show that oxiracetam is 100 times more active in antiemetic test than piracetam. These data comprise the novel properties of nootropic drugs.     

Study of anti-amnesic activity of amiridin in a model of amnesic syndrome

The model of amnestic syndrome obtained by treatment with scopolamine during 20 days in rats was used to study anti-amnesic activity of amiridin in comparison with that of tacrine, physostigmine and piracetam. Multiple injection of Sc resulted in significant deterioration of rats, performance in passive avoidance test. Behavioral disorders were accompanied by such changes in lipid composition of brain synaptosomes which indicated a decreased membrane fluidity. Amiridin and tacrine as well as piracetam showed anti-amnesic action which in the course of treatment correlated with their normalizing effect on lipid content of synaptosomes. The diverse effect of amiridin and tacrine with respect to physostigmine implies that the former drugs can't be attributed to anticholinesterase preparations which are traditionally used in the treatment of Alzheimer disease.     

Disruption of imprinting by memory inhibitors

Several amnestic drugs were administered intracranially to day-old chicks at selected times around a 10-min exposure to an imprinting stimulus. The drugs used were monosodium glutamate, ouabain, cycloheximide and amino-iso-butyrate. The chicks were tested for 10 min in the same apparatus two days later, and the time spent following the stimulu was recorded., The index of memory retention was the difference between the time spent following on test and the time spent following on the initial exposure. When compared with saline-injected control, glutamate administered 5 min before the beginning of the initial exposure was effective in producing a reduction in following times and hence amnesia. Ouabian was effective when injeced before the beginning and immediately after the end of the initial exposure; while cycloheximide was effective when administered as late as 5 min after the initial exposure. The effective times of administration for the drugs to produce a reduction in following times were similar to that observed for amnesia in passive avoidance memory tasks. The increase in following shown by the control chicks was not a developmental effect due to the increae in age on test. Experiments involving a choice of stimuli on test support the invovement of a memoryrelated phenomenon in these experiments.     

Passive avoidance deficit following intracerebroventricular administration of cholecystokinin tetrapeptide amide in rats

The effect of cholecystokinin tetrapeptide amide (CCK-4) injected into the lateral cerebral ventricle on memory processes was examined by a one-trial passive avoidance test in the rat. CCK-4 injection 30 and 60 min before the first retention test caused a shortened latency to response, and its chronic infusion into the lateral ventricle at a rate of 2 micrograms/day shortened the latency of the response to the level of almost complete amnesia. CCK-4 also reduced arginine-vasopressin effect on memory processes when administered simultaneously 30 min before the first retention test, but its amnestic action is short-lasting and antagonized by relatively small amounts of cholecystokinin octapeptide (CCK-8). In addition, the shortened latency to response was admitted to be not always associated with the motility effect of CCK-4.     

Experimental study of the effects of amiridin and tacrine on learning and memory

The authors studied the influence of amiridin and tacrine on learning and memory in mice and rat by passive avoidance conditioning test at norm and under scopolamine induced amnesia as well as of their effect on acetylcholine esterase (AChE) activity in brain cortex homogenates. Amiridin in doses 0.1 and 0.2 mg/kg showed a beneficial action on conditioning in untreated animals, its effect being comparable with that of piracetam. Tacrine was ineffective. In scopolamine treated animals amiridin and tacrine showed anti-amnestic action at dose of 0.1 mg/kg which was found ineffective with respect to AChE activity. The data suggests that the ameliorating effect of amiridin and tacrine on cognitive abilities in patients with senile dementia is not related their anticholinesterase properties.     

Reproduction of a memory trace in amnesia and forgetting following alteration in the activity of pre- and postsynaptic dopamine receptors

The paper deals with analysis of the action of enantiomers 3-PPP on memory trace reproduction disturbed by amnestic effects and spontaneous forgetting in mice. A considerable antiamnestic effect is shown of (+)3-PPP and (-)3-PPP in 10 mg/kg doze changing the activity of postsynaptic dopamine receptors. The influence of drugs in 2 mg/kg doze changing the activity of presynaptic receptors consisted in recovery of conditioned habit only in situation of a weak amnestic effect and at forgetting, when the level of reproduction was like a weak amnesia. The range of enantiomers 3-PPP action on reproduction processes disturbed by amnesia or forgetting is determined by the possibility of specific activation of pre- and postsynaptic receptors at different depth of disturbances of memory trace reproduction causing differentiation of 3-PPP effects.     

