Potentiation Of Gamma-aminobutyric Acid Research Articles

Gamma-aminobutyric acid (GABA)-mediated bone formation and its implications for anti-osteoporosis strategies: Exploring the relation between GABA and GABA receptors

Osteoporosis is a significant global health concern, linked to reduced bone density and an increased fracture risk, with effective treatments still lacking. This study explored the potential of gamma-aminobutyric acid (GABA) and its receptors as a novel approach to promote osteogenesis and address osteoporosis. GABA concentrations up to 10 mM were well-tolerated by MC3T3-E1 preosteoblast, stimulating osteoblast differentiation and mineralization in a concentration- and time-dependent manner. In vivo experiments with zebrafish larvae demonstrated the ability of GABA to improve vertebral formation and enhanced bone density, indicating the potential therapeutic value for osteoporosis. Notably, GABA countered the adverse effects of prednisolone on vertebral formation, bone density, and osteogenic gene expression in zebrafish larvae, suggesting a promising therapeutic solution to counteract corticosteroid-induced osteoporosis. Moreover, our study highlighted the involvement of GABA receptors in mediating the observed osteogenic effects. By using GABAA, GABAB, and GABAC receptor antagonists, we demonstrated that blocking these receptors attenuated GABA-induced osteoblast differentiation and vertebral formation in both MC3T3-E1 cells and zebrafish larvae, underscoring the importance of GABA receptor interactions in promoting bone formation. In conclusion, these findings underscore the osteogenic potential of GABA and its ability to mitigate the detrimental effects of corticosteroids on bone health. Targeting GABA and its receptors could be a promising strategy for the development of novel therapeutic interventions to address osteoporosis. However, further investigations are warranted to fully elucidate the underlying molecular mechanism of GABA and its clinical applications in treating osteoporosis.

GABA Prevents Age-Related Sarcopenic Obesity in Mice with High-Fat-Diet-Induced Obesity.

Sarcopenic obesity is characterized by concurrent obesity and muscle wasting (sarcopenia) and is common in the elderly. Sarcopenic obesity has steadily increased as the aging population has grown and is an increasing public health burden. Both obesity and sarcopenia independently increase health risks of the elderly, but sarcopenic obesity has a greater effect on metabolic disease than either obesity or sarcopenia alone. The metabolic mechanisms of obesity and sarcopenia are strongly interconnected, and obesity and sarcopenia form a vicious cycle, with each pathology exacerbating the other. The pathogenesis of sarcopenic obesity is more complex than either disease alone and remains incompletely understood, underscoring the significant unmet clinical need for effective sarcopenic obesity treatments. We aimed to determine the efficacy and underlying regulatory mechanisms of Gamma-aminobutyric acid (GABA) in sarcopenic obesity in high-fat-diet-fed obese aged mice and alterations in related mechanisms to determine the potential of GABA as a therapeutic modality for sarcopenic obesity. In this study, we used young (3 months) and aged (20 months) mice to evaluate age-related sarcopenic obesity. The daily administration of GABA for 8 weeks resulted in decreased fat mass and increased muscle mass and strength in aged mice. GABA also enhanced energy expenditure in both adipose tissue and skeletal muscle. In addition, GABA promoted muscle synthesis and decreased muscle degradation by activating the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. These findings demonstrate that GABA has potential uses in preventing age-related sarcopenic obesity and related metabolic diseases.

Effects of gamma aminobutyric acid on performance, blood cell of broiler subjected to multi-stress environments.

Stress factors such as high temperatures, overcrowding, and diurnal temperature range exert profound negative effects on weight gain and productivity of broiler chickens. The potential of gamma aminobutyric acid (GABA) as an excitatory neurotransmitter was evaluated under various stress conditions in this study. The experiment was conducted under four different environmental conditions: normal, high temperature, overcrowded, and in an overcrowded-diurnal temperature range. The experimental groups were divided into (-) control group without stress, (+) control group with stress, and G50 group (GABA 50 mg/kg) with stress. Weight gain, feed intake, and feed conversion ratio were measured, and stress reduction was evaluated through hematologic analysis. The effects of GABA on broilers in four experimental treatments were evaluated. GABA treated responded to environmental stress and improved productivity in all the experimental treatments. The magnitude of stress observed was highest at high temperature, followed by the overcrowded environment, and was least for the overcrowded-diurnal temperature range. Various stress factors in livestock rearing environment can reduce productivity and increase disease incidence and mortality rate. To address these challenges, GABA, an inhibitory neurotransmitter, was shown to reduce stress caused due to various environmental conditions and improve productivity.

