Effects of Red and White Ginseng Preparations on Electrical Activity of the Brain in Elderly Subjects: A Randomized, Double-Blind, Placebo-Controlled, Three-Armed Cross-Over Study.

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 ß2 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.

Effects of an Adaptogenic Extract on Electrical Activity of the Brain in Elderly Subjects with Mild Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled, Two-Armed Cross-Over Study.

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® 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® 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® Forte significantly improved cognitive performance in the d2-Test for attention and the concentration performance test after four weeks' treatment, and was positively correlated with increases in δ and θ power in the quantitative EEG compared with placebo during cognitive challenges. CONCLUSION: The results of this study suggest that Adaptra® Forte exhibits a calming and anxiolytic effect without sedation, and is associated with overall stress-protective activity.

Assessing the Quality and Potential Efficacy of Commercial Extracts of Rhodiola rosea L. by Analyzing the Salidroside and Rosavin Content and the Electrophysiological Activity in Hippocampal Long-Term Potentiation, a Synaptic Model of Memory.

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.

Effect of Zembrin® and four of its alkaloid constituents on electric excitability of the rat hippocampus.

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.

Electropharmacogram of Sceletium tortuosum extract based on spectral local field power in conscious freely moving rats.

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 5h 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.

Effects of sarizotan in animal models of ADHD: challenging pharmacokinetic-pharmacodynamic relationships.

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 Raphé serotonergic cells paralleled by plasma sampling showed that there was ~60% inhibition of firing rate­indicating significant activation of 5-HT1A receptors­at 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.

Pharmacological classification of herbal extracts by means of comparison to spectral EEG signatures induced by synthetic drugs in the freely moving rat.

Herbal extracts targeting at the brain remain a continuous challenge to pharmacology. Usually, a number of different animal tests have to be performed in order to find a potential clinical use. Due to manifold possibly active ingredients biochemical approaches are difficult. A more holistic approach using a neurophysiological technique has been developed earlier in order to characterise synthetic drugs. Stereotactic implantation of four semi-microelectrodes into frontal cortex, hippocampus, striatum and reticular formation of rats allowed continuous wireless monitoring of field potentials (EEG) before and after drug intake. After frequency analysis (Fast Fourier Transformation) electric power was calculated for 6 ranges (delta, theta, alpha1, alpha2, beta1 and beta2). Data from 14 synthetic drugs - tested earlier and representative for different clinical indications - were taken for construction of discriminant functions showing the projection of the frequency patterns in a six-dimensional graph. Quantitative analysis of the EEG frequency pattern from the depth of the brain succeeded in discrimination of drug effects according to their known clinical indication (Dimpfel and Schober, 2003). Extracts from Valerian root, Ginkgo leaves, Paullinia seed, Hop strobile, Rhodiola rosea root and Sideritis scardica herb were tested now under identical conditions. Classification of these extracts based on the matrix from synthetic drugs revealed that Valerian root and hop induced a pattern reminiscent of physiological sleep. Ginkgo and Paullinia appeared in close neighbourhood of stimulatory drugs like caffeine or to an analgesic profile (tramadol). Rhodiola and Sideritis developed similar frequency patterns comparable to a psychostimulant drug (methylphenidate) as well to an antidepressive drug (paroxetine).

Effect of Neurexan on the pattern of EEG frequencies in rats.

BACKGROUND: Various medications of natural origin have effectively treated stress-related disorders, such as sleep disturbances and agitated conditions. The efficacy of Neurexan, a multicomponent, low-dose medication, has been demonstrated in observational studies, but its exact mechanism of action has not been determined. METHODS: To characterize the effects of Neurexan on the central nervous system, we analyzed the spectral frequencies of field potentials in four rat brain areas after a single oral administration of Neurexan. Different doses of Neurexan were tested within a crossover design, and effects were compared with vehicle control. RESULTS: Significant effects were observed with 0.5 tablets of Neurexan, predominantly on δ- and θ-waves in the frontal cortex and reticular formation (P < 0.01). In the reticular formation, significant changes of δ- and θ-waves occurred as early as during the first hour after administration. The time course revealed a significant and longer-lasting increase of δ- and θ-waves in the frontal cortex and reticular formation, whereas other spectral frequencies were only transiently affected in the frontal cortex, reticular formation, and striatum. CONCLUSION: In conclusion, this study demonstrated that the low-dose medication Neurexan influences central nervous system activity in rats. The resulting electroencephalographic profile of Neurexan shows several similarities with those of other calming agents, such as Valeriana and Passiflora, suggesting a potential benefit of Neurexan for patients with stress-related disorders. Moreover, this report demonstrates that electroencephalographic signatures are also valid biomarkers for the assessment of low-dose medications, such as Neurexan.

Early effect of NEURAPAS® balance on current source density (CSD) of human EEG.

UNLABELLED: 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.

Ingested oat herb extract (Avena sativa) changes EEG spectral frequencies in healthy subjects.

