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Neurexan is a multicomponent natural medicinal product used for stress-related symptoms such as nervous restlessness and insomnia. The present study investigated the efficacy of Neurexan on stress-induced changes of brainwave frequencies using quantitative analysis of spectral EEG power. Thirty healthy male and female volunteers were tested in a randomized, placebo controlled cross-over trial under conditions of relaxation and experimental stress-in- duction. Recording of the EEG was performed over four hours after drug administration. Data was analyzed using the proprietary fast dynamic EEG technology Neurocode-Tracking. Quantitative EEG revealed a task dependent increase of beta2 power as a surrogate parameter of stress induced anxiety. The elevated frontotemporal beta2 power was ameliorated by intake of Neurexan during the second and third hour after administration. This indicates that Neurexan is effectively helping subjects to better cope with task-related stress situations.

Vertigo is a common symptom with impact on daily life. Vertigoheel® (VH-04) has demonstrated to be effective for Vertigo in former studies. This paper aims to investigate the mode of action of the medicinal product VH-04 in the rat brain. In an in vitro study neurophysiological recording from hippocampal slices from adult male Sprague Dawley® rats was performed in order to substantiate a possible direct effect on the brain of VH-04 in different concentrations. In an in vivo cross-over study with 11 Fischer 344® rats, a neurophysiological method was applied to systemically analyse VH-04’s activity in the rat brain. This method combines quantitative assessments of telemetrically transmitted field potentials after drug treatment with subsequent discriminant analysis to classify the compound. The database used for the analysis of classification contained numerous chemicals and medicinal products of different dosages, all tested in the same paradigm, which is continuous wireless monitoring of the EEG of freely moving rats before and after drug intake. Following single stimuli on the Schaffer collaterals in the presence of VH-04 in different concentrations, in vitro responses of pyramidal cells increased depending on the VH-04 concentration (0.25 - 4 ml/L). Results were statistically significant for concentrations above 2.5 ml/L. Long-term potentiation was only marginally affected. Out of several specific glutamate receptor antagonists the effect of VH-04 was only antagonized by AMPA and kainic acid receptor-mediated signalling. Their enhancement indicates better information processing in the hippocampus, a brain structure primarily involved in memory processes. The in vivo characterisation of VH-04-induced changes in EEG-signatures of four brain areas (the frontal cortex (FC), the hippocampus (HC), the striatum (ST) and the reticular formation (RF)) revealed a dose-dependent attenuation of delta, theta, alpha 2 and beta 1 waves. The subsequent discriminant function analysis classified the VH-04 EEG-signature into a subset of cognition-enhancing medicinal products.

Clinical indications for herbal drugs very often only rely on traditional knowledge. Single plant-derived preparations are used for many purposes and cannot be classified to belong to a single category like calming or stimulating drugs. With respect to the brain a unique possibility exists to analyze drug effects by recording the EEG. It is common knowledge that many drugs change the frequency content of electric brain activity. Quantitative analysis of the EEG by Fast Fourier Transformation reveals parameters like spectral power, which can be processed further (CATEEM®). Source density was determined from 17 channels of the quantitative EEG from 10 clinical studies recorded in a relaxed state with open eyes. Linear discriminant analysis was used to differentiate the effects of Placebo (circadian rhythm) from CNS-active herbal drugs in comparison to Valium®. Calmvalera®, L-Theanine, Lasea®, Neurapas®, Neuravena®, Neurexan®, Nutrifin Relax®, Pascoflair® (herbal calming drugs) as well as memoLoges®, Zembrin® (herbal stimulating drugs) induced different changes of the frequency content of brain electric activity. Discriminant analysis revealed that Nutrifin Relax®, Pascoflair® and Suntheanine® could not be separated well from each other indicating a similar mechanism of action. The effect of Valium® was projected at a very isolated position far away from the herbal preparations indicating a totally different mechanism of action. Zembrin® and memoLoges® grouped together with respect to the first three discriminant functions, but were different with respect to the 4th to 6th discriminant function. Lasea® as anxiolytic drug and Neurapas® as antidepressive drug were projected at isolated positions indicating their different clinical indications. The results indicate that discriminant analysis of human quantitative EEG data allows for unique pharmacological description of individual effect profiles of herbal drugs.

Background: Recently, the superior efficacy of hydroponically cultivated red ginseng preparation HRG80® compared to wild growing white ginseng (WG) in preventing stress-induced symptoms related to the daily work situation of healthy subjects was reported. The aim of this study was to compare the effects of HRG80®, WG, and placebo on the electrical activity in the brain of elderly human subjects during relaxation and mental challenges. Methods: Changes in the electroencephalogram (EEG) frequency ranges of 17 different brain regions were measured after single and repeated administration of HRG80®, WG, and placebo across a four-week randomized, double-blind, placebo-controlled three-armed cross-over trial. Results: Both red and white ginseng preparations had a strong impact on brain activity, with different effects on various brain regions depending on the mental load during relaxation and cognitive tasks associated with memory, attention, and mental performance. Both ginseng preparations exhibited significant effects on spectral powers compared to placebo, reflecting an activating action. The spectral changes in the quantitative EEG induced by HRG80® indicated an improvement in mood as well as calming effects, evidenced by the modulation of β2 waves, representing changes in GABA-ergic neurotransmission. HRG80® attenuated δ/θ powers during relaxation, suggesting the potential improvement of pathologically enhanced spectral power in aging. Conclusion: The results of this study suggest that both hydroponically cultivated red and wild growing white ginseng have similar beneficial effects on the cognitive functions of elderly subjects, as reflected by electric brain activity, but their modes of action on the brain are different.

Background: The current and potential uses of adaptogens are mainly related to treatment of stress-induced fatigue, impaired cognitive function, mental illness, and behavioral- and age-related disorders. However, clinical evidence regarding the efficacy of adaptogens is limited. The primary aim of this study is to determine whether a combination of adaptogenic plant extracts from Andrographis paniculata and Withania somnifera (Adaptra&reg, Forte) could be used as effective and safe treatment for impaired cognitive, memory, or learning ability functions and sleep disorders. Methods: The changes in electroencephalogram (EEG) frequency ranges in 17 different brain regions, psychometric tests of cognitive performance, as well as standard questionnaires of assessment of mood and sleep were measured after single and repeated administration of Adaptra&reg, or placebo for four weeks and after a two-week treatment-free follow-up period within a randomized, double-blind, placebo-controlled two-armed cross-over study. Results: Adaptra&reg, Forte significantly improved cognitive performance in the d2-Test for attention and the concentration performance test after four weeks&rsquo, treatment, and was positively correlated with increases in &delta, and &theta, power in the quantitative EEG compared with placebo during cognitive challenges. Conclusion: The results of this study suggest that Adaptra&reg, Forte exhibits a calming and anxiolytic effect without sedation, and is associated with overall stress-protective activity.