GABA and fermented litchi juice enriched with GABA promote the beneficial effects in ameliorating obesity by regulating the gut microbiota in HFD-induced mice.

Gamma-aminobutyric acid (GABA) dietary intervention is considered to have therapeutic potential against obesity. Microbial enrichment is an effective strategy to naturally and safely enhance GABA production in food. As litchi is "the king of GABA" in fruits, the retention or enrichment of its content during processing has been a key issue in the litchi industry. This study aimed to investigate the potential of GABA and fermented litchi juice enriched with GABA (FLJ) to protect against obesity in a high-fat diet (HFD) mouse model. Supplementation of GABA and FLJ displayed an anti-obesogenic effect by attenuating body weight gain, fat accumulation, and oxidative damage, and improving the serum lipid profile and hepatic function. Sequencing (16S rRNA) of fecal samples indicated that GABA and FLJ intervention displayed different regulatory effects on HFD-induced gut microbiota dysbiosis at different taxonomic levels. The microbial diversity, the relative abundance of Firmicutes and Bacteroidetes as well as the F/B ratio of GABA and FLJ groups were reversed compared to those of the HFD-induced mice. Our finding broadens the potential mechanisms by which GABA regulates gut flora in the amelioration of obesity and provides guidance for developing FLJ as a functional food to prevent obesity.

Therapeutic Anti-Depressant Potential of Microbial GABA Produced by Lactobacillus rhamnosus Strains for GABAergic Signaling Restoration and Inhibition of Addiction-Induced HPA Axis Hyperactivity

The role of the microbiota–gut–brain (MGB) axis in mood regulation and depression treatment has gained attention in recent years, as evidenced by the growing number of animal and human studies that have reported the anti-depressive and associated gamma-aminobutyric acid-ergic (GABAergic) effects of probiotics developed from Lactobacillus rhamnosus bacterial strains in the gut microbiome. The depressive states attenuated by these probiotics in patients suffering from clinical depression also characterize the severe and relapse-inducing withdrawal phase of the addiction cycle, which has been found to arise from the intoxication-enabled hyperregulation of the hypothalamic–pituitary–adrenal (HPA) axis, the body’s major stress response system, and a corresponding attenuation of its main inhibitory system, the gamma-aminobutyric acid (GABA) signaling system. Therefore, the use of probiotics in the treatment of general cases of depression provides hope for a novel therapeutic approach to withdrawal depression remediation. This review discusses potential therapeutic avenues by which probiotic application of Lactobacillus rhamnosus strains can be used to restore the central GABAergic activity responsible for attenuating the depression-inducing HPA axis hyperactivity in addiction withdrawal. Also, information is provided on brain GABAergic signaling from other known GABA-producing strains of gut microbiota.

Optimization of Gamma Aminobutyric Acid Production Using High Pressure Processing (HPP) by Lactobacillus brevis PML1.

In the present research, the production potential of gamma aminobutyric acid (GABA) using Lactobacillus brevis PML1 was investigated. In addition, the microorganism viability was examined in MAN, ROGOSA, and SHARPE (MRS) after undergoing high hydrostatic pressure at 100, 200, and 300 MPa for 5, 10, and 15 min. Response surface methodology (RSM) was applied to optimize the production conditions of GABA as well as the bacteria viability. Analysis of variance (ANOVA) indicated that both the independent variables (pressure and time) significantly influenced the dependent ones (GABA and bacteria viability) (P < 0.05). The optimum extraction conditions to maximize the production of GABA included the pressure of 300 MPa and the time of 15 min. The amount of the compound was quantified using thin-layer chromatography (TLC) and spectrophotometry. For the process optimization, a central composite design (CCD) was created using Design Expert with 5 replications at the center point, whereby the highest content of GABA was obtained to be 397.73 ppm which was confirmed by high performance liquid chromatography (HPLC). Moreover, scanning electron microscopy (SEM) was utilized to observe the morphological changes in the microorganism. The results revealed that not only did have Lactobacillus brevis PML1 the potential for the production of GABA under conventional conditions (control sample) but also the content of this bioactive compound could be elevated by optimizing the production parameters.