OBJECTIVE: 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. DESIGN: 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. RESULTS: 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. CONCLUSIONS: These changes suggest that oat herb extract might be effective in healthy subjects, resulting in a positive impact on cognitive performance.

Electropharmacograms of rasagiline, its metabolite aminoindan and selegiline in the freely moving rat.

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.

Rat electropharmacograms of the flavonoids rutin and quercetin in comparison to those of moclobemide and clinically used reference drugs suggest antidepressive and/or neuroprotective action.

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.

Sleep improving effects of a single dose administration of a valerian/hops fluid extract - a double blind, randomized, placebo-controlled sleep-EEG study in a parallel design using electrohypnograms.

Repetitive administrations of valerian/hops combinations have been widely used for self-administered therapy of sleep disturbances. This investigation focuses on the question if a single administration can be an effective sleep aid. Two parallel groups of n = 20 (verum) and n = 22 (placebo) were tested. Each subject spent two consecutive nights in the lab (reference night and medication night). Medication consisted in giving verum or placebo to poor sleepers identified by a validated sleep questionnaire (Schlaffragebogen SF-B). Two ml of the liquid ex?tract or similar smelling placebo were diluted in 50 ml water (flavoured with honey) and administered 15 minutes before EEG recording during the medication night. The data analysis is based on the electrohypnogram - a method derived from a validated computer assisted automatic analysis for depth of sleep. Differences between the reference nights and medication nights were evaluated and tested for significance. Time spent in sleep (values of the sleep frequency index "SFx" of the electrohypnogram of 74% or lower) was significantly higher for the verum group in comparison to the placebo group (p<0.01). The difference with respect to time spent in deeper sleep (i.e. 68% and lower or 62% and lower) between reference and medication night was also statistically significant at p<0.01. This parameter correlated with the difference in quality of sleep between the two consecutive nights as derived from the sleep inventory SF-A sub-score (subjects evaluation) with r = 0.48 at p<0.0001. The EEG derived parameter "sleep quantity" as calculated from the electrohypnogram proved superiority of the valerian/hops combination over placebo. Thus, the present investigation has shown evidence that a valerian/hops fluid extract can be used successfully using a single administration.

Pharmacological modulation of dopaminergic brain activity and its reflection in spectral frequencies of the rat electropharmacogram.

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.

Theogallin and L-theanine as active ingredients in decaffeinated green tea extract: II. Characterization in the freely moving rat by means of quantitative field potential analysis.

The model Tele-Stereo-EEG (continuous recording of intracerebral field potentials in the freely moving rat to produce an electropharmacogram) has been used to see if L-theanine- and theogallin-enriched decaffeinated green tea extract would change electrical brain activity after oral administration, to provide proof of access of active components to the brain via the blood-brain barrier. Baseline recording (45 min) was followed by a 5-h recording session after oral ingestion of the extract or single components: L-theanine, theogallin and quinic acid, a suggested metabolite of theogallin. Power spectra from Fast Fourier Transformed (FFT) field potential changes were divided into six frequency bands (delta, theta, alpha1, alpha2, beta1 and beta2). No effects could be measured using a saline solution for control purposes. Oral administration of 75 mg kg(-1) total extract led to power decreases mainly in delta and alpha2 frequencies during the first hour. This pattern has been observed in the presence of stimulatory synthetic compounds. Oral administration of 30 mg kg(-1) L-theanine led to power decreases of nearly all frequencies, being more pronounced during the second and following hours in comparison with the first hour. Ingestion of 20 mg kg(-1) theogallin also showed a power decreasing effect on cortical activity. Its possible metabolite quinic acid (10 mg kg(-1), p.o.) also produced decreases in delta, alpha2 and beta1 frequencies. Measurement of motion resulted in an increase during the first hour in the presence of theogallin and L-theanine. A tendential decrease was observed in the presence of L-theanine during the last hour at its presumably highest plasma levels. The results with the administration of the total extract provided evidence for the maior involvement of L-theanine and theogallin (or its presumable metabolite quinic acid) in its action, since no other active compounds were present in the extract. These compounds could be classified by comparison with reference drugs using discriminant analysis as being antidepressive and cognition enhancing, respectively. The extract appeared among those drugs having stimulatory effects.

Theogallin and L-theanine as active ingredients in decaffeinated green tea extract: I. electrophysiological characterization in the rat hippocampus in-vitro.

