Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis.

The recent discovery that genetically modified α cells can regenerate and convert into ß-like cells in vivo holds great promise for diabetes research. However, to eventually translate these findings to human, it is crucial to discover compounds with similar activities. Herein, we report the identification of GABA as an inducer of α-to-ß-like cell conversion in vivo. This conversion induces α cell replacement mechanisms through the mobilization of duct-lining precursor cells that adopt an α cell identity prior to being converted into ß-like cells, solely upon sustained GABA exposure. Importantly, these neo-generated ß-like cells are functional and can repeatedly reverse chemically induced diabetes in vivo. Similarly, the treatment of transplanted human islets with GABA results in a loss of α cells and a concomitant increase in ß-like cell counts, suggestive of α-to-ß-like cell conversion processes also in humans. This newly discovered GABA-induced α cell-mediated ß-like cell neogenesis could therefore represent an unprecedented hope toward improved therapies for diabetes.

Alcohol-related posterior reversible encephalopathy syndrome: a case report of a patient managed with a benzodiazepine-sparing regimen for alcohol withdrawal.

We report a case of posterior reversible encephalopathy syndrome (PRES) during treatment for alcohol withdrawal syndrome with gabapentin and clonidine. The patient developed severe hypertension, confusion and tremor, culminating in bilateral vision loss and a seizure. Imaging revealed posterior cerebral edema. Treatment with benzodiazepines, antihypertensives, and anti-seizure medications led to resolution. One year later, imaging showed resolution of the findings. We review the associated literature and propose the recognition of a PRES sub-entity, Alcohol-Related PRES (ARPRES), which can appear in the setting of alcohol withdrawal syndrome, chronic alcohol use, and acute alcohol intoxication, with or without hypertension.

A double-blind, placebo-controlled, randomised-designed GABA tea study in children diagnosed with autism spectrum conditions: a feasibility study clinical trial registration: ISRCTN 72571312.

Objective: The research has shown an association with sensorimotor integration and symptomology of Autism Spectrum Conditions (ASC). Specific areas of the brain that are involved in sensorimotor integration, such as the cerebellum and basal ganglia, are pathologically different in individuals with ASC in comparison to typically developing (TD) peers. These brain regions contain GABAergic inhibitory neurons that release an inhibitory neurotransmitter, γ-Aminobutyric acid (GABA). Brain GABA levels are decreased in ASC. This study explored the effect of introducing a non-invasive GABA substitute, in the form of GABA Oolong tea, on sensorimotor skills, ASC profiles, anxieties and sleep of children with ASC. Methods: Nine children took part: (5 male, 4 female). Each child participated in three tea conditions: high GABA, high L-Theanine (a compound that increases GABA), placebo with low GABA. A double-blind, repeated measures design was employed. Measures were taken after each tea condition. Sensory and ASC profiles were scored using parental questionnaires. Motor skills were assessed using a gold standard coordination assessment. Sleep was monitored using an actiwatch and anxiety measured through cortisol assays. Subjective views were sought from parents on 'best' tea. Results: The results showed significant improvement in manual dexterity and some large individual improvements in balance, sensory responsivity, DSM-5 criteria and cortisol levels with GABA tea. Improvements were also seen in the L-Theanine condition although they were more sporadic. Conclusions: These results suggest that sensorimotor abilities, anxiety levels and DSM-5 symptomology of children with ASC can benefit from the administration of GABA in the form of Oolong tea.

GABA consumption during early pregnancy impairs endometrial receptivity and embryo development in mice.