The growth and potential of gamma-aminobutyric acid (GABA) by lactic acid bacteria isolated from fish fermented food from Maluku, Indonesia

GABA is a non-protein amino acid that is widely distributed in plants, animals and microorganisms. GABA can increase plasma concentration, growth hormone and protein synthesis in the brain. Several studies have shown that LAB can reduce pathological conditions due to oxidative stress, which indicates that LAB has antioxidant activity. One of the metabolites produced by LAB is GABA. The purpose of this study was to determine the growth of LAB isolates, the ability of GABA production and to know the character of INS-A2 and INS A4 isolates as a result of isolation from fish fermented. Bacterial growth was carried out for 60 hours 37°C. The growth of LAB isolates INS-A2 and INS-A4 were treated with the addition of MSG and non-MSG 2% in MRSB. GABA production can be identified qualitatively by the Thin Layer Chromatography (TLC) method using the aluminum TLC plate (Silica gel F254, Merck, Mumbai India). The LAB inoculum which was treated on MRSB media was centrifuged at a speed of 6000 rpm for 20 minutes at 4°C, the supernatant was deposited or dropped on the TLC plate. TLC was carried out using an eluent consisting of a mixture of n-butanol: acetic acid: distilled water in a ratio of 5:3:2. The Rf value of GABA compound produced by LAB INS-A2 and INS A4 isolates was 0.62, GABA standard (Pregabalin) 0.62, Rf MSG = 0.23. Based on the results of the study it can be concluded that the highest growth of INS A2 MSG isolate at 24 hours, INS-A2 non MSG highest at 30 hours. The highest growth of INS A4 MSG isolate at 30 hours and INS-A4 non MSG highest at 36 hours. The highest GABA concentration was owned by INS-A2 MSG isolate of 20,0 mg/ml. INS-A2 non MSG isolate 17,5 mg/ml, INS-A4 MSG 18,8 mg/ml and INS-A4 non-MSG 15,9 mg/ml. LAB characterization of INS-A2 and INS-A4 isolates obtained negative catalase, negative motility, fermentation type test (homofermentative) and gram-positive staining in accordance with the characteristics of BAL in general.

Early Treatment with Empagliflozin and GABA Improves β-Cell Mass and Glucose Tolerance in Streptozotocin-Treated Mice.

While the autoimmune character of T1D (type 1 diabetes) is being challenged, it is currently recognized that inflammation plays a key role in its development. We hypothesized that glucotoxicity could contribute to β-cell mass destruction through participation in islet inflammation. We evaluated the potential of empagliflozin (EMPA) and GABA (gamma-aminobutyric acid) to protect β-cell mass against glucotoxicity and to increase β-cell mass after diagnosis of T1D. Empagliflozin is a SGLT2 (sodium-dependent glucose cotransporter) inhibitor which thereby blocks glucose recapture by the kidney and promotes glucose excretion in urine. GABA is an inhibitory neurotransmitter, which stimulates α-to-β cell transdifferentiation. In streptozotocin-treated mice, empagliflozin and/or GABA were delivered for a period of five days or three weeks. As compared to untreated T1D mice, EMPA-treated T1D mice had decreased FFA (free fatty acid) levels and improved glucose homeostasis. EMPA-treated T1D mice had higher islet density, with preserved architecture, compared to T1D mice, and EMPA-treated T1D mice also differed from T1D mice by the total absence of immune cell infiltration within islets. Islets from EMPA-treated mice were also less subjected to ER (endoplasmic reticulum) stress and inflammation, as shown by qPCR analysis. Glucose homeostasis parameters and islet area/pancreas area ratio improved, as compared to diabetic controls, when T1D mice were treated for three weeks with GABA and EMPA. T1D EMPA+GABA mice had higher glucagon levels than T1D mice, without modifications of glucagon area/islet area ratios. In conclusion, empagliflozin and GABA, used in monotherapy in streptozotocin-induced diabetic mice, have positive effects on β-cell mass preservation or proliferation through an indirect effect on islet cell inflammation and ER stress. Further research is mandatory to evaluate whether empagliflozin and GABA may be a potential therapeutic target for the protection of β-cell mass after new-onset T1D.