Summary Ethnopharmacological relevance Sceletium tortuosum (Mesembryanthemaceae), a succulent plant indigenous to South Africa. is consumed in the form of teas, decoctions and tinctures and is sometimes smoked and used as snuff. In recent years, Sceletium has received a great deal of commercial interest for relieving stress in healthy people, and for treating a broad range of psychological, psychiatric and inflammatory conditions. Material and methods The whole extract (Zembrin®) was tested ex vivo in the hippocampus slice preparation after one week of daily oral administration of 5 and 10 mg/kg. Four alkaloids – mesembrine, mesembranol, mesembrenol and mesembrenone – were tested directly in vitro. All four were also tested in the presence of different glutamate receptor agonists. Results Zembrin® ex vivo as well as all alkaloids in vitro attenuated the amplitude of the population spike during electric stimulation as single shock as well as theta burst stimulation. Only Mesembranol and Mesembrenol having a hydroxyl group at position C6 instead of carbonyl group as in mesembrine and mesembrenone acted by attenuation of AMPA receptor mediated transmission as documented for the whole extract. Discussion The current experimental series revealed a new physiological effect of Zembrin® on the electric activity of the hippocampus. Attenuation of AMPA mediated transmission has been related to successful adjunctive treatment of epileptic patients. Administered doses of 5 and 10 mg/kg are in line with a dosage of 50 mg/subject as tested clinically. Conclusion We have discovered a new structure activity relationship for Sceletium alkaloids. Since attenuation of AMPA mediated transmission has been related to successful adjunctive treatment of epileptic patients), Mesembrenol and Mesembranol may serve as new chemical leads for the development of new drugs for the treatment of epilepsy.

Zembrin® is a botanical functional food and dietary supplement ingredient sold in the USA, and Canada for enhancing mood, decreasing anxiety and stress and improving cognitive function under stress. It is a proprietary extract of a cultivated selection of Sceletium tortuosum. The present investigation aimed at the measurement of the effect of 25 or 50 mg of Zembrin® in comparison to placebo after daily repetitive intake for 6 weeks. Sixty healthy male (n = 32) and female (n = 28) right-handed subjects between 50 and 80 years old (59.7 ± 5.43 and 56.7 ± 5.88 years, respectively) were recruited. The EEG was recorded bipolarly from 17 surface electrodes (CATEEM®) before and 1 h after intake. Six cognitive tests were performed: d2-test, memory test, calculation performance test, reaction time test, number identifying test and number connection test. Three questionnaires were included: Profile of Mood States, Hamilton Anxiety Rating Scale and a sleep questionnaire. Quantitative EEG revealed increases of delta activity during performance of the d2-test, the number identification and number connection test in the fronto-temporal brain region. Higher theta activity was seen during relaxation and performance of the d2-test after intake of 50 mg of Zembrin®. Statistically conspicuous increases of alpha1 spectral power were seen in the relaxed state. With respect to alpha2 spectral power larger increases were observed in the centro- occipital region. Discriminant analysis revealed a projection of Zembrin® data into the vicinity of the calming preparation Calmvalera tablets and a Ginkgo-Ginseng mixture. Statistically significant improvement during performance of the arithmetic calculation test and number connection test was documented. The HAM-A anxiety score revealed a statistically significant decrease (p = 0.03) after six weeks. Zembrin® showed significant activity on three levels of evidence: questionnaires, psychometry and quantitative EEG. The results indicate that in healthy people Zembrin® improves some aspects of cognitive function, decreases anxiety, and may enhance mood.

Mild cognitive impairment (MCI) can be regarded as a non-demented transitional stage during the development of Alzheimer’s disease. Early recognition of this stage might increase the chance of prevention by early treatment. Within a pilot study, two plant-derived preparations and mixtures thereof were tested successfully in subjects suffering from MCI. A combination of Sideritis scardica and Bacopa monnieri extract (memoLoges®) was chosen now for a repetitive dosing during 4 weeks. Thirty-two subjects aged 50 to 80 years and suffering from MCI (having a DemTect questionnaire score between 8 and 13) were recruited for intake of 2 capsules of the preparation per day. Quantitative EEG recording during relaxation and concomitant performance of three 5 minutes lasting psychometric tests (d2-concentration test, arithmetic calculation test and memory test) was achieved at the first day and one day after the last repetitive intake. Seventeen channels of EEG and one channel EOG (for artefact rejection) were recorded. After frequency analysis (FFT) current source density was calculated as reported earlier. One, two and three hours after intake of the herbal extract or placebo the whole procedure was repeated. Brain imaging was achieved by conversion of numerical values of spectral EEG power into spectral colors and additive color mixture according to RGB as used in TV settings. Intake of memoLoges® induced a trend of improvement of performance in psychometric testing (all three tests). During relaxation quantitative assessment of EEG data revealed attenuation of delta and theta spectral power in frontal brain as likewise reported in the presence of the Alzheimer drug rivastigmine, bringing the spectrum back to “normality”. During mental work memoLoges® induced statistically significant increases of beta power. Since MCI subjects produce less beta power in comparison to healthy subjects, this increase must likewise be seen as a positive effect pointing to a healthier spectrum.

The pharmaco-dynamic action of plant-derived drugs still remains a big challenge in the field of pharmacology. This applies especially for the discovering of the possible mechanism of action. With respect to the brain, surrogate parameters may be very helpful. Non-invasive pharmaco-EEG has been proven to provide valid information on drug effects in general. Fast dynamic EEG recording with epoch length of 364 ms has now been achieved in combination with Eye-Tracking in order to elucidate single scenes during cognitive and emotional challenges (EnkephaloVision). The present investigation deals with the psychophysiological characterization of the effect of a plant-derived preparation marketed in Germany under the name of PASCOFLAIR® containing 425 mg of passionflower extract in subjects suffering from examination anxiety. Forty healthy volunteer subjects (17 men and 23 woman), with ages varying between 18 and 40 years (26 ± 6.726 for men and 25 ± 5.397 for women) were included into the study when having a score higher than 60 in the PAF (PrUfungsangstfragebogen). Spectral power analysis of pre-drug data with respect to beta waves revealed a significant correlation to the score of the PAF. Increases of delta, theta and beta waves as induced by 4 cognitive and 4 emotional challenges were attenuated in the presence of 2 tablets of PASCOFLAIR® already 45 minutes after intake in a statistically significant manner in comparison to placebo. Regarding attenuation of beta1 and beta2 spectral power, effects on glutamatergic and GABAergic neurotransmission, respectively, can be suspected according to our knowledge of frequency—transmitter relations. Accordingly, this attenuation must be interpreted as ability to counteract examination induced stress symptoms. Results confirm and extend earlier experimental data showing a calming action of PASCOFLAIR®.

