Nootropic and anxiolytic properties of endogenous ligands of benzodiazepine receptors and their structural analogs

Experiments on mice and rats were made to study the nootropic and anxiolytic properties of endogenous ligands of benzodiazepine receptors of nicotinamide and inosin and of their new structural analogs--NMF and AZN. They were shown to have overt antihypoxic and anxiolytic effects. NMF and AZN given in 10-fold lower doses than endogenous benzodiazepine ligands appeared more active than these compounds and almost similar to diazepam as regards the activity. The data obtained point to the possibility of a purposeful search for new efficacious psychotropic and nootropic substances in the series of compounds structurally related to endogenous ligand of benzodiazepine receptors.     

Detection of nootropic activity indicated by acute inhibition of orientation reaction

Exploratory locomotor activity was studied in the experiments on adult male mice. It was shown that routine nootropic drugs as well as newly synthesized nootropic compounds were able to facilitate the development of inhibition during one registration session. Inhibition may be used for revealing only selective nootropic drugs devoid of sedative and stimulating effects.     

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.     

Effect of pineal peptides on the adrenal gland cortex glucocorticoid function and behavior in rats orally immunized with ovalbumin

The influence of intraperitoneal injections of pineal peptides (5 mg/100 g of body mass during first five days of three weeks' oral immunization by ovalbumin) on the rats' behavior in the "open field" tests and on the blood corticosterone level, was investigated. It was found out that rats' oral immunization resulted in increasing of secretion activity of Peyer's patches antibody-producing cells, in decreasing of blood leukocyte cytokine-producing activity, in depression of the searching behavior and locomotor activity and in a significant (p < 0.05) lowering of the blood corticosterone level after 15 minutes in the "open field" tests. The pineal peptide injections caused an intensification of humoral immune response, a more obvious suppression of locomotor activity and searching behavior, and a significant decrease of the corticosterone level compared to the animals intraperitoneally injected by physiological solution. These data indicate that immuno-stimulative effect of pineal peptides combines with their ability to decrease glucocorticoid hormone secretion during stress-reaction.     

Pharmacokinetic, behavioral and neurophysiological aspects of the action of 2-ethyl-6-methyl-3-hydroxypyridine in rats

Specific features of 2-ethyl-6-methyl-3-hydroxypyridine (3-OP) action were investigated in white rats. A correlation has been established between pharmacokinetic parameters and basic manifestations of psychotropic 3-OP effect. Correlations have been also observed between the level of manifestation of anxiolytic effect and changes in 3-OP concentrations in the rat brain. Electroencephalographic findings of the nootropic effect in sensorimotor cortex correlate with 3-OP brain concentrations. The authors describe specific drug pharmacokinetics and possible mechanisms of realization of psychotropic effects.     

MIF-1 potentiates the action of tricyclic antidepressants in an animal model of depression.

In the present paper, the effect of simultaneous treatment of rats with low doses of MIF-1 and tricyclic antidepressants on rat behavior in the forced swim test was studied. It was found that MIF-1 stimulated in a dose-dependent manner "active" behavior of animals in this paradigm. The effect of MIF-1 appeared to be independent of changes in rats' locomotion in the open field test. The combined treatment of rats with MIF-1 (0.01 mg/kg IP) and amitriptyline (5 mg/kg IP) or desipramine (1.25 mg/kg) IP) significantly stimulated active behavior in the forced swim test above the level obtained with each of the drugs given separately. The present data suggest the potential clinical efficacy of a combined therapy of depressive patients with MIF-1 and small doses of tricyclic antidepressants.     