The therapeutic potential of GABA in neuron-glia interactions of cancer-induced bone pain

The development of effective therapeutics for cancer-induced bone pain (CIBP) remains a tremendous challenge owing to its unclear mechanisms. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). Emerging studies have shown that disinhibition in the spinal cord dorsal horn may account for the development of chronic pain. However, the role of GABA in the development of CIBP remains elusive. In addition, accumulating evidence has shown that neuroglial cells in the peripheral nervous system, especially astrocytes and microglial cells, played an important role in the maintenance of CIBP. In this study, we investigated the expression of GABA and Gamma-aminobutyric acid transporter-1 (GAT-1), a transporter of GABA. Our results demonstrate that GABA was decreased in CIBP rats as expected. However, the expression of glutamic acid decarboxylase (GAD) 65 was up-regulated on day 21 after surgery, while the expression of GAD 67 remained unchanged after surgery. We also found that the expression of GAT-1 was up-regulated mainly in the astrocytes of the spinal cord. Moreover, we evaluated the analgesic effect of exogenous GABA and the GAT-1 inhibitor. Intrathecal administration of exogenous GABA and NO-711 (a GAT-1 selective inhibitor) significantly reversed CIBP-induced mechanical allodynia in a dose-dependent manner. These results firstly show that neuron-glia interactions, especially on the GABAergic pathway, contribute to the development of CIBP. In conclusion, exogenous GABA and GAT-1 inhibitor might be alternative therapeutic strategies for the treatment of CIBP.

HPLC-Based Activity Profiling for GABAA Receptor Modulators in Murraya exotica

A dichloromethane extract from twigs and leaves of Murraya exotica produced allosteric potentiation of gamma aminobutyric acid (GABA) induced chloride currents in a microelectrode assay in Xenopus laevis oocytes expressing GABA receptors of α1, β2, γ2s subunit composition. The activity was tracked by HPLC-based activity profiling utilizing a zebrafish locomotor activity assay. Osthol (9) was identified as the main active compound. In addition, five other coumarins and four flavonols were identified. Osthol (9) and structurally related coumurrayin (10) were tested in the Xenopus oocyte assay. Compound 9 potentiated GABAA-induced chloride currents by 487 ± 42%, with an EC50 of 46 ± 10 μM, while 10 showed negligible effects on chloride currents. In silico evaluation of physicochemical properties showed that 9 and 10 had properties that are favorable for oral bioavailability and BBB permeability.

The Association Between Clinical Characteristics of Migraine and Brain GABA Levels: An Exploratory Study

Migraine is prevalent and disabling yet is poorly understood. One way to better understand migraine is to examine its clinical characteristics and potential biomarkers such as gamma-aminobutyric acid (GABA). The primary objective of this study was to explore whether relevant disease characteristics of migraine are associated with brain GABA levels. Twenty adults fulfilling the established diagnostic criteria for migraine and 20 age- and gender-matched controls completed this cross-sectional study. Pain, central sensitization, negative emotional state, and perceived disability were measured using Short-form McGill Pain Questionnaire-2, Central Sensitization Inventory, Depression Anxiety Stress Scales-21, and Headache Impact Test-6, respectively. Secondary analysis of brain GABA levels of the same cohort measured using proton magnetic resonance spectroscopy was conducted. The migraine group had significantly higher scores than the control group on pain, central sensitization, and disability. Correlation analyses showed fair positive association between GABA levels and pain and central sensitization scores. No association was found between GABA levels and emotional state and disability. These findings are preliminary evidence supporting the use of questionnaires and GABA levels in characterizing migraine better and broadening the diagnostic process. These findings also strengthen the rationale for the role of GABA in migraine pathophysiology and corroborate the potential of GABA as a migraine biomarker. Higher pain and central sensitization scores were associated with increased brain GABA levels in individuals with migraine. These findings offer preliminary evidence for the usefulness of measuring pain and central sensitization in migraine and provide some support for the possible role of GABA in migraine pathophysiology and its potential as a diagnostic marker.

Role of GABAA receptors in the physiology and pharmacology of sleep

Most sedative-hypnotics used in insomnia treatment target the gamma-aminobutyric acid (GABA)(A) receptors. A vast repertoire of GABA(A) receptor subtypes has been identified and displays specific electrophysiological and functional properties. GABA(A)-mediated inhibition traditionally refers to 'phasic' inhibition, arising from synaptic GABA(A) receptors which transiently inhibit neurons. However, there is growing evidence that peri- or extra-synaptic GABA(A) receptors are continuously activated by low GABA concentrations and mediate a 'tonic' conductance. This slower type of signaling appears to play a key role in controlling cell excitability. This review aims at summarizing recent knowledge on GABA transmission, including the emergence of tonic conductance, and highlighting the importance of GABA(A) receptor heterogeneity. The mechanism of action of sedative-hypnotic drugs and their effects on sleep and the electroencephalogram will be reported. Furthermore, studies using genetically engineered mice will be emphasized, providing insights into the role of GABA(A) receptors in mechanisms underlying physiological and pharmacological sleep. Finally, we will address the potential of GABA(A) receptor pharmacology for the treatment of insomnia.