γ-Aminobutyrate (GABA) is commonly used as a food supplement and a health care product by young females, due to its positive roles in relieving stress, alleviating anxiety, and improving sleep. However, its recommended daily dose in different products varies widely. Besides, it is unknown whether, and how, GABA consumption during early pregnancy influences pregnancy establishment. In this study, we found that when pregnant mice were treated with a high (12.5 mg/g) dose of GABA (orally) during preimplantation, there was a reduction in the number of implantation sites on day 5 of pregnancy. Also, among these unimplanted embryos, most exhibited morphological degeneration and developmental retardation, and only a few of them developed into blastocysts but could not implant into the uterus. Moreover, the expression of uterine receptivity-related factors-LIF, E-cadherin, and HOXA10-were all downregulated, while the number of uterine glands was reduced in the high GABA dose group. Finally, in vitro results demonstrated that GABA (ranging from 10 to 50 µg/µL) markedly inhibited preimplantation embryo development in a dose-response manner. However, this inhibitory effect was not observed when the embryos were pretreated with 40 µΜ 2-hydroxysaclofen, a GABAB antagonist, indicating that GABA exerts its inhibitory effects via its B-type receptor. Our results suggest that exposure to certain GABA concentrations, during early pregnancy, can impair preimplantation embryo development via its B-type receptor, and endometrial receptivity, which greatly disturbs early embryo implantation in mice. These findings could raise concerns about GABA consumption during the early stages of pregnancy.

Modulation of brain function by targeted delivery of GABA through the disrupted blood-brain barrier.

The technology of transcranial focused ultrasound (FUS) enables a novel approach to neuromodulation, a tool for selective manipulation of brain function to be used in neurobiology research and with potential applications in clinical treatment. The method uses transcranial focused ultrasound to non-invasively open the blood-brain barrier (BBB) in a localized region such that a systemically injected neurotransmitter chemical can be delivered to the targeted brain site. The approach modulates the chemical signaling that occurs in and between neurons, making it complimentary to most other neuromodulation techniques that affect the electrical properties of neuronal activity. Here, we report delivering the inhibitory neurotransmitter GABA to the right somatosensory cortex of the rat brain during bilateral hind paw electrical stimulation and measure the inhibition of activation using functional MRI (fMRI). In a 2 × 2 factorial design, we evaluated conditions of BBB Closed vs BBB Open and No GABA vs GABA. Results from fMRI measurements of the blood oxygen level-dependent (BOLD) signal show: 1) intravenous GABA injection without FUS-mediated BBB opening does not have an effect on the BOLD response; 2) FUS-mediated BBB opening alone significantly alters the BOLD signal response to the stimulus, both in amplitude and shape of the time course; 3) the combination of FUS-mediated BBB opening and GABA injection further reduces the peak amplitude and spatial extent of the BOLD signal response to the stimulus. The data support the thesis that FUS-mediated opening of the BBB can be used to achieve non-invasive delivery of neuroactive substances for targeted manipulation of brain function.

GABA-containing compound gammapyrone protects against brain impairments in Alzheimer's disease model male rats and prevents mitochondrial dysfunction in cell culture.

Neuroinflammation, oxidative stress, decreased glucose/energy metabolism, and disrupted neurotransmission are changes that occur early in sporadic Alzheimer's disease (AD), manifesting as mild cognitive impairment. Recently, the imbalanced function of the gamma-aminobutyric acid (GABA) system was identified as a critical factor in AD progression. Thus, maintaining balance among neurotransmitter systems, particularly the GABA system, can be considered a beneficial strategy to slow AD progression. The present study investigated the effects of the compound gammapyrone, a molecule containing three GABA moieties: "free" moiety attached to the position 4 of the 1,4-dihydropyridine (DHP) ring, and two "crypto" moieties as part of the DHP scaffold. The "free" and "crypto" GABA moieties are linked by a peptide bond (-CONH-), resulting in a peptide-mimicking structure. In a nontransgenic male rat AD model generated by intracerebroventricular (icv) streptozocin (STZ) administration, gammapyrone (0.1 and 0.5 mg/kg ip) mitigated the impairment of spatial learning and memory, prevented astroglial and microglial neuroinflammation, and normalized acetylcholine breakdown and GABA biosynthesis. In PC12 cells, gammapyrone protected against oxidative stress, mitochondrial dysfunction and apoptosis caused by the mitochondrial toxin di-2-ethylhexyl phthalate (DEHP). Gammapyrone did not bind to GABA-A and GABA-B receptors in vitro; therefore, we cannot attribute its neuroprotective action to a specific interaction with GABA receptors. Nevertheless, we suggest that the peptide-like regulatory mechanisms of gammapyrone or its allosteric modulatory properties are essential for the observed effects. Since, the icv STZ model resembles the early stages of AD, gammapyrone, and/or its congeners could be useful in the design of anti-dementia drugs.