Subjects suffering from anxiety during examinations often take drugs with considerable side effects. As alternative, homeopathic preparations virtually lack side effects in general. However, clinical efficacy has to be demonstrated. This experimental series was initiated to provide evidence, that Calmvalera Hevert tablets, marketed for treatment of nervous restlessness and better coping with stress, have an influence on brain electric activity. In order to test this, a new clinical design was used: “EnkephaloVision”. It consists of the combination of quantitative EEG recording with time epochs of 364 ms (Neurocode-Tracking) with conventional Eye-Tracking. Seventeen channels of EEG and one channel EOG were recorded. After frequency analysis (FFT) current source density was calculated. Recording was performed in the presence of a video clip, which contained several different cognitive and emotional challenges in series. Twenty-four male and female subjects having a score >60 in an anxiety questionnaire (Prufungsangstfragebogen PAF-S) were recruited to participate. A correlation between the Hamilton anxiety score and spectral alpha1 power during the recording condition “eyes open” before drug intake was detected. Spectral power was averaged including Cz, F3 and F4 electrode positions. Audiovisual challenges induced spectral changes with respect to delta, theta and beta power, not in the alpha ranges, to a different but statistically significant degree. Intake of Calmvalera Hevert tablets resulted in statistically significant increases of alpha1 and alpha2 spectral power during most of the recording conditions within the left hemisphere. Increases of alpha activity have been related to relaxation and calmness as reported in the literature. Discriminant analysis of the whole data set revealed a clear difference between verum and placebo and a projection of the data into the vicinity of other plant-derived calming preparations. Performance of psychometric tasks was not disturbed. Efficacy of Calmvalera Hevert tablets points to active molecules contained due to low triturations (D2 - D8).

Anatomical functionality is a major topic in brain research. Numerous investigations have shown task dependent activation of focal brain areas, with most information based on time-averaged data due to methodological limitations. Ultra-fast quantitative EEG, especially in the newly developed combination with eye tracking (EnkephaloVision), is very suitable to follow activities of local electric circuits. This investigation in 57 subjects revealed transient focal frequency changes reaching up to more than 6000% of global median spectra power during cognitive and emotional challenges at frontal electrode positions. Recording epochs of 364 ms uncovered coherences with respect to focal brain areas and single frequencies, which are typically lost during averaged calculations. When averaging data over a whole scene, a least demanding challenge like viewing a boring animal video only activated the lateral frontal lobe, whereas solving brain-teasers and performance of mathematical calculations led to delta (modulated by acetylcholine) and theta (modulated by norepinephrine) increases in all brain regions in a statistically significant manner. In addition to delta and theta increases, performance of the Stroop test led to beta2 (related to GABA-ergic transmission) increases in the temporal lobe. The higher the mental demand the more brain regions were involved during 10 different challenges. There was no challenge which did not activate the lateral frontal brain in terms of increases of delta and theta spectral power. The results are in line with the view that the lateral frontal lobe is involved primarily during cognitive and emotional behavior related to activity changes of acetylcholine and norepinephrine.

Psychophysiological effects of Sideritis herba extracts depend on biologically active ingredients, which might be different for several botanical types of this plant. The present investigation aimed at the characterization of extracts from Sideritis scardica and Sideritis euboa in vivo and in vitro. Construction of electropharmacograms on the base of recording of electrical field potentials from four different brain regions was used to compare the possible pharmacological effects to a database of reference drugs with known clinical indications. Whereas Sideritis scardica produced decreases of spectral power in line with stimulatory frequency patterns as observed in the presence of Ginkgo biloba extract, administration of Sideritis euboa produced opposite effects. Electrical stimulation of the Schaffer Collaterals was used to elicit a pyramidal cell response called population spike in vitro. The amplitude of this spike was determined in the presence of single as well as theta burst stimuli. Direct exposure of brain matter to Sideritis scardica extract led to concentration dependent increases of the population spike amplitude under both stimulation patterns in the range from 12.5 to 100 mg/L. On the opposite, extract from Sideritis euboa did not change the electric response up to 50 mg/L. Higher concentrations of this extract attenuated the signal amplitude. A 1:1 blend of both gave intermediate results. The in vitro results are in line with the in vivo EEG recordings, where both extracts induced opposite changes of the electric power with respect to electric frequency patterns. The results from both models suggest a stimulatory and/or memory-enhancing action for the extract from Sideritis scardica but not for Sideritis euboa extract, where a more tranquillizing effect like that observed in the presence of Humulus cone extract may be expected.

To find possible therapeutic applications involving the Central Nervous System (CNS) for herbals is a major challenge during functional food and drug discovery and development programmes. Despite the availability of numerous in vitro and in vivo tests, there is no single agreed screening procedure for pharmacological testing of herbal extracts with anticipated CNS activity. Experience gained from more than 25 years of testing has shown that two models give reasonably reliable orientation for future CNS applications: construction of an electropharmacogram based on wireless recording of field potentials from the depth of the brain of freely moving rats (Tele-Stereo-EEG) and recording of the population spike produced by pyramidal cells from hippocampal slices in vitro. A combination of these two methods has now been used to characterize the pharmacological profile of extracts from Rhodiola rosea root, Oenothera paradoxa seeds and Paullinia cupana seeds. Spectral analysis of field potentials revealed attenuation of alpha2 and beta1 waves was common for all extracts. According to previous studies, this is interpreted as activation of the dopaminergic and glutamatergic transmission. In addition, Oenothera and Rhodiola extracts attenuated delta and theta power, probably related to interference with the cholinergic and norepinephrinergic transmission, respectively. Using discriminant analysis for comparison with reference pharmaceutical and botanical drugs, Rhodiola projected near the position of Ginkgo extract, whereas Oenothera extract was projected near the position of Tramadol, an analgesic drug. Physical motion was increased only in the presence of Paullinia extract and caffeine. Increases of long-term potentiation were observed in the presence of Rhodiola extract, Paullinia extract and caffeine. The combined information predicts stimulant and cognitive function-enhancing activities in humans for the Rhodiola extract, which could also be used as a possible caffeine-replacement, and antidepressant and analgesic activity for the Oenothera extract.