Effect of a change in the effectiveness of a benzodiazepine-GABA-ionophore complex blockade on the reproduction of an amnesic memory trace in mice after preliminary diazepam administration

The paper deals with the results of analysis of the influence of blocked of BD-GABA-ionophore complex and its separate components on recover of memory trace amnesia during BD-receptors activation in experiments on elaboration of CR of passive avoidance in mice. It is shown that at "neurochemical tuning" the improvement of conditioned reaction reproduction on the 2-nd and 21-st day after learning and amnestic action was observed only at GABAA receptor blockade by bicuculline, while the blockade of BD-receptor by flumazepil and of chlorine channel by picrotoxin was ineffective. Simultaneous blockade of all BD-GABA-ionophore complex components was not more effective in comparison with the blockade of its separate links in the recovery of conditioned reaction reproduction. The presented data allow to suppose that "psychogenic" amnesia development is determined by the functional state of neurotransmitter brain systems at learning and amnestic action which stipulates subsequent possibility of memory trace retrieval.     

Nootropic activity of nicotinamide and its structural analogs

It is known that endogenic nicotinamide has a tranquilizing and stress-protective activity. The present investigations show the nootropic effect of this drug and its analogs nicomorpholine and acethylnicotinate on acute models of hypoxia and amnesia. The present results revealed that the observed nootropic activity of nicotinamide and its analogs is more expressed than this of piracetam, pyritinol and meclofenoxate. Having in mind the similarity of pharmacological effects of piracetam and nicotinamide (antihypoxic, antiamnestic and anxiolytic) we try if these drugs have electronic-structure similarities. The analysis revealed some similarity of these drugs' molecules in relation to the composition and distribution of polar centres pi- and p-electronic areas) distance between them, topography of separate molecule parts.     

The role of GABA-A and GABA-B receptors in the development of amnesia

The paper deals with analysis of the influence of blockade of separate components of benzodiazepine-GABA-ionophore complex on the recovery of memory trace amnesia under GABA-A and GABA-B receptors activation in the experiments with conditioned reaction of passive avoidance of mice. Activation of GABA-A receptors did not change the behavioural amnesia manifestation at all terms of testing. Activation of GABA-B receptors before learning and amnestic influence caused spontaneous recovery of avoidance reaction. Blockade of chloride channel by picrotoxin and of benzodiazepine receptor by flumazepil restored the reproduction of the memory trace disturbed against the background of GABA-B receptors activation. Systemic flumazepil administration contributed to the memory trace reproduction against the background of GABA-A receptors activation by muscimol in the dose of 0.5 mg/kg. In conditions of amnesia development against the background of muscimol in the dose of 1 mg/kg the blockade of any component of benzodiazepine-GABA-ionophore complex was not effective. The obtained data testify that activation of GABA-A and GABA-B receptors changes the amnesia development and correction of amnesia memory trace by the blockade of separate components of benzodiazepine-GABA-ionophore complex.     

Analgesic Effect of Piracetam on Peripheral Neuropathic Pain Induced by Chronic Constriction Injury of Sciatic Nerve in Rats

Despite immense advances in the treatment strategies, management of neuropathic pain remains unsatisfactory. Piracetam is a prototype of nootropic drugs, used to improve cognitive impairment. The present study was designed to investigate the effect of piracetam on peripheral neuropathic pain in rats. Neuropathic pain was induced by the chronic constriction injury of the sciatic nerve. Following this, piracetam was intraperitoneally administered for 2 weeks in doses of 50, 100 and 200 mg/kg, and pain was assessed by employing the behavioural tests for thermal hyperalgesia (hot plate and tail flick tests) and cold allodynia (acetone test). After the induction of neuropathic pain, significant development of thermal hyperalgesia and cold allodynia was observed. The administration of piracetam (50 mg/kg) did not have any significant effect on all the behavioural tests. Further, piracetam (100 mg/kg) also had no effect on the hot plate and tail flick tests; however it significantly decreased the paw withdrawal duration in the acetone test. Piracetam in a dose of 200 mg/kg significantly modulated neuropathic pain as observed from the increased hot plate and tail flick latencies, and decreased paw withdrawal duration (in acetone test). Therefore, the present study suggests the potential use of piracetam in the treatment of neuropathic pain, which merits further clinical investigation.     

