Participation of dihydropyridine-sensitive calcium channels in psychotropic effects of nootropic drugs

Administration of Ca-entry blockers with different chemical structure before the braining sessions produced the reduction of memory retention in mice and rats in the one-trial passive avoidance tests. This effect was absent in animals treated immediately after training test. Nootropic drugs piracetam and oxiracetam corrected the retention of memory when injected just after training test. Chronic treatment of rats with increasing doses of the nootropic drugs produced about two-fold tissue-specific elevation in the density of DHP-receptors, associated with L-type Ca-channels in synaptosomal membranes of rat cerebral cortex. Maximal effect was observed in a dose of 10 mg/kg. Diltiazem, administrated in a dose of 10 mg/kg, produced about two-fold decrease in the receptors density measured 24 hrs after the first injection. Oxiracetam (10 mg/kg) completely antagonized the effect of Ca-entry blocker. These data imply that nootropic action of piracetam and oxiracetam is mediated by L-type Ca-channels.     

Nootropic Drugs Positively Modulate α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic Acid-Sensitive Glutamate Receptors in Neuronal Cultures

Micromolar concentrations of piracetam, aniracetam, and oxiracetam enhanced alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-stimulated 45Ca2+ influx in primary cultures of cerebellar granule cells. Nootropic drugs increased the efficacy but not the potency of AMPA and their action persisted in the presence of the voltage-sensitive calcium channel blocker nifedipine. Potentiation by oxiracetam was specific for AMPA receptor-mediated signal transduction, as the drug changed neither the stimulation of 45Ca2+ influx by kainate or N-methyl-D-aspartate nor the activation of inositol phospholipid hydrolysis elicited by quisqualate or (+-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid. Piracetam, aniracetam, and oxiracetam increased the maximal density of the specific binding sites for [3H]AMPA in synaptic membranes from rat cerebral cortex. Taken collectively, these results support the view that nootropic drugs act as positive modulators of AMPA-sensitive glutamate receptors in neurons.     

Neurophysiological analysis of the correction by nootropic substances of disorders in the bioelectric activity of the brain in animals during chronic administration of ethanol

The influence of some drugs (piracetam and 3-oxypyridine derivative) having a nootropic effect on ethanol-induced changes of bioelectrical activity was studied in experiments on freely moving rats. Discontinuation of ethanol administration (1, 2 g/kg, i.p. for 40 days) has been found to provoke destructuring of Fourier's spectral power of sensorimotor cortex and dorsal hippocamp on the EEG. Long-term administration of piracetam or 3-oxypyridine derivative (300 and 50 mg/kg, respectively, i.p. for 40 days) with ethanol has a protective effect and normalizes EEG at the cortical level. The authors discuss possible neurophysiological mechanisms of nootropic drug action in ethanol-induced pathology.     

Effect of piracetam, a nootropic agent, on rat brain monoamines and prostaglandins

Piracetam is the prototype of a new class of psychotropic drugs, the nootropic agents, which are claimed to selectively improve the higher telencephalic integrative activities. The effect of piracetam on rat brain monoamines and prostaglandins (PGs) was assessed so as to garner information on its mode of action. Two doses of the drug were used, a lower dose (20 mg/kg ip) and a higher dose (100 mg/kg, ip), the latter being known to exert a facilitatory effect on learning and memory. Piracetam produced a dose-related effect on rat brain serotonin (5HT) and noradrenaline (NA), with the lower dose inducing a decrease in 5HT levels and an increase in NA concentrations. The higher dose of piracetam produced the opposite effect. Dopamine (DA) levels were not significantly affected. The lower dose of the drug attenuated 5HT turnover and augmented that of NA, whereas the higher dose of piracetam produced the reverse effects, in clorgyline treated rats. The lower dose of piracetam produced a slight and statistically insignificant increase in rat brain PGE2 and PGF2 alpha. However, the higher dose of the drug produced marked increase in the levels of both the PGs. The observed biochemical effects may provide a basis for the nootropic effect of piracetam. However, they may also be due to the GA-BA-mimetic action of the drug, particularly those observed with the lower dose of piracetam.     

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.     