Gabapentin Enacarbil Extended-Release for Alcohol Use Disorder: A Randomized, Double-Blind, Placebo-Controlled, Multisite Trial Assessing Efficacy and Safety.

BACKGROUND: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended-release (GE-XR) (HORIZANT® ), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). METHODS: Men and women (n = 346) who met DSM-5 criteria for at least moderate AUD were recruited across 10 U.S. clinical sites. Participants received double-blind GE-XR (600 mg twice a day) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were prespecified for the last 4 weeks of the treatment period. RESULTS: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs. 21.5, respectively, p = 0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. CONCLUSIONS: Overall, GE-XR at 600 mg twice a day did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the U.S. Food and Drug Administration for treating other medical conditions.

GABA, γ-Aminobutyric Acid, Protects Against Severe Liver Injury.

BACKGROUND: Acute liver failure (ALF) from severe acute liver injury is a critical condition associated with high mortality. The purpose of this study was to investigate the impact of preemptive administration of γ-aminobutyric acid (GABA) on hepatic injury and survival outcomes in mice with experimentally induced ALF. MATERIALS AND METHODS: To induce ALF, C57BL/6NHsd mice were administered GABA, saline, or nothing for 7 d, followed by intraperitoneal administration of 500 µg of tumor necrosis factor α and 20 mg of D-galactosamine. The study mice were humanely euthanized 4-5 h after ALF was induced or observed for survival. Proteins present in the blood samples and liver tissue from the euthanized mice were analyzed using Western blot and immunohistochemical and histopathologic analyses. For inhibition studies, we administered the STAT3-specific inhibitor, NSC74859, 90 min before ALF induction. RESULTS: We found that GABA-treated mice had substantial attenuation of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive hepatocytes and hepatocellular necrosis, decreased caspase-3, H2AX, and p38 MAPK protein levels and increased expressions of Jak2, STAT3, Bcl-2, and Mn-SOD, with improved mitochondrial integrity. The reduced apoptotic proteins led to a significantly prolonged survival after ALF induction in GABA-treated mice. The STAT3-specific inhibitor NSC74859 eliminated the survival advantage in GABA-treated mice with ALF, indicating the involvement of the STAT3 pathway in GABA-induced reduction in apoptosis. CONCLUSIONS: Our results showed that preemptive treatment with GABA protected against severe acute liver injury in mice via GABA-mediated STAT3 signaling. Preemptive administration of GABA may be a useful approach to optimize marginal donor livers before transplantation.

Instrumental, clinical and subjective evaluation of the efficacy of a cosmetic treatment for home use.

Background: In the last few years, there has been increasing demand for aesthetic procedures to improve the effects of skin aging. Aim: To evaluate the anti-aging efficacy, tolerability and skin changes induced by the topical products containing hyaluronic acid, N-acetyl glucosamine and gamma-amino butyric acid through instrumental techniques, clinical and subjective evaluation. Patients/Method: Twenty female enrolled applied a day and night cream after applying a serum, once week applied a mask, for 2 months. A clinical assessment of smoothness, expression wrinkles, fine wrinkles and measurements of the parameters using Reveal Imager, X-Rite, Corneometer, Dermalab, Moisture Meter EpiD were taken at day 0, 15, 30 and 60 of study period. A final assessment questionnaire was submitted. Results: The products were accepted by all the volunteers. The hydration (Corneometer: T0 49.17 vs T60 61.11, average variation 24.28%) (Moisture Meter EpiD: T0 45.73 vs T60 61.10, average variation 33.60%), elasticity (Dermalab: T0 56.06 vs T60 62.78, average variation 11.98%) and lightening of the skin (X-Rite: T0 60.23 vs T60 63.36, average variation 5.26%) improved. All changes were statistically significant (p < 0.05). Conclusion: The efficacy of the topical products is confirmed by subjective, clinical and instrumental assessment. This should be a routine approach in dermatologic practice.

Analysis of the protective effects of γ-aminobutyric acid during fluoride-induced hypothyroidism in male Kunming mice.