Metabotropic glutamate receptors (mGluRs) are involved in early phase of memory formation: possible role of modulation of glutamate release

Metabotropic glutamate receptors (mGluRs) groups I and II are involved in the cellular processes of long-term potentiation (LTP) and learning and memory formation. I.c.v. injection of the mGluRs agonist 1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) can impair memory formation in some types of learning task. The role of mGluRs in neurotransmitters release and production of second messengers has been suggested. The aim of the present study was to determine the effect of i.c.v. administration of the new potent mGluRs agonist ABHxD-I and compare its effect with that of ACPD. We studied the effect of both agonists on acquisition and memory for a one-trial passive avoidance learning task in day-old chicks and on the training related glutamate (Glu) release. ACPD or ABHxD-I (50 nmole per chick, i.c.v. injection) were administered at different times before or after training and chicks were tested at various times after training. Chicks injected with ABHxD-I 30 min before training showed amnesia when tested 30 min or 3h after training. The amnestic effect of ACPD was significant only 30 min after training. Glu release evoked by 70 mM KCl was measured in slices prepared from the IMHV of chick brain isolated from animals injected with either ACPD or ABHxD-I 30 min before training and tested 30 min after training. Glu concentration was measured using HPLC. Both ACPD and ABHxD-I significantly increased Glu release in slices isolated from untrained chicks (30 and 48% compare to control, respectively, P<0.05). Training itself increased Glu release (41% compared to control, P<0.01) and no additional effect of either ACPD or ABHxD-I was observed. These results suggest that mGluRs groups I and II are involved in the early stages of memory formation and that application of either of the studied mGluRs agonists may interfere with that process. The amnestic effect of ABHxD-I seems to be stronger and longer lasting. Although the mechanism of this effect still remains unclear, our results suggest that disregulation of Glu release by mGluR agonists may participate in this process.     

Participation of the central noradrenergic system in the mechanisms of latent inhibition

Male Wistar rats were learnt to conditioned reaction of passive avoidance 10 days after intraperitoneal administration of 50 mg/kg of specific neurotoxin DSP4. The character of conditioned reaction reproduction, duration of its conservation and its stability against amnestic processing were analyzed. It has been found that reduction of activity of noradrenergic coerulo-cortical system does not influence the conditioned reaction reproduction but inhibits its spontaneous extinction and prevents amnesia development. The obtained data are discussed in aspect of central noradrenaline participation in latent inhibition mechanisms.     

Effect of piracetam derivatives on antibody formation

Immunomodulatory effects of piracetam and a number of its derivatives were studied in mice. It was shown that multiple injections of such substances at a dose of 50-200 mg/kg change the amount of antibody-forming cells in the spleen of animals immunized with sheep red blood cells. The dose of 200 mg/kg was the most effective one, with the direction of immunomodulatory activity depending on the chemical composition of the compounds. Thus joining of phenol radical to piracetam molecule strengthened immunosuppression, and vice versa insertion of hydrazide group led to stimulation of antibody formation. It is stressed that immunosuppressive effect of piracetam must be taken into consideration during the clinical use of the drug.     

A study to evaluate the effect of nootropic drug-piracetam on DNA damage in leukocytes and macrophages

Piracetam is a nootropic drug that protects neurons in neuropathological and age-related diseases and the activation and modulation of peripheral blood cells in patients with neuropathological conditions is well known. Therefore, in the present study, in vivo, ex vivo, and in vitro tests were conducted to investigate the effect of piracetam on leukocytes and macrophages. Lipopolysaccharide (LPS) causes oxidative DNA damage; thus, in the present study, LPS was used as a tool to induce DNA damage. In vivo experiments were conducted on Sprague Dawley rats, and piracetam (600mg/kg, oral) was provided for five consecutive days. On the fifth day, a single injection of LPS (10mg/kg, i.p.) was administered. Three hours after LPS injection, blood leukocytes and peritoneal macrophages were collected and processed, and a variety of different assays were conducted. Ex vivo treatments were performed on isolated rat blood leukocytes, and in vitro experiments were conducted on rat macrophage cell line J774A.1. Cell viability and the level of reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and DNA damage were estimated in untreated (control) and piracetam-, LPS- and LPS+piracetam-treated leukocytes and macrophages. In vivo experiments revealed that rats pretreated with piracetam were significantly protected against LPS-induced increases in ROS levels and DNA damage. Ex vivo isolated leukocytes and J774A.1 cells treated with LPS exhibited augmented ROS levels and DNA damage, which were attenuated with piracetam treatment. Thus, the present study revealed the salutary effect of piracetam against LPS-induced oxidative stress and DNA damage in leukocytes and macrophages.