Activation of A‐Type γ‐Amino Butyric Acid Receptors Excites Gonadotrophin‐Releasing Hormone Neurones Isolated from Adult Rats

Gonadotrophin-releasing hormone (GnRH) neurones represent the final output neurones in the neuroendocrine control of reproduction, and gamma-amino butyric acid (GABA) is one of the major players in the regulation of GnRH neurones. GABA inhibits a large proportion of brain neurones in adult animals by acting on A-type GABA receptors (GABA(A)Rs). Two contradictory reports on the action of GABA in the GnRH neurones of adult mice have been published. DeFazio et al. (Mol Endocrinol 2002; 16: 2872) demonstrated that activation of GABA(A)Rs excites the GnRH neurones of adult mice, whereas Han et al. (Endocrinology 2002; 143: 1459) showed that the response to GABA on GnRH neurones switches from depolarisation to hyperpolarisation around puberty in female mice. Therefore, we examined the reversal potential of GABA(A)R currents by means of perforated patch-clamp recording with gramicidin in overnight-cultured GnRH neurones isolated from adult GnRH-enhanced green fluorescent protein transgenic rats. The reversal potential was -26 +/- 1.4 mV (mean +/- SEM, n = 42) in GnRH neurones, whereas it was -57 +/- 2.7 mV (n = 34) in unidentified neurones, and GABA depolarised the GnRH neurones in current-clamp condition. The GABA(A)R currents in rat GnRH neurones were augmented by neurosteroids, allopregnanolone and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one, at submicromolar concentrations. In addition, the expression patterns of GABA(A)R subunit mRNAs were determined by multi-cell reverse transcription-polymerase chain reaction, which revealed that the alpha2, beta 3, gamma 1 and gamma 2 subunits were dominant and the alpha 6 and gamma 3 subunits were negative in rat GnRH neurones. These results indicate that GABA(A)Rs in the soma of rat GnRH neurones are comprised mainly of alpha2, beta 3 and gamma 1 or gamma 2 subunits and that they are sensitive to neurosteroids; moreover, they suggest that activation of these receptors depolarises GnRH neurones. Thus, GABA and neurosteroids influence the electrical activity of GnRH neurones.

Opioids block long-term potentiation of inhibitory synapses

Excitatory brain synapses are strengthened or weakened in response to specific patterns of synaptic activation, and these changes in synaptic strength are thought to underlie persistent pathologies such as drug addiction, as well as learning. In contrast, there are few examples of synaptic plasticity of inhibitory GABA (gamma-aminobutyric acid)-releasing synapses. Here we report long-term potentiation of GABA(A)-mediated synaptic transmission (LTP(GABA)) onto dopamine neurons of the rat brain ventral tegmental area, a region required for the development of drug addiction. This novel form of LTP is heterosynaptic, requiring postsynaptic NMDA (N-methyl-d-aspartate) receptor activation at glutamate synapses, but resulting from increased GABA release at neighbouring inhibitory nerve terminals. NMDA receptor activation produces nitric oxide, a retrograde signal released from the postsynaptic dopamine neuron. Nitric oxide initiates LTP(GABA) by activating guanylate cyclase in GABA-releasing nerve terminals. Exposure to morphine both in vitro and in vivo prevents LTP(GABA). Whereas brief treatment with morphine in vitro blocks LTP(GABA) by inhibiting presynaptic glutamate release, in vivo exposure to morphine persistently interrupts signalling from nitric oxide to guanylate cyclase. These neuroadaptations to opioid drugs might contribute to early stages of addiction, and may potentially be exploited therapeutically using drugs targeting GABA(A) receptors.