Catecholaminergic component of the action of a heptapeptide analog of ACTH4-10 on the open-field behavior of rats

Heptapeptide Met-Glu-His-Phe-Pro-Gly-Pro (ACTH4-10 analog) at a dose of 0.015 mg/kg failed to alter open field behaviour of rats in the first test series. The peptide abolished amphetamine-induced stimulation of the exploratory and grooming behaviour. Extinction of the rats' exploratory behaviour during second test series in the open field (7 days later) was disturbed when haloperidol or apomorphine were injected before the first test series. When the peptide was administered with haloperidol or apomorphine, the extinction tended to become normal. Heptapeptide failed to change noradrenaline, dopamine or 5-hydroxytryptamine content in the rat forebrain. However, this peptide at a concentration of 10(-4) M moderately diminished tyrosine hydroxylation velocity in the rat striatal or hypothalamic synaptosomes, the effect depending on tyrosine concentration. These data suggest the involvement of catecholaminergic component into the heptapeptide action on the behaviour of rats.     

Neuro-and psychotropic activity of <Emphasis Type="Italic">N</Emphasis>-uronoylamino acids and <Emphasis Type="Italic">N</Emphasis>-uronoylpeptides

Peculiarities of the rat behavior were studied in a series of experimental stress models after a systemic administration of new N-uronoyl derivatives of amino acids. The psychotropic effect was shown to be determined by the nature of the amino acid fragment. N-(1,2:3,4-Di-O-isopropylidene-α-D-galactopyraneuronoyl)-glycylglycine exhibited an anxiolytic effect more pronounced than that of pyracetam, whereas N-(1,2:3,4-di-O-isopropilidene-α-D-galactopyranuronoyl)-glycylglutamic acid has antidepressant action stronger than that of amitriptyline. Mechanisms for the psychotropic effects of the examined derivatives are discussed.     

Aniracetam Does Not Alter Cognitive and Affective Behavior in Adult C57BL/6J Mice

There is a growing community of individuals who self-administer the nootropic aniracetam for its purported cognitive enhancing effects. Aniracetam is believed to be therapeutically useful for enhancing cognition, alleviating anxiety, and treating various neurodegenerative conditions. Physiologically, aniracetam enhances both glutamatergic neurotransmission and long-term potentiation. Previous studies of aniracetam have demonstrated the cognition-restoring effects of acute administration in different models of disease. No previous studies have explored the effects of aniracetam in healthy subjects. We investigated whether daily 50 mg/kg oral administration improves cognitive performance in naïve C57BL/6J mice in a variety of aspects of cognitive behavior. We measured spatial learning in the Morris water maze test; associative learning in the fear conditioning test; motor learning in the accelerating rotarod test; and odor discrimination. We also measured locomotion in the open field test, anxiety through the elevated plus maze test and by measuring time in the center of the open field test. We measured repetitive behavior through the marble burying test. We detected no significant differences between the naive, placebo, and experimental groups across all measures. Despite several studies demonstrating efficacy in impaired subjects, our findings suggest that aniracetam does not alter behavior in normal healthy mice. This study is timely in light of the growing community of healthy humans self-administering nootropic drugs.     

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.     

The "sensory" safety of drugs: photosensitizing damage to the structures of the eye]

Phototoxic side effects of a number of different drugs and natural photosensitizers [correction of photosensors] (psoralenes, psychotropic phenotiazines, anti-malaria drugs, porphirines, adriamycine, etc.) have been analyzed. The ways of study of sensory harmlessness of drugs have been discussed.     

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.     

Influence of small doses human interferon-alpha intranasal injection on behavior of rats of different age

Behavior of young (3-4 month old) and ageing (12-15 month old) rats was studied during chronic intranasal application of low doses (10 ME or 350 ME) of human interferon-alpha (HIA). In ageing rats HIA did not affect dynamics (days 0th, 8th and 16th) of (a) locomotive and (b) investigative activity in the "open field" test and in two-side defensive conditioning, and (c) decreased anxiety ("open field", "light-darkness" test). In young rats HIA (a) increased locomotive activity by 16th day (it decreased in control), (b) investigative activity did not change (in control it decreased by 8th day; "open field" test), (c) anxiety decreased in the "open field" and increased in "light-darkness" tests, (d) development of conditioned reflex improved (during 2nd learning session in 5 days after the first one). Thus, small doses of HIA differently affected behavior of rats depending on the age and experimental situation. However, both HIA doses changed rats' behavior in the same direction. We suggest that chronic low doses of HIA can regulate different aspects of behavior, but not suppress activity as it is commonly thought. This regulation can be performed via modulation of neuro-immuno-endocrine complex.     