Ethnopharmacological relevance The endemic succulent South African plant, Sceletium tortuosum (L.) N.E. Br. (synonym Mesembryanthemum tortuosum L.), of the family Mesembryathemaceae, has an ancient oral tradition history of use by San and Khoikhoi people as an integral part of the indigenous culture and materia medica . A special standardized extract of Sceletium tortuosum (Zembrin®) has been developed and tested pre-clinically in rats, and clinically in healthy subjects. Aim of the study The present investigation aimed at the construction of electropharmacograms of Zembrin® in the presence of three dosages (2.5, 5.0 and 10.0 mg/kg), and comparative electropharmacograms and discriminatory analyses for other herbal extracts, citicoline and rolipram. Material and methods Seventeen adult Fischer rats were each implanted with a set consisting of four bipolar concentric steel electrodes fixed by dental cement and three screws driven into the scalp. After two weeks of recovery from surgery the animals were adapted to oral administration by gavage and to experimental conditions (45 min pre-drug period and 5 h of recording after a rest of 5 min for calming down). Data were transmitted wirelessly and processed using a Fast Fourier Transformation (FFT). Spectral power was evaluated for 8 frequency ranges, namely delta, theta, alpha1, alpha2, beta1a, beta1b, beta2 and gamma power. Results Zembrin® dose dependently attenuated all frequency ranges, to varying degrees. The most prominent was the statistically significant reduction in alpha2 and beta1a waves, correlated with activation of the dopaminergic and glutamatergic transmitter systems respectively. This feature is common to all synthetic and herbal stimulants tested to date. The second strongest effects were reduction in both the delta and the theta frequency ranges, correlated with changes in the cholinergic and norepinephrine systems respectively, a pattern seen in preparations prescribed for neurodegenerative diseases. Theta wave reduction in common with the delta, alpha2 and beta1 attenuation has been noted for analgesic drugs. Attenuation of alpha1 waves emerged during the highest dosage in all brain areas, a feature seen in all antidepressants. Discussion The electropharmacogram of Zembrin® was compared to the electropharmacograms of herbal extracts archived in our database. Extracts of Oenothera biennis and Cimicifuga racemosa gave a very similar electropharmacograms to that of Zembrin®, and extracts of Ginkgo biloba and Rhodiola rosea gave rather similar electropharmacograms to Zembrin®. Linear discriminant analysis confirmed these similarities and demonstrated that all three dosages of Zembrin® plotted in close neighbourhood to each other. Citocoline, a synthetic compound originally developed for cognitive enhancement, had a similar electropharmacogram to Zembrin®. Similarity to the electropharmacograms of the synthetic phosphodiesterase-4 inhibitor, rolipram, suggests Zembrin® has antidepressant and cognitive function enhancing potential. Conclusion The combined results from the electropharmacograms and comparative discriminatory analyses suggest that Zembrin® has dose dependent activity, with potential applications as a cognitive function enhancer, as an antidepressant, and as an analgesic.

The endemic South African succulent plant Sceletium tortuosum (L.) N.E. Br., family Mesembryathemaceae, is known as kanna in Nama, kougoed in Afrikaans, and sceletium in English. The plant has been used as a tea and as a masticatory for millennia by indigenous San hunter-gatherers and Nama pastoralists for endurance and well-being. It has been reported that the plant “gives strength to their limbs, and takes away pain, and makes their memory strong”. The current investigation aimed at the psychophysiological characterization of 25.0 and 50.0 mg of a special extract marketed as Zembrin® in comparison to placebo using a new methodology called “EnkephaloVision”. This combination of EEG Neurocode-Tracking and Eye-Tracking allows for concomitant analysis of time epochs of only 364 ms duration. Spectral EEG analysis during cognitive and emotional challenges revealed statistically significant increases of delta (p < 0.01 during arithmetic calculation and watching a boring animal video) and theta spectral power (p < 0.10 during these same challenges) in the presence of Zembrin® within the frontal brain. It is these same increases of slow waves in the frontal brain that are described in the literature during performance of mental tests. This indicates a positive effect of Zembrin® on the electrical activity of the brain during cognitive processing. In addition, alpha1 and alpha2 spectral power in the frontal brain was increased during several challenges including brain teasing, arithmetic calculations and performance of a memory test. From the literature, increases of spectral alpha1 power indicate a greater degree of calmness and may represent decreased depressive symptoms, while increases in alpha2 waves have been related to memory. Beta2 waves increased during mental performance in the presence of the higher dosage of Zembrin® in parietal, occipital and temporal brain regions. In comparison to placebo, Zembrin® induced frequency changes in the brain, which have been related to enhanced attention and memory. These results may represent a positive action of Zembrin® on cognitive and emotional processes in the brain.

A hydroethanolic extract (20% V/V) from Herba Sideritis scardica has been recognized to positively influence cognition. The present investigation aimed at the question if this extract would be able to modify intra-hippocampal communication after oral administration of 100 mg/kg daily for one week. The glutamatergic synapse between Schaffer Collaterals and pyramidal cells can be tested by electric stimulation using single pulses or theta burst stimulation. The resulting population spike is modulated by compounds acting at the central nervous system or other preparations directly or as ex vivo approach. In this case the effect of the special extract was tested in vitro the next day after repetitive in vitro administration. Conventional recording technique in the in vitro hippocampus slice revealed an increase of the population spike in the presence of single stimuli and theta burst stimuli resulting in increased long-term potentiation. This effect was tried to modulate by several glutamate receptor antagonists, among them compounds targeting at the ionic NMDA receptor (CGS19755), AMPA receptor (NBQX), Kainate receptor (UBP301) and targeting at three metabotropic glutamate receptors (mGluR I (YM298198), mGluRII ((RS)-APICA)) and mGluRIII (MSOP). Only NBQX was able to prevent the action of the Sideritis scardica extract. Since the AMPA receptor has been related to cognition in several reports in the literature, it is concluded from this result that the positive action of Sideritis scardica extract on brain function involves a modulation of AMPA receptor dependent neurotransmission.

Rhodiola rosea L. roots and rhizome extracts are active ingredients in adaptogenic herbal medicinal products (HMP) and dietary supplements for temporary relief of symptoms of stress, such as fatigue and weakness. R. rosea extract has a stimulating effect on the CNS, suggesting potential benefits on cognitive functions, memory, learning, and attention. The reproducible efficacy and quality of preparations of the underground parts of R. rosea depend on the highly variable content of the active markers, salidroside and rosavin, which affect the quality of HMP and dietary supplements. However, it is not clear which analytical markers are important for assessing the efficacy of R. rosea preparations intended for use in aging-induced mild cognitive disorders, such as attenuated memory, attention, and learning. Furthermore, the activity of various commercial R. rosea extracts has not been correlated with their content. Here, the biological activities of salidroside, rosavin, and seven commercial extracts of underground parts of R. rosea were assessed using a synaptic model of memory: long-term potentiation (LTP) of synaptic transmission in hippocampus slices. A high degree of variation in the content of all active markers was observed. One extract from China lacked rosavin, and there was even variation in the extracts from the Altai geographic region. In vitro, rosavin, salidroside and all tested R. rosea extracts potentiated electric stimulation of an intra-hippocampal electric circuit, which resulted in higher responses of the pyramidal cells in isolated hippocampus slices. Rosavin was more active at higher concentrations than salidroside; while, salidroside was more effective at lower concentrations. The highest content of both active markers was found in the extracts that were active at the lowest concentrations tested; while, some extracts contained some other compounds that presumably reduced the efficacy due to antagonistic interactions. Standardized content of active markers is necessary for the quality control of herbal preparations containing R. rosea extracts, but insufficient for assessment of their potential efficacy. Additional bioassays are needed to assure the reproducible pharmacological activity of R. rosea extracts; therefore, the LTP of synaptic transmission in hippocampus slices may serve as a validation tool for the quality control of R. rosea extracts.