Beta and Gamma Range EEG Power‐Spectrum Correlation with Spiking Discharges in DBA/2J Mice Absence Model: Role of GABAB Receptors

To describe the correlations between spiking pattern and EEG power spectrum frequency in DBA/2J mice, a model for murine absence seizures, after gamma-aminobutyric acid (GABA)(B) modulation. The animals were first tested with the GABA(B) agonist l-baclofen followed by the GABA(B) antagonist SCH 50911. Moreover, digital EEGs recorded under experimental conditions were processed at baseline and 10 and 20 min after l-baclofen injection. This procedure was followed by injection of the GABA(B) antagonist SCH50911 and by an additional EEG evaluation at 10 and 20 min from drug administration. The power spectra analysis of signals was obtained for delta (0.5-3 Hz), theta (3.5-7.5 Hz), alpha (8-12 Hz), beta (13-20 Hz), and gamma (21-50 Hz) frequencies. The spiking pattern and power spectrum of beta activity was increased by <or=80% after administration of 5 mg/kg l-baclofen, whereas gamma power frequency decreased to the same extent. After administration of 50 mg/kg SCH 50911, spiking activity and beta power frequencies were markedly reduced (>80%), whereas gamma power increased (correlation, 0.92; p < 0.001). The remaining frequency bands were unaffected. This study confirms the potential of GABA(B) antagonists in contrasting seizure absence in rodent models and suggests the application of drugs with a similar mechanism in humans. In addition, because GABA(B) antagonists not only contrast seizure in rodent models of absence but also improve "cognitive" performance, it could be hypothesized that gamma increase, correlated with optimized cortical binding during coherent percepts, may produce potential cognition-enhancing effects.

Elevated endogenous GABA level correlates with decreased fMRI signals in the rat brain during acute inhibition of GABA transaminase

Vigabatrin and gabaculine, both highly specific inhibitors of GABA (gamma-aminobutyric acid) transaminase, cause significant elevation of endogenous GABA levels in brain. The time course of GABA concentration after acute GABA transaminase inhibition was measured quantitatively in the alpha-chloralose-anesthetized rat brain using in vivo selective homonuclear polarization transfer spectroscopy. The blood oxygenation level-dependent (BOLD) effect in functional magnetic resonance imaging (fMRI) has been considered to be coupled tightly to neuronal activation via the metabolic demand of associated glutamate transport. Correlated with the rise in endogenous GABA level after vigabatrin or gabaculine treatment, the intensity of BOLD-weighted fMRI signals in rat somatosensory cortex during forepaw stimulation was found to be reduced significantly. These results are consistent with previous findings that inhibition of GABA transaminase leads to augmented GABA release and potentiation of GABAergic inhibition.

Effects of isoflurane and propofol on glutamate and GABA transporters in isolated cortical nerve terminals.

Depression of glutamate-mediated excitatory transmission and potentiation of gamma-aminobutyric acid (GABA)-mediated inhibitory transmission appear to be primary mechanisms by which general anesthetics produce anesthesia. Since effects on transmitter transport have been implicated in anesthetic actions, the authors examined the sensitivity of presynaptic glutamate and GABA transporters to the effects of a representative volatile (isoflurane) and a representative intravenous (propofol) anesthetic. A dual-isotope (l-[3H]glutamate and [14C]GABA) approach allowed simultaneous comparisons of anesthetic effects on three independent assays of glutamate and GABA transporters in adult rat cerebral cortex: transmitter uptake into isolated nerve terminals (synaptosomes), transmitter binding to lysed and washed synaptosomes (synaptic membranes), and carrier-mediated release (reverse transport) of transmitter from preloaded synaptosomes using a modified superfusion system. Isoflurane produced small but statistically significant inhibition of l-[3H]glutamate and [14C]GABA uptake, while propofol had no effect. Inhibition of uptake by isoflurane was noncompetitive, an outcome that was mimicked by indirectly affecting transporter function through synaptosomal depolarization. Neither isoflurane nor propofol affected l-[3H]glutamate or [14C]GABA binding to synaptic membranes or Ca(2+)-independent carrier-mediated l-[3H]glutamate or [14C]GABA release (reverse transport). These findings suggest that isoflurane and propofol at clinical concentrations do not affect excitatory glutamatergic transmission or inhibitory GABAergic transmission directly effects on their presynaptic neuronal transporters.

The diverse roles of anticonvulsants in bipolar disorders.