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.     

New aspects of the neurophysiological mechanism of the action of nootropic preparations

The influence of nootropic drugs on EEG spectral power of the cortex and hippocamp was studied in resting rats. All these drugs had a specific action on EEG spectral power, causing an increase and stabilization of maximum basic distribution peak of the EEG spectral power. Such action may be attributed to better organization of rhythmic activity in theta-range. The drugs also decreased interhemispheric asymmetry of the cortical and hippocampal EEG. The authors suggest that the increase and improvement of the basic rhythmic activity in the brain and an increased level of distant (spatial) synchronization form the basis for the nootropic drug effect.     

Synthesis and pharmacochemical study of novel polyfunctional molecules combining anti-inflammatory, antioxidant, and hypocholesterolemic properties

We have designed and synthesized a series of novel molecules having a residue of a classical NSAID and an antioxidant moiety, both attached through amide bonds to a known nootropic structure, an L-proline, trans-4-hydroxy-L-proline or DL-pipecolinic acid residue. The compounds were found to retain anti-inflammatory and antioxidant activities, to acquire hypocholesterolemic action, and to possess a greatly reduced gastrointestinal toxicity. The novel molecules could find useful applications, among others, in slowing the progression or delaying the onset of neurodegenerative diseases.     

Een kwalitatieve exploratie van het chronisch gebruik van psychofarmaca in woonzorgcentra

Background

Although guidelines put forward non-pharmacological therapies and advise against the chronic use of psychotropic drugs, these are still being prescribed regularly in Belgian nursing homes.

Goal

To explore the reasons for initiation, continuation and cessation of psychotropic drug treatment of elderly with dementia and behavioral problems, residing in the nursing home.

Method

Twenty-seven interviews from an earlier project were used, in which a semi-structured interview was conducted with the nursing staff, the physicians and the caretakers of eleven randomly selected residents from three nursing homes. A qualitative analysis was performed by three independent researchers according to ‘The Qualitative Analysis Guide of Leuven (QUAGOL)’. A first analysis focused on the process of initiation, continuation and cessation of medication. A second analysis compared the different participants of each interview and looked for similarities and differences.

Results

Seventeen codes were developed for four themes: (1) To initiate, to continue or to cease?; (2) Behavior; (3) Therapy; and (4) Alternatives. The reasons for initiating psychotropic drugs were reducing disruptive behavior and improving the quality of life of the resident. A comparison between the interviewed showed that psychotropic drugs were initiated at the request of the nursing staff. Neither doctors nor nurses considered the monitoring of the drug therapy their task, and tended to pass on this responsibility. Once psychotropic drugs were started, the treatment was chronic but remained part of a dynamic process in which a balance was sought between benefits and adverse effects. More insights into the behavior of the resident led to a better treatment of the behavioral problems.

Conclusion

Nurses play an important role in the initiation and continuation of psychotropic drugs. Physicians should take a more active role in the process of indication and monitoring of psychopharmaceuticals. Discontinuation of psychotropic drugs and the use of non-pharmacological alternatives are important bottlenecks in nursing homes. Education and training, updated practice guidelines, appropriate research, professionalization and management elements can, in a complex interaction, change this situation for the better.

     

4-Aminopiperidine derivatives as a new class of potent cognition enhancing drugs

Extrusion of one of the nitrogens of the piperazine ring of potent nootropic drugs previously described gave 4-aminopiperidine analogues that maintained high cognition enhancing activity in the mouse passive avoidance test. One of the new compounds (9, active at 0.01 mg/kg ip) may represent a new lead for the development of cognition enhancers useful to treat the cognitive deficit produced by neurodegenerative pathologies like Alzheimer's disease.     

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.