Sceletium tortuosum (Mesembryanthemaceae), a succulent plant indigenous to South Africa. is consumed in the form of teas, decoctions and tinctures and is sometimes smoked and used as snuff. In recent years, Sceletium has received a great deal of commercial interest for relieving stress in healthy people, and for treating a broad range of psychological, psychiatric and inflammatory conditions.The whole extract (Zembrin®) was tested ex vivo in the hippocampus slice preparation after one week of daily oral administration of 5 and 10 mg/kg. Four alkaloids - mesembrine, mesembranol, mesembrenol and mesembrenone - were tested directly in vitro. All four were also tested in the presence of different glutamate receptor agonists.Zembrin® ex vivo as well as all alkaloids in vitro attenuated the amplitude of the population spike during electric stimulation as single shock as well as theta burst stimulation. Only Mesembranol and Mesembrenol having a hydroxyl group at position C6 instead of carbonyl group as in mesembrine and mesembrenone acted by attenuation of AMPA receptor mediated transmission as documented for the whole extract.The current experimental series revealed a new physiological effect of ZembrinWe have discovered a new structure activity relationship for Sceletium alkaloids. Since attenuation of AMPA mediated transmission has been related to successful adjunctive treatment of epileptic patients), Mesembrenol and Mesembranol may serve as new chemical leads for the development of new drugs for the treatment of epilepsy.

Sarizotan 1-[(2R)-3,4-dihydro-2H-chromen-2-yl]-N-[[5-(4-fluorophenyl) pyridin-3-yl]methyl] methenamine, showed an in vivo pharmaco-EEG profile resembling that of methylphenidate which is used in attention deficit/hyperactivity disorder (ADHD). In turn, we tested sarizotan against impulsivity in juvenile rats measuring the choice for large delayed vs. a small immediate reward in a T-maze and obtained encouraging results starting at 0.03 mg/kg (plasma levels of ~11 nM). Results from rats treated neonatally with 6-hydroxydopamine (6-OHDA), also supported anti-ADHD activity although starting at 0.3 mg/kg. However, microdialysis studies revealed that free brain concentration of sarizotan at active doses were below its affinity for 5-HT1A receptors, the assumed primary target. In contrast, electrophysiological experiments in mid-brain Raphe serotonergic cells paralleled by plasma sampling showed that there was ~60 % inhibition of firing rate—indicating significant activation of 5-HT1A receptors—at a plasma concentration of 76 nM. In line with this, we observed that sarizotan concentrations in brain homogenates were similar to total blood levels but over 500 fold higher than free extracellular fluid (ECF) concentrations as measured using brain microdialysis. These data suggest that sarizotan may have potential anti-ADHD effects at low doses free of the previously reported side-effects. Moreover, in this case a classical pharmacokinetic–pharmacodynamic relationship based on free brain concentrations seems to be less appropriate than target engagement pharmacodynamic readouts.

Background: A quantitative EEG (qEEG) study was performed to investigate the cerebral bioavailability of Silexan. Method: Twenty-four male and female healthy volunteers between 20 and 62 years of age were eligible for participation and received 160 or 80 mg/day Silexan or placebo in randomised order according to a 3-way crossover design. Treatment phases of 14 days were separated by 14-day washout periods. qEEG recordings in conditions “eyes open”, “eyes closed”, as well as during performance of 3 different cognitive tasks, were performed at 0, 1, 2, 3, and 4 h after drug administration on the first (single-dose assessment) and last day of each treatment period (repetitive dose assessment). Result: Compared with placebo, qEEG analysis revealed a significant increase of spectral power within two hours in the alpha1 range (7.0 - 9.5 Hz), particularly in the fronto-temporal region, where it was more pronounced after administration of Silexan 160 mg/day than after the 80 mg/day dose. Changes in other frequency bands were mainly attributable to circadian rhythm. No EEG changes typically seen during the investigation of sedative drugs (general theta increase) were observed. Cognitive task performance under both doses of Silexan was not inferior compared with that in the placebo period. Conclusions: The study provides evidence that ingredients of the anxiolytic lavender oil preparation Silexan penetrate the blood-brain barrier and induce functional changes in the CNS. The types of changes observed in the qEEG are consistent with the anxiolytic clinical effect of the drug represented by increases of alpha1 spectral power. No sedative effects were observed. Silexan was well tolerated during repetitive administration of doses up to twice the marketed dose.

The term “neuromarketing” suggests a combination of marketing research and brain research. Within marketing research, objective assessment of TV commercials is performed by use of Eye-Tracking devices. Brain research has been dominated by NMRI technologies during the last years. However, information content and time resolution are much better when monitoring electric activity by spectral analysis. The current experimental approach was initiated in order to test the combination of a newly developed EEG technology (Neurocode-Tracking) with commercially available Eye-Tracking. Ten male subjects were exposed to a reference recording condition (watching a fixed cross on the screen) followed by 5 TV commercials representing 5 different banks. Video films obtained from Eye-Tracking (so-called heat maps) were synchronized with the results of Neurocode-Tracking in form of a second video with a time resolution of 364 ms per image. Spectral power analysis of the EEG in different brain regions allowed for assessment of single scenes for cognitive and emotional responses. Averaging of data over the whole time course gave information on mental activation, attention, visual perception, memory, pleasure and tension. Comparison of the 5 commercials to reference recording revealed the clip of the Targo-Bank having the highest values with respect to mental activation and attention.These experiments have proven that the combination of Neurocode-Tracking with Eye-Tracking can be successfully used in advertisement research and gives valid information on individual as well as group dependent cognitive and emotional responses leading to objective assessment of TV commercials.

Quantitative assessment of local field potentials by means of Fast Fourier Transformation (FFT) results in the so-called power density spectrum. Within this spectrum particular frequency ranges are defined in order to relate these to behavior. Frequencies above 35 Hz are generally labeled as gamma oscillations, especially as low gamma (40 - 55 Hz) or high gamma (70 - 100 Hz). In order to learn more about this feature, we implanted a set of 4 bipolar concentric steel electrodes in frontal cortex, hippocampus, striatum and midbrain reticular formation of 10 rats. After recovery, field potentials were recorded and wirelessly transmitted to our computer for frequency analysis. At the same time, motion was registered during the whole experimental period of 5.75 hours. Results revealed that low gamma activity only emerged when the animal moved—at least his head. FFT of the data showed—besides other frequencies—a slow gamma activity peaking around 47 Hz pre-dominantly within the striatum, less in frontal cortex and reticular formation and nearly none in the hippocampus. Spectral analysis was performed for single epochs of 4 seconds and all 15 minutes intervals. Correlation analysis of these intervals was done to motion data. All rats showed a highly significant correlation between gamma activity and movement. We therefore conclude from these experiments that this slow gamma activity of the field potentials is not only related to movement, but possibly part of the general neuronal coding of movement.