Anticonvulsant drugs (ACs) have diverse antiseizure, psychotropic, and biochemical effects. Carbamazepine and valproate have mood-stabilizing actions, benzodiazepines and gabapentin have anxiolytic actions, lamotrigine is useful in rapid cycling and acute treatment and prophylaxis of bipolar depression, and topiramate and zonisamide can yield weight loss. Limited controlled data suggest the carbamazepine keto derivative oxcarbazepine has antimanic effects. A categorical approach to the diverse roles of ACs in bipolar disorders is proposed, using broad categories of ACs, on the basis of their predominant psychotropic profiles. Thus, some ACs have "sedating" profiles that may include sedation, cognitive difficulties, fatigue, weight gain, and possibly antimanic and/or anxiolytic effects. In contrast, some newer ACs have "activating" profiles that may include improved energy, weight loss, and possibly antidepressant and even anxiogenic effects. Still other newer ACs have novel "mixed" profiles, combining sedation and weight loss. A categorical-mechanistic extension of this approach is also presented, with hypotheses that "sedating" profiles might be related to prominent potentiation of gamma-aminobutyric acid (GABA) inhibitory neurotransmission, "activating" profiles could be related to prominent attenuation of glutamate excitatory neurotransmission, and for "mixed" profiles, sedation and weight loss might be related to concurrent GABAergic and antiglutamatergic actions, respectively. The categorical approach may have utility as an aid to clinicians in reinforcing the heterogeneity ACs, and recalling psychotropic profiles of individual ACs, but is limited as it fails to address the etiology of the heterogeneity of AC psychotropic effects. The categorical-mechanistic extension strives to address this issue, but requires systematic clinical investigation of more precise relationships between psychotropic profiles and discrete mechanisms of action to assess its merits.

Electrophysiological actions of γ-aminobutyric acid and clomethiazole on recombinant GABA A receptors

Clomethiazole is a γ-aminobutyric acid (GABA)-mimetic agent with anticonvulsant, sedative and neuroprotective properties. The pharmacological actions of clomethiazole that underlie its functional profile have not been fully explored, but are known to result from an interaction with the GABA A receptor. Here, we present a quantitative electrophysiological study of clomethiazole action at human recombinant GABA A receptors. Whole-cell currents were recorded from murine L(tk-) cells stably transfected with either α1, β1 and γ2 or α1, β2 and γ2 GABA A receptor subunits. Clomethiazole directly activated GABA A currents in α1/β1/γ2- and α1/β2/γ2-containing cells, with EC 50 values of 0.3 and 1.5 mM, respectively. A low concentration of clomethiazole (30 μM) also potentiated the action of GABA in both cell types, equivalent to a 3-fold increase in potency and up to 1.8-fold increase in maximal current. Both direct activation and gamma-aminobutyric acid potentiation are likely to contribute to the in vivo profile of clomethiazole.

Antiepileptic Drug Therapy in Migraine Headache.

Severe migraine affects more than 28 million Americans. It is associated with episodic as well as long-term disability and suffering, yet it is underdiagnosed and undertreated. Acute treatments have advanced considerably, ignited by sumatriptan and the subsequent triptans; unfortunately migraine prevention has lagged far behind. There are no great migraine preventives! No migraine preventive agent studied in good randomized, double blind, placebo-controlled trials proved to be 50% better than placebo. Migraine trials typically focus on episodic migraine, a milder, gentler type of migraine that is selected for low frequency, lack of daily headaches, no preventive need, and previous failure to no more than a few preventive agents. These features are not typical of the usual migraine patient seen in most neurologic practices, thus the results of clinical trials may not carryover to real world situations. Treatment of frequent, chronic, or pervasive migraine is inadequate, and never has been studied in randomized controlled trials. Traditional migraine preventives, eg, beta-blockers, calcium channel blockers, and tricyclic antidepressants, are often ineffective in difficult or complicated populations. The antiepileptic drugs represent a category of pharmaceutics that target the neuronal instability and central hyperexcitability of migraine, and, through these actions, may be more effective than traditional preventives. Episodic migraine attacks are associated with peripheral and central sensitization; however, if attacks are frequent, severe, or long lasting, this sensitization may increase the risk of developing daily headaches. If antiepileptic drugs have an effect on central sensitization, perhaps mediated via glutamate inhibition or gamma-aminobutyric acid potentiation, it is appropriate to use these agents early in migraine treatment, particularly in the highly comorbid patient, possibly in conjunction with agents that antagonize the 5HT2 receptor. This report reviews the best currently available evidence on antiepileptic drugs in the prevention of episodic migraine, and tabulates potential drug-drug and cytochrome P450 interactions. All antiepileptic drugs presented are effective in migraine prevention. However, deciding on the best agent for each individual patient will require recognizing comorbidity and assessing antiepileptic drug pharmacodynamics, tolerability, and safety.