CONTEXT: Compounds to treat hypothyroidism in the absence of cardiac side effects are urgently required. In this regard, γ-aminobutyric acid (GABA) has gained interest due to its anti-anxiolytic, antihypertensive and antioxidant properties, and reported benefits to the thyroid system. OBJECTIVE: We investigated the ability of GABA to ameliorate fluoride-induced thyroid injury in mice, and investigated the mechanism(s) associated with GABA-induced protection. MATERIALS AND METHODS: Adult male Kumning mice (N = 90) were exposed to NaF (50 mg/kg) for 30 days as a model of hypothyroidism. To evaluate the effects of GABA administration, fluoride-exposed mice received either thyroid tablets, or low (25 mg/kg), medium (50 mg/kg) or high (75 mg/kg) concentrations of pure GABA orally for 14 days groups (N = 10 each). The effects of low (50 mg/kg); medium (75 mg/kg) and high (100 mg/kg) concentrations of laboratory-separated GABA were assessed for comparison. Effects on thyroid hormone production, oxidative stress, thyroid function-associated genes, and side-effects during therapy were measured. RESULTS: GABA supplementation in fluoride-exposed mice significantly increased the expression of thyroid TG, TPO, and NIS (P < 0.05), significantly improved the thyroid redox state (P < 0.05), modulated the expression of thyroid function-associated genes, conferred liver metabolic protection, and prevented changes to myocardial morphology, thus reducing side effects. Both pure and laboratory-separated GABA displayed comparative protective effects. DISCUSSION AND CONCLUSION: Our findings support the assertion that GABA exerts therapeutic potential in hypothyroidism. The design and use of human GABA trials to improve therapeutic outcomes in hypothyroidism are now warranted.

Brief activation of GABAergic interneurons initiates the transition to ictal events through post-inhibitory rebound excitation.

Activation of γ-aminobutyric acid (GABAA) receptors have been associated with the onset of epileptiform events. To investigate if a causal relationship exists between GABAA receptor activation and ictal event onset, we activated inhibitory GABAergic networks in the superficial layer (2/3) of the somatosensory cortex during hyperexcitable conditions using optogenetic techniques in mice expressing channelrhodopsin-2 in all GABAergic interneurons. We found that a brief 30ms light pulse reliably triggered either an interictal-like event (IIE) or ictal-like ("ictal") event in the in vitro cortical 4-Aminopyridine (4-AP) slice model. The link between light pulse and epileptiform event onset was lost following blockade of GABAA receptors with bicuculline methiodide. Additionally, recording the chronological sequence of events following a light pulse in a variety of configurations (whole-cell, gramicidin-perforated patch, and multi-electrode array) demonstrated an initial hyperpolarization followed by post-inhibitory rebound spiking and a subsequent slow depolarization at the transition to epileptiform activity. Furthermore, the light-triggered ictal events were independent of the duration or intensity of the initiating light pulse, suggesting an underlying regenerative mechanism. Moreover, we demonstrated that brief GABAA receptor activation can initiate ictal events in the in vivo 4-AP mouse model, in another common in vitro model of epileptiform activity, and in neocortical tissue resected from epilepsy patients. Our findings reveal that the synchronous activation of GABAergic interneurons is a robust trigger for ictal event onset in hyperexcitable cortical networks.

PACAP-(6-38) or kynurenate microinjections in the RVLM prevent the development of sympathetic long-term facilitation after acute intermittent hypoxia.