Information processing within the brain relies on electro-chemical features. Electric events are accessible by recording of the EEG. These electric oscillations might be regarded as a neuronal code carrying information on important motor, cognitive and emotional events. A new approach of quantitative assessment of very short time epochs of 364 ms has been developed on the base of particularly defined frequency ranges and called “Neurocode-Tracking”. The new method was technically validated by the use of a signal generator and was found to correspond to classical quantitative EEG analysis except for some smudging during the transition from one frequency range to the next. Real data from a subject were obtained during relaxation and performance of three mental tasks. Data were time averaged for 180 s using the classical method and compared to data averaging during 16.4 s. Results were nearly identical with respect to spectral signatures showing the expected midline frontal theta increases during performance of three cognitive tests but not during relaxation. Collection of very short time epochs of 728 ms duration confirmed task dependent frontal theta increases, most prominent during calculation performance test (CPT), less during d2-concentration and memory test, none during relaxation. Finally, the new technique was combined with eye-tracking. Capture of the EEG mapping video of Neurocode-Tracking and synchronization with the gaze overlay video by starting recording with an audio signal (gong) allowed a match of gazes precisely with the corresponding electric events. Use of this technical combination in research will hopefully lead to a new understanding of spectral signatures of electric activity called enkephaloglyphs.

It has been suggested that in patients with Parkinson’s disease (PD) metabolism of the MAO-B inhibitor selegiline to methamphetamine may contribute and/or exacerbate sleep problems, possibly leading to deficits of cognition. This open-label exploratory study included 30 PD patients currently being treated with selegiline (7.5 mg/day) and complaining of sleep disturbances. The aim of the study was to determine whether switching from selegiline to another MAO-B inhibitor without amphetamine-like metabolites, namely rasagiline, would improve sleep behaviour and cognitive function in PD patients. Pathologic aberrations as determined by comparison of the frequency pattern of patients to a database consisting of healthy subjects revealed an approximation of electric brain activity to normality. For verification of efficacy, a combination of questionnaires, quantitative source density EEG recording with CATEEMo and performance of two psychometric tasks (d2-test of attention and reading) during the EEG recording were done on the last day of selegiline treatment (7.5 mg/day) as well as 2 and 4 months later, during which the patients were treated with rasagiline (1 mg/day). In addition, performance of the mental tasks revealed a statistically significant (p < 0.05) increase of theta power (4.75 - 6.75 Hz) indicative of improved cognitive abilities at the end of the treatment period. At the same time evaluation of the psychometric test results indicated a statistical improvement with respect to the score of the d2-test (increase from 6.54 to 7.37; p < 0.05). Serum levels of methamphetamine were measured before and after intake of selegiline or rasagiline. They were correlated to alpha2 power, which is under dopaminergic control, within the temporal lobe. From these results it is concluded that the switch from selegiline to rasagiline not only improved sleep behaviour as reported separately but also had a positive effect on electric brain activity and on cognition in these patients.

Mild cognitive impairment is sometimes regarded as related to aging. However, statistically every second case turns into full dementia, which still is resistant to any treatment. It is therefore desir-able to recognize deviations from normality as early as possible. This might be feasible by using quantitative EEG analysis in the presence of mental work. The present retrospective data analysis revealed a new quantitative biomarker indicating the degree of impairment. Current source density was calculated from 16 channel EEG using CATEEM software. Four different conditions were analyzed: relaxed state, performing a d2-concentration test, a calculation performance test and a memory test for 5 min each. Subjects older than 40 years were divided into two groups according to their DemTect score: 13 - 18 (HC; n = 44) or 8 - 12 (MCI; n = 45). Spectral power was chopped into six frequency ranges (delta, theta, alpha 1, alpha 2, beta 1 and beta 2). Average spectral power was enhanced in the MCI group in comparison to healthy subjects with respect to delta (p = 0.05) during relaxed state when all electrode positions were regarded. With respect to EEG recording during performance of three different psychometric tests it was recognized that mainly spectral changes during performance of the d2-concentration test were related to mild cognitive impairment. With regard to all electrode positions statistically significantly lower spectral power values were reached during the d2-test for delta (p = 0.001), theta (p = 0.0001) and alpha 1 waves (p = 0.08) in impaired subjects in comparison to healthy subjects. Regarding regions of interest increases of delta and theta power were seen in the fronto-temporal brain during performance of the d2-concentration test. These increases disappeared when looking at MCI data. In the centro-parietal region decreases of alpha and beta 1 power emerged, which were even larger in MCI subjects. No MCI-dependent changes were observed in the other two tests. A correlation was found between psychometric performance of the d2-test and the DemTect score (r = 0.51). MCI subjects had statistically significant worse performance in all three mental challenges in comparison to healthy volunteers. It is concluded that MCI can be characterized at an early stage by EEG recording in the relaxed state. High spectral delta and theta power in general and specifically at fronto- temporal electrode positions (especially at T3) was recognized as a biomarker for MCI. A DemTect score of 8-12 was validated as indicative for MCI.

Different behavioral states are characterized by distinct patterns of global brain activity. Therefore, the biological effects of herbal extracts on brain functions can be assessed by analyzing the local field potentials, the so-called electropharmacogram analysis. Inspired by our recent findings that a specified oregano extract (OE) exhibited a triple-reuptake activity in vitro, this extract was tested in model of Tele-Stereo-electroencephalogram (EEG) to elucidate how OE affects the electrical brain activity in freely moving rats. Furthermore, discriminant analysis was performed to compare the electric brain activity of four standardized brain regions with those produced by several reference compounds, representing a whole variety of clinical indications. Oral intake of OE produced fast and robust dose and time dependent EEG alterations consisting of significant changes of spectral power in comparison to controls. Strongest effects were seen with respect to alpha1, alpha2 and beta1 waves representing an activation of serotonergic, dopaminergic and glutamatergic neurotransmission, respectively. Moreover, the discriminant analysis revealed that OE’s pattern of activity locates in close vicinity to antidepressant and neuroprotective compound. The presented data support the hypothesis suggesting the use of OE as a neuroprotective dietary supplement to promote mood, motivation and mental wellbeing.

Pascoflair? 425 mg is a herbal drug based on Passiflora incarnata dry extract and is registered in different countries for the treatment of nervous restlessness and anxiety and also as an aid to sleep. The study was initiated for the quantitative assessment of the effect of this preparation on brain electric activity and cognition in human volunteers. Quantitative electroencephalographic current source density (CSD) from 16 healthy male and female human volunteers (average age 49 years) was used in a randomized, placebo-controlled crossover study. Data were taken 0.5, 1.5, 3 and 4 hours after administration of the preparations under the conditions of 6 minutes eyes open, 5 minutes d2 concentration test, mathematical calculation test and memory test respectively. During mental load, changes in spectral band power were used to analyse drug-induced effects. All variables were fed into a linear discriminant analysis (LDA) for comparison with other drug profiles. Spectral power in the delta and theta range was significantly attenuated at 3 and 4 hours after administration in comparison with the time-dependent increase normally observed due to circadian rhythm. Discriminant analysis revealed a difference to placebo for all recordings as early as 30 minutes after intake of 3 coated tablets of Pascoflair? 425 mg. Using LDA data location within the poly-dimensional space, verum was projected into the area of the effects of Gingko/Ginseng as reference drugs tested earlier under identical conditions. Psychometric performance was not disrupted. Pascoflair? 425 mg can be regarded as a well characterized plant-derived drug with anxiolytic and calming properties without negative sedative and cognition-attenuating side effects. Current results document the effecttiveness of the preparation as early as after 30 minutes. In addition, they indicate persistence of good mental performance for hours. Trial registration: the study has been registered at ClinicalTrials.gov under NCT01047605.