Effects of oxiracetam and piracetam on the electrical activity of neurons of the cerebral cortex

The effect of oxiracetam and piracetam on the spontaneous impulse neuronal activity of the somatosensory cortex of the cat and rabbit was studied. Oxiracetam and piracetam when applied microiontophoretically changed neuronal activity by depressing in the majority of the cases studied or sometimes facilitating the spontaneous firing rate. A small percentage of neurons (about 30%) remains unaffected by the application of the nootropics. In some cases oxiracetam and piracetam diminished the depress effect of morphine and DADLE on the spontaneous impulse neuronal activity.     

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.     

Preservation of plastic properties of synaptic transmission in long-lasting hippocampal slices under the effects of a peptide analog of piracetam, L-pGlu-D-Ala-NH2

The tetanic stimulation of the Schaffer collaterals (SC) in rat hippocamp slices after 6 hrs in vitro conditions did not produce long-term potentiation (LTP) of the field response amplitude in the CA1 pyramidal cell layer. In contrast, LTP after the late tetanization was well preserved in the slices that were perfused for 20 minutes with 0.5 mkM L-pGlu-D-Ala-NH2 (PGAA) after 4-4.5 hrs in vitro. There were no significant reactivity changes during the perfusion of the slices with this drug concentration. Two other drugs with nootropic activity, piracetam (100 mkM) and gamma-hydroxybutyrate (100 mkM, Na-salt) did not prevent the disappearance of LTP in the late period in vitro, while enhanced the reactivity during perfusion period. The maintenance of the plastic properties of the SC-CA1 synaptic transmission under the influence of PGAA is thought to be the result of some specific interaction of the drug with LTP induction mechanisms. LTP damaged in the late period in vitro might be a new model of memory disturbances and this model can turn out to be useful for the comparative estimation of the effectiveness of the drugs with proposed nootropic activity and for the analysis of the possible mechanisms of their action.     

Effect of nootropic drugs on the dopamine release and dopamine uptake in structures of the rat striatum

Nootropics increase the overflow of dopamine from rat striatum slices in a concentration dependent manner, but without relation to their clinical effectiveness. The influence of a nootropic drugs and of amphetamine on the stimulus induced dopamine release points to a relationship between nootropic and nooanaleptic activity, on the one hand, and transmitter release, on the other. Dopamine re-uptake is not altered by nootropics like piracetam.     

Protein kinase C increase in rat brain cortical membranes may be promoted by cognition enhancing drugs.

Protein Kinase C (PKC) activity was measured in soluble and particulate fractions of rat individual brain cortices after in vivo treatment with two cognition enhancers: oxiracetam and alpha-glicerylphosphorylcholine. Both drugs induced an increase (+40-50%) of PKC particulate activity at 1 hr after the treatment. The effect was transient; at 5 hours PKC activity was lower than in controls. The dose response curve to oxiracetam was bell shaped, the increase of PKC being significant at 100 mg/kg. At higher doses the drug induced a decrease in enzyme activity. The increased PKC activity may be related to the cortical effects of these compounds.     

Effects of nootropic drugs on brain cholinergic and dopaminergic transmission

High affinity choline uptake (HACU) in the hippocampus and striatal concentration of dopamine (DA) and homovanillic acid (HVA) as measures of the in vivo acetylcholine and DA turnover, respectively, were estimated in male rats, Long-Evans, following 6-day administration of various nootropics in clinically relevant doses: piracetam and its derivatives pramiracetam and oxiracetam (100 mg/kg/day), pyritinol (50 mg/kg/day). Piracetam treatment was without effect on HACU, but induced significant increase of HVA in the striatum leaving striatal DA concentration unchanged. On the contrary, pyritinol, pramiracetam and oxiracetam increased HACU, but did not change striatal DA and HVA levels.     

In Vitro Effects of Cognitives and Nootropics on Mitochondrial Respiration and Monoamine Oxidase Activity