The in-vitro hippocampus slice preparation was used to mimic a physiological situation where nervous tissue is exposed directly to the water soluble extract of green tea and some of its constituents. This investigation provides evidence that L-theanine- and theogallin-enriched decaffeinated green tea extract is able to change the physiological pattern of electrical hippocampus activity in a concentration dependent manner (EC50 3 mg L(-1)). Of the seven fractions or single components tested (fraction containing all amino acids without L-theanine, fractions containing all amino acids plus L-theanine, glutamic acid, theogallin, its metabolites quinic acid and gallic acid, and L-theanine alone), glutamic acid produced the strongest changes in terms of increased population spike amplitude after single stimuli and increased long-term potentiation, commonly taken as representative for enhancement of spatial and time dependent memory. The presence of theogallin alone shifted the activity in the same direction. Similar results as with theogallin were obtained in the presence of quinic acid. No effect was seen with gallic acid. Opposite changes (decrease of population spike amplitude and attenuated long-term potentiation) were observed in the presence of L-theanine alone. No effects were detected during the addition of the amino acid mixture unless L-theanine was added, leading to a decrease of the responses as observed for the action of L-theanine alone. The results provide evidence for the involvement of several active principles in the action of enriched green tea extract on electrical brain activity. The overall enhancement of hippocampal pyramidal cell responses as observed for the crude extract seems to be due to the combined action of glutamic acid and theogallin (or its presumable metabolite quinic acid), whereas L-theanine seems to have an opposite effect. However, this action was not strong enough to antagonize the effects of glutamic acid and theogallin. The results are in line with the observation that the tested green tea extract improves cognition at concomitant mental relaxation in man.

Different anticonvulsive effects of hesperidin and its aglycone hesperetin on electrical activity in the rat hippocampus in-vitro.

This study investigated the possibility that hesperidin or hesperetin might interact directly with brain matter in a physiological manner. The effects of both compounds were followed in the in-vitro hippocampus preparation by continuous superfusion in a concentration-dependent manner in the presence of single stimuli and theta-burst stimulation of the Schaffer Collaterals. Hesperidin increased the population spike response at a concentration up to 10 microM, especially after induction of long-term potentiation, but attenuated it significantly at higher concentrations of up to 60 microM. Hesperetin only attenuated the response within the same concentration range. Modulation of the pyramidal cell response in the presence of tetraethylammonium (TEA) and pentylentetrazol on one hand and 4-aminopyridine (4-AP) and bicuculline on the other was influenced in a different way. Whereas hesperidin attenuated the response to 4-AP and bicuculline but not to TEA or pentylentetrazol, hesperetin was able to attenuate the response to TEA and pentylentetrazol, but not to 4AP or bicuculline. This feature was reproduced and confirmed ex-vivo after repetitive administration of hesperidin and hesperetin in-vivo for one week (500 mg kg(-1) orally) before in-vitro testing against the challenging effects of 4-AP and TEA. Since the action of hesperidin was sensitive to the presence of iberiotoxin, the involvement of a large conductance calcium-dependent potassium channel might be assumed. In summary, the results provide the possibility for use of both compounds to control pathophysiological disturbances of brain excitability in drug abuse, migraine and epilepsy.

Pharmacological modulation of cholinergic brain activity and its reflection in special EEG frequency ranges from various brain areas in the freely moving rat (Tele-Stereo-EEG).

Due to the electrochemical nature of the communication structure of the brain an intimate relationship between neurotransmitter activity on one side and field potentials (EEG) on the other side can be suspected. In order to learn more about this relationship pharmacological manipulation of the cholinergic transmitter system by means of agonistic and antagonistic receptor active drugs was used. Continuous recording of electrical activity from four selected brain areas (frontal cortex, hippocampus, striatum and reticular formation) in freely moving day-night converted Fisher rats was used (Tele-Stereo-EEG). Frequency analysis of telemetrically transmitted data and special definitions of frequency ranges were used to analyse the data from 45 min pre-drug and 180 min postdrug periods. Pharmacological modulation of brain activity by the selective nicotinic agonist metanicotine as well as the alpha 7 selective nicotinic antagonist methyllycaconitine revealed major changes in delta (1-4.5 Hz) and alpha2 (9-12.5 Hz) frequencies. In general blockade of the cholinergic system resulted in electrical power increases and activation in decreases. Unspecific modulation of cholinergic activity by using the cholinesterase inhibitors physostigmine, tacrine and galantamine led to alpha1 frequency (7-9.5 Hz) changes in addition to the delta and alpha2 changes. These three drugs produced a nearly identical pattern of frequency changes. Theta (4.75-6.75 Hz) and beta1 frequencies (12.75-18.5 Hz) changed to a lesser degree. A peculiar finding arose with respect to the effects of the antagonistic drugs scopolamine and biperiden since biperiden-besides the massive increase of delta and alpha1 power in common-induced a general decrease of alpha2 frequencies within all brain areas opposite to the effect of scopolamine. This special property of biperiden gives a plausible explanation for its efficacy in Parkinsonian patients since decreases of alpha2 waves in this model indicate enhancement of dopaminergic transmission [Dimpfel, W., Spüler, M., Koch, R., Schatton, W., 1987. Radioelectroencephalographic comparison of memantine with receptor-specific drugs acting on dopaminergic transmission in freely moving rats. Neuropsychobiology 18, 212-218]. Except for the effects of methyllycaconitine (p<10%) all results were statistically significant at least at the p<5% level. The results are best explained by assuming that electrical delta activity reflects cholinergic transmitter control followed by and closely linked to changes in dopaminergic transmission as indicated by additional concomitant changes in alpha2 electrical power.