This study aimed at using quantitative assessment of human electric brain activity during mental work for determining acute effects of ingested oat herb extract on cognitive performance.Within a double-blind, randomized, placebo-controlled crossover study, two dosages of a special oat preparation of Avena sativa herba (1250 or 2500 mg of Neuravena®) were compared to placebo. An electroencephalogram was recorded while the patient had eyes open for 6 minutes, eyes closed for 4 minutes, performance of a concentration test (d2) for 5 minutes, and performance of mental arithmetic (KLT) for 5 minutes. Source density was calculated and spectral frequency changes were averaged to give one value for each frequency range.Using quantitative brain mapping technology (CATEEM®), main effects were observed in the left frontotemporal area, known to be involved in cognitive tasks. Statistically significant differences were observed during resting (lowering of spectral δ power) and during performance of the d2-concentration test (enhancement of spectral θ power) (p 0.01 and p 0.05, respectively). Also, during performance of mental arithmetic, greater enhancement of θ power was observed but only at a lower error probability (p = 0.115). No effects could be seen using the P300 paradigm during presentation of a visual stimulus.These changes suggest that oat herb extract might be effective in healthy subjects, resulting in a positive impact on cognitive performance.

Background: Rasagiline and selegiline are classified as monoamine oxidase B (MAO-B) inhibitors. The present investigation deals with time-dependent electrical frequency changes (electropharmacograms) induced by these, as well as by aminoindan, the major metabolite of rasagiline. Method: Adult rats (day-night converted, >5 months old) were fitted with 4 bipolar concentric steel electrodes connected to a small base plate, which was positioned stereotactically for insertion of the electrodes into the frontal cortex, hippocampus, striatum and reticular formation. The plate carried a small plug to receive a telemetric device during the experimental session. Changes in field potentials were recorded during a pre-drug reference period of 45 min, followed by intraperitoneal administration and 5 h of recording thereafter. Data were transmitted wirelessly for frequency analysis. Data from 10 animals treated within a crossover design were averaged. Results: A dose of 0.25 mg/kg i.p. rasagiline produced statistically significant decreases in spectral alpha2 and beta1 power. Higher dosages showed a linear enhancement of this effect. A similar pattern was obtained after administration of aminoindan (2–10 mg/kg), but of shorter duration. Selegiline produced a similar pattern only for the first 1–2 h. After this, statistically significant increases in delta and theta power were observed. Conclusion: Despite the feature of MAO-B inhibition in both drugs and its reflection in the initial changes of the frequency pattern during the first hour, the pharmacological action of selegiline during the following hours differs profoundly from that of rasagiline, presumably due to the toxicity of its major metabolites methamphetamine and amphetamine.

Background: Particular frequencies of electropharmacograms have been attributed to cholinergic, noradrenergic or dopaminergic mediated neurotransmission. This investigation deals with changes induced by L-DOPA or dopamine D2 receptor agonists. Method: Adult rats (day-night converted) were instrumented with four bipolar concentric semi-micro-electrodes into the frontal cortex, hippocampus, striatum and reticular formation. Field potentials were recorded during a pre-drug reference period followed by 4 h of recording thereafter. Data were transmitted wirelessly for spectral frequency analysis. Results: At low doses of L-DOPA (1–5 mg kg–1) and of the D2 agonists talipexole and quinpirole (0.1 mg kg–1), a delayed increase of delta and theta power was observed. Higher doses led to immediate stable decreases of alpha1, alpha2 and beta1 power as reported for dopamine D1 receptor agonists. Administration of the D2 blocker sulpiride (10–20 mg kg–1) resulted in increases of alpha2 power. Conclusion: A common denominator for changes of dopaminergic transmission could be seen in immediate changes of spectral alpha2 power. Delayed increases of delta and theta activity after low dosages of the medication are considered to originate from heterosynaptic, presynaptic D2 receptors sitting on cholinergic neurons. This pattern could explain daytime tiredness or sudden sleep attacks in Parkinson patients.

a Departement fur Innere Medizin, Institut fur Naturheilkunde, UniversitatsSpital Zurich, Schweiz, b Universitatsklinik fur Psychiatrie und Psychotherapie, Medizinische Universitat Wien AKH, Osterreich, c Justus-Liebig-Universitat Giesen, c/o NeuroCode AG, Wetzlar, Deutschland, d Klinik fur Alterspsychiatrie, Gerontopsychiatrisches Zentrum Hegibach, Psychiatrische Universitatsklinik Zurich, Gartentherapeut, Zurich, f Institut fur komplementare und integrative Medizin, Universitatsspital Zurich, Schweiz, Universitares Cancer Center Hamburg, Deutschland, h Sudtiroler Sanitatsbetrieb, Gesundheitsbezirk Meran, Dienst fur Komplementarmedizin, Meran, Italien, i Gesundheitszentrum Zurich-Oerlikon, Zurich, Schweiz, j Lehrstuhl fur Pharmazeutische Chemie, Institut fur Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universitat Wurzburg, Deutschland

Antimuscarinic compounds are increasingly used to treat the symptoms of overactive bladder; however, their use is often restricted by peripheral adverse effects (AEs). On the other hand, data regarding their influence on the central nervous system (CNS) are limited. This randomized, single-blind, parallel-group quantitative-topographical EEG (qEEG) study of clinical phase I investigates the potential CNS adverse effects of the three antimuscarinic drugs--tolterodine, oxybutynin, and trospium chloride--in comparison to placebo. Overall, 4 x 16 (total 64) young, healthy male volunteers were included in the study. The subjects were given either placebo or the clinically recommended daily doses of the drugs dispensed in three doses on a single day (tolterodine 2 mg bid and once placebo, total 4 mg/d; oxybutynin 5 mg tid, total 15 mg/d; and trospium chloride 15 mg tid, total 45 mg/d). The qEEG was recorded prior to and up to 4 hours after each intake of the trial medication (a total of 10 qEEG sessions) under three different conditions: at rest with eyes open, eyes closed, and under mental demand. The drug tolerability was subjectively evaluated by the volunteer and the investigator. In comparison to placebo (10% confidence interval), tolterodine and trospium chloride did not induce changes of the qEEG power in five of the six frequency bands (i.e., delta, alpha 1, alpha 2, beta 1, and beta 2). Isolated power decreases were only observed in the theta frequency band. In contrast, oxybutynin caused significant power reductions in four frequency bands (theta, alpha 1, alpha 2, and beta 1; p < 0.01). The subjectively evaluated drug tolerability was comparable between all treatment groups, although differences in the AE occurrence existed, with the AE frequency being higher in the oxybutynin group. The results of this study support the findings that oxybutynin as a tertiary amine crosses the blood-brain barrier, causing significant qEEG activity changes and more pronounced central adverse effects. Although tolterodine is also a tertiary amine, it shows limited effects on qEEG activity (i.e., slight theta power reductions), comparable to the effects of trospium chloride, a quarternary amine, which barely crosses the blood-brain barrier. The minimal qEEG changes observed with tolterodine and trospium chloride reflect most probably a rebound message from the peripheral target organs. Prescription of oxybutynin thus implicates a higher risk of CNS side effects.