Impairment of mitochondrial metabolism, particularly the electron transport chain (ETC), as well as increased oxidative stress might play a significant role in pathogenesis of Alzheimer’s disease (AD). Some effects of drugs used for symptomatic AD treatment may be related to their direct action on mitochondrial function. In vitro effects of pharmacologically different cognitives (galantamine, donepezil, rivastigmine, 7-MEOTA, memantine) and nootropic drugs (latrepirdine, piracetam) were investigated on selected mitochondrial parameters: activities of ETC complexes I, II + III, and IV, citrate synthase, monoamine oxidase (MAO), oxygen consumption rate, and hydrogen peroxide production of pig brain mitochondria. Complex I activity was decreased by galantamine, donepezil, and memantine; complex II + III activity was increased by galantamine. None of the tested drugs caused significant changes in the rate of mitochondrial oxygen consumption, even at high concentrations. Except galantamine, all tested drugs were selective MAO-A inhibitors. Latrepirdine, donepezil, and 7-MEOTA were found to be the most potent MAO-A inhibitors. Succinate-induced mitochondrial hydrogen peroxide production was not significantly affected by the drugs tested. The direct effect of cognitives and nootropics used in the treatment of AD on mitochondrial respiration is relatively small. The safest drugs in terms of disturbing mitochondrial function appear to be piracetam and rivastigmine. The MAO-A inhibition by cognitives and nootropics may also participate in mitochondrial neuroprotection. The results support the future research aimed at measuring the effects of currently used drugs or newly synthesized drugs on mitochondrial functioning in order to understand their mechanism of action.     

Nootropic activity of tuber extract of Pueraria tuberosa (Roxb)

Nootropic effect of alcoholic (ALE; 50, 75, 100 mg/kg) and aqueous (AQE; 100, 200, 400 mg/kg) extracts of P. tuberosa was evaluated by using Elevated Plus Maze (EPM), scopolamine-induced amnesia (SIA), diazepam-induced amnesia (DIA), clonidine-induced (NA-mediated) hypothermia (CIH), lithium-induced (5-HT mediated) head twitches (LIH) and haloperidol-induced (DA- mediated) catalepsy (HIC) models. Piracetam was used as the standard drug. A significant increase in inflexion ratio (IR) was recorded in EPM, SIA and DIA models. A significant reversal effect was observed on rectal temperature in CIH model, reduction of head twitches in LIH models. However no significant reduction in catalepsy scores in HIC models were observed with test extracts and standard piracetam. The results indicate that nootropic activity observed with ALE and AQE of tuber extracts of P. tuberosa could be through improved learning and memory either by augmenting the noradrenaline (NA) transmission or by interfering with 5-hydroxytryptamine (5-HT) release. Further, the extracts neither facilitated nor blocked release of the dopamine (DA). Thus ALE and AQE elicited significant nootropic effect in mice and rats by interacting with cholinergic, GABAnergic, adrenergic and serotonergic systems. Phytoconstituents like flavonoids have been reported for their nootropic effect and these are present in both ALE and AQE extracts of tubers of P. tuberosa (Roxb) and these active principles may be responsible for nootropic activity.     

Synthesis and nootropic activity of some 2,3-dihydro-1H-isoindol-1-one derivatives structurally related with piracetam

Three 2,3‐dihydro‐1H‐isoindol‐1‐ones structurally related with piracetam (=2‐oxopyrrolidine‐1‐acetamide) have been synthesized and tested for their nootropic effects in the passive avoidance test in mice. Compounds (RS)‐ 2 , (R,R)‐ 3 , and (R,S)‐ 3 were obtained in good yields in only two steps starting from methyl dl ‐phthaloylalanine. Compound (RS)‐ 2 exhibited nootropic activity at lower doses than piracetam, used as reference drug, but it showed lower efficacy. Whereas diastereoisomers (R,R)‐ 3 and (R,S)‐ 3 were as potent as piracetam to revert amnesia induced by scopolamine, (R,S)‐ 3 showed lower efficacy than (R,R)‐ 3 . Only (R,R)‐ 3 showed myorelaxant effect at doses of 10 and 30 mg/kg; other compounds did not exhibit any anticonvulsant, sedative, myorelaxant, or impaired motor‐coordination effect in mice. These synthesized 2,3‐dihydro‐1H‐isoindol‐1‐one derivatives constitute a new kind of nootropic compounds.     

Evaluation of nootropic potential of Ocimum sanctum Linn. in mice

Dementia is one of the age related mental problems and a characteristic symptom of various neurodegenerative disorders including Alzheimer's disease. Certain drugs like diazepam, barbiturates and alcohol disrupt learning and memory in animals and man. However, a new class of drugs known as nootropic agents is now used in situations where there is organic disorder in learning abilities. The present work was undertaken to assess the potential of O. sanctum extract as a nootropic and anti-amnesic agent in mice. Aqueous extract of dried whole plant of O. sanctum ameliorated the amnesic effect of scopolamine (0.4 mg/kg), diazepam (1 mg/kg) and aging induced memory deficits in mice. Elevated plus maze and passive avoidance paradigm served as the exteroceptive behavioral models. O. sanctum extract decreased transfer latency and increased step down latency, when compared to control (piracetam treated), scopolamine and aged groups of mice significantly. O. sanctum preparations could of beneficial in the treatment of cognitive disorders such as dementia and Alzheimer's disease.     