The aim of this randomized, double-blind, placebo-controlled 16-week study was to investigate the clinical efficacy of cyclandelate (Natil, 1,600 mg/day) in 139 adult outpatients with cognitive impairment (70 allocated to cyclandelate; 69 to placebo). Quantitative-topological EEG, event-related potentials (P300) and psychophysiological interview-based rating scales were used. The efficacy of cyclandelate was demonstrated in the confirmatory statistical sense using a global Hailperin-Ruger test on 10 predefined primary variables at global significance level of 0.05 relating to psychopathology, psychometry, neuropsychophysiology and behavior. At psychopathological and behavioral level the reduction of the total scores of the rating scales (Alzheimer Disease Assessment Scale, Sandoz Clinical Assessment Geriatric Scale, and Nurnberger Selbsteinschatzungs-Liste) following a 16-week therapy revealed also an individual significant cyclandelate-placebo distinction in the confirmatory statistical sense. A difference between verum and placebo was also observed by the increase of the number of correct answers during performance of the number symbol test (psychometrical level). The objective electrophysiological data (neuropsychophysiological level) support these findings. Of particular interest is that following cyclandelate treatment the absolute theta power remained almost unchanged and an increase of P300 amplitude was observed. At the same time placebo led to a distinct theta power increase and a decrease of P300 amplitude, which was interpreted as the reflection of an impairment of the initial clinical state. Summarizing, cyclandelate proved to be efficacious compared to placebo in patients with mild to moderate cognitive impairment.

We conducted in vitro studies to clarify the possible involvement of GABA A receptor-mediated processes in the anticonvulsant effects of losigamone and its optical isomers AO-242 (+losigamone) and AO-294 (-losigamone). In binding experiments with cortical and cerebellar membrane preparations of rat brain, ≤100 μM losigamone did not affect the specific binding of [ 3 H]GABA, [ 3 H]flunitrazepam, or [ 35 S]t-butyl-bicyclophosphorothionate (TBPS) to their receptors. Losigamone, however, in concentrations of 10 -8 -10 -5 M, stimulated 36 Cl influx into spinal cord neurons in the absence of exogenous GABA. This effect was inhibited by the GABA antagonists bicuculline (BIC) and picrotoxin (PIC). Losigamone 10 -5 M potentiated the effect of a suboptimal concentration of exogenous GABA 10 -5 M on 36 Cl influx. Both isomers of losigamone likewise stimulated 36 Cl influx into spinal cord neurons, and these effects were similarly antagonized by BIC and PIC. Losigamone and its optical isomers AO-294 and AO-242 antagonized potassium-induced hyperexcitability in rat hippocampal slices concentration dependently. There were no clear differences in the potencies of losigamone, AO-242, or AO-294. However, AO-294 and AO-242 differed significantly in their ability to suppress TBPS-induced hyperexcitability of hippocampal slices. Such observations demonstrate that although losigamone does not bind to GABA, benzodiazepine (BZD) or PIC binding sites of the neuronal chloride channel, it is capable of stimulating 36 Cl influx in the spinal cord neurons by a GABA-sensitive mechanism and at a side distant from the GABA channel.

Psychiatric patients often suffer from stress, anxiety and depression. Various plant extracts are known to fight stress (valerian), anxiety (passion flower) or depression (St. John's wort). NEURAPAS® balance is a mixture of these three extracts and has been designed to cover this complex of psychiatric conditions. The study was initiated to quantitatively assess the effect of this combination on brain electric activity. Method Quantitative electroencephalogram (EEG) current source density (CSD) recording from 16 healthy male and female human volunteers (average age 49 years) was used in a randomized, placebo-controlled cross over study. Recordings were performed 0. 5, 1. 5, 3 and 4 hours after administration of the preparations under the conditions of 6 min eyes open and 5 min d2 concentration test, mathematical calculation test and memory test, respectively. All variables (electric power within 6 frequency ranges at 17 electrode positions) were fed into a linear discriminant analysis (eyes open condition). In the presence of mental load these variables were used to construct brain maps of frequency changes. Results Under the condition of mental load, centro-parietal spectral power remained statistically significantly lower within alpha1, alpha2 and beta1 frequencies in the presence of verum in comparison to placebo. Discriminant analysis revealed a difference to placebo 3 and 4 hours after intake of 6 tablets of NEURAPAS® balance. Data location within the polydimensional space was projected into the area of the effects of sedative and anti-depressive reference drugs tested earlier under identical conditions. Results appeared closer to the effects of fluoxetine than to St. John's wort. Conclusions Analysis of the neurophysiological changes following the intake of NEURAPAS® balance revealed a similarity of frequency changes to those of calming and anti-depressive drugs on the EEG without impairment of cognition. Trial registration ClinicalTrials.gov: NCT01047605

In order to be able to test single constituents of herbal plant extracts with respect to possible clinical usefulness, the model of local field potential analysis leading to the so-called electropharmacogram has been successfully used in rats to classify the effects of theanine and theogallin in the past. The present investigation aims at the prediction of efficacy and possible mechanisms of action of rutin and quercetin. Adult rats (day-night converted) were instrumented with four bipolar concentric electrodes into the frontal cortex, hippocampus, striatum and reticular formation. Field potentials were recorded during a pre-drug reference period of 45 min followed by oral administration of the particular test compound and 4h recording thereafter. Data were transmitted wirelessly to the computer for spectral frequency analysis. Rutin (5-80 mg/kg) as well as quercetin (5-40 mg/kg orally) produced similar electropharmacograms with dose dependent decreases of spectral alpha2 and beta1 frequencies within all brain areas. Peak effects were reached 4h after administration. The pattern of changes approached that obtained after 2.5mg/kg of moclobemide during the first hour as revealed by discriminant analysis in comparison to a large matrix of other drugs with known clinical indications. Data suggest antidepressant capabilities for rutin and quercetin with inhibition of monoamino oxidase at least as part of the mechanism of action. Both compounds should be tested clinically in patients with symptoms of depression.