Effects of psychotropic drugs of different classes injected in super small doses

Effects of benzodiazepine tranquillizers (phenazepam, flunitrazepam), antidepressants (amitriptiline, imipramine) and nootropic piracetam injected in supersmall dozes were studied in outbred albino rats. It was found that in supersmall doses (10(-12)-10(-14) mol/kg) all these substances exert characteristic for each of these classes specific effects revealed by means of adequate pharmacological techniques. Benzodiazepine tranquillizers increased the number of punished water lickings in the conflict situation test. Antidepressants increased the number of wheel rotations in the test of the forced swimming in a tank with freely rotating wheels and enhanced a correlation between the number of wheel turns during the first and the second five minutes of the experiment. Nootrop piracetam increased the rate of acquisition of the active avoidance reflex in a shuttle box. The effects of all investigated drugs injected in supersmall doses were not accompanied by side effects, characteristic for them at administration in usual dosages. The conclusion is made, that the action of the drugs injected in supersmall doses is an universal property of psychotropic drugs. When administered in supersmall doses the pharmacological substances still exert their specific activity, but are devoid of side effects.     

Antagonism of piracetam with proline in relation to mnestic effects

Based on the authors' previous data showing that the lipophylic cethyl group promotes the penetration of amino acids through the blood-brain barrier, proline cethyl ester was synthesized and studied as a neuropharmacological tool. The substance administered to rats systemically (intraperitoneally) was shown to be able to provoke a deep amnesia when tested by the conditioned avoidance performance. Piracetam abolished the amnestic effect of proline cethyl ester while sodium hydroxybutyrate administered in the dosage range provoking the nootropic effect did not change that amnesia. The data suggest that proline may be considered as one of the possible endogenous amnestic factors. The close structural similarity of the piracetam cyclic fragment to proline, which resulted in their competition, appears to be one of the reasons for piracetam antiamnestic activity.     

Influence of protective drugs on the elevation of extracellular potassium ion concentration in the brain during ischaemia

Influence of drugs on the changes of extracellular potassium ion concentration in the brain during total cerebral ischaemia was investigated. The aorta of the dogs was clamped twice with an intermittent reperfusion period of 60 min. In control experiments no significant difference was found in the elevation of extracellular potassium ion concentration of the brain during the first and second clampings. In the present study drugs were administered 10 min prior the second aorta occlusion. Verapamil in a dose of 0.125 mg/kg proved to be ineffective. Piridoxilate in a dose of 10 mg/kg and piracetam in a dose of 100 mg/kg delayed to a small extent the potassium outflow. The following drugs enhanced significantly the duration before the steep increase of potassium ion outflow: phenytoin in a dose of 10 mg/kg by 31.8 sec (p less than 0.01), ethyl-butyl-thiobarbital in a dose of 15 mg/kg by 30.2 sec (p less than 0.05), and lidocaine in a dose of 100 mg/kg by 115.8 sec (p less than 0.01). Comparing present results to our earlier data (obtained after 50 sec ischaemia) it can be concluded, that these protective influences become more effective during longer ischaemic period (2-5 min), when lidocaine, phenytoin and ethyl-butyl-thiobarbital were used. Moreover, in spite of the observation seen during shorter ischaemia, even piridoxilate and piracetam exerted some degree of protective effect. No such effect of verapamil could be detected in the present experimental model.     

Specificity of the action of piracetam, encephabol and Cleregil on the transcallosal evoked potential

The influence of some drugs having nootropic effect on transcallosal evoked potential was studied in the experiments on non-anesthetized rabbits. Pyracetam, pyritinol and cleregil have been established to increase the amplitude of transcallosal evoked potential. Each of these drugs was found to exert specific effects on this neurophysiological phenomenon. The authors suggest that transcallosal evoked potential can prove helpful in the detection of new drugs with possible nootropic effect.