Intermittent hypoxia causes a persistent increase in sympathetic activity that progresses to hypertension in chronic conditions such as obstructive sleep apnea. Pituitary adenylate cyclase-activating polypeptide (PACAP) is an excitatory neurotransmitter that causes long-lasting sympathetic excitation. We aimed to determine if intermittent activation of the rostral ventrolateral medulla (RVLM) causes PACAP-mediated elevation of sympathetic nerve activity, termed sympathetic long-term facilitation (sLTF). The role of PACAP in mediating sLTF in response to intermittent activation of the RVLM was investigated in urethane-anaesthetized and artificially ventilated rats ( n = 65, Sprague-Dawley). Bilateral RVLM microinjections of the PACAP type 1 receptor/vasoactive intestinal polypeptide receptor type 2 receptor antagonist PACAP-(6-38) [ n = 6, change (Δ): -16.4 ± 6.5%) or an ionotropic glutamate antagonist, kynurenate ( n = 6, Δ:-7.2 ± 2.3%), blocked the development of acute intermittent hypoxia-induced sLTF ( n = 6, Δ: 49.2 ± 14.2%). Intermittent RVLM microinjections of glutamate caused sLTF ( n = 5, Δ: 56.9 ± 14.7%) that was abolished by PACAP-(6-38) pretreatment ( n = 5, Δ:-1.2 ± 4.7%). Conversely, intermittent microinjections of PACAP in the RVLM did not elicit sLTF. Intermittent bilateral disinhibition of the RVLM by microinjection of γ-aminobutyric acid in the caudal ventrolateral medulla did not elicit sLTF. Direct activation of RVLM neurons is crucial for the development of sLTF. PACAP and glutamate act synergistically in the RVLM, with both being necessary for the sLTF response. We found that activation of glutamate but not PACAP receptors is necessary and sufficient to generate sLTF, even in the absence of intermittent hypoxia. Our results demonstrate that PACAP within the RVLM may contribute to the development of obstructive sleep apnea -induced hypertension. NEW & NOTEWORTHY Pharmacological blockade of either pituitary adenylate cyclase-activating polypeptide (PACAP) or ionotropic glutamate receptors in the rostral ventrolateral medulla prevents development of sympathetic long-term facilitation. PACAP receptor inhibition prevents the occurrence of hypoxia-induced peripheral chemoreflex sensitization. Thus, PACAP receptors may be a potential therapeutic target serving to reduce heightened sympathetic tone and hypersensitized cardiovascular reflexes.

Pharmacokinetics of immediate release, extended release, and gastric retentive gabapentin formulations in healthy adults
.

OBJECTIVE: Gabapentin immediate release (GBP-IR), gabapentin gastric retentive (GBP-GR), and the prodrug gabapentin enacarbil extended release formulation (GEn) have been approved for management of postherpetic neuralgia (PHN) in adults. This is the first pharmacokinetic (PK) comparison of all three formulations using FDA-recommended doses for PHN. MATERIALS: This study compared the steady-state PK of GBP-IR 600 mg t.i.d., GBP-GR 1,800 mg q.d., and GEn 600 mg b.i.d. in healthy adults. METHODS: The open-label study consisted of a 3-day lead-in of escalating doses of GBP-IR, 5 days of treatment with each formulation (GPB-IR, GPB-GR, and GEn), and a 7-day taper period on 600 mg GEn q.d.. Plasma concentrations were collected on day 5 for each formulation. PK parameters were estimated from plasma concentration data. RESULTS: 14 healthy subjects (7 men, 7 women; mean (SD) age, 46.8 (7.60) years; mean (SD) body mass index, 26.7 (1.7) kg/m2) received all doses and completed the study. GBP-GR resulted in substantially (~ 4-fold) higher peak-to-trough ratio and percent fluctuation compared to GEn. GEn resulted in more sustained and less fluctuating daily exposure relative to GBP-IR, particularly at the end of 24 hours of dosing. In contrast, gabapentin fluctuation from GBP-IR consisted of 3 distinct peaks. After dose normalization, gabapentin exposure with GEn was ~ 2.2-fold and ~ 1.4-fold higher compared to GBP-GR and GBP-IR, respectively. All treatments were well tolerated. CONCLUSION: GEn requires less frequent dosing compared with GBP-IR and fluctuates less with sustained gabapentin exposure throughout the day. These PK differences may have clinically relevant implications.
.

GABA-containing liposomes: neuroscience applications and translational perspectives for targeting neurological diseases.

There are multiple challenges for neuropharmacology in the future. Undoubtedly, one of the greatest challenges is the development of strategies for pharmacological targeting of specific brain regions for treatment of diseases. GABA is the main inhibitory neurotransmitter in the central nervous system, and dysfunction of GABAergic mechanisms is associated with different neurological conditions. Liposomes are lipid vesicles that are able to encapsulate chemical compounds and are used for chronic drug delivery. This short review reports our experience with the development of liposomes for encapsulation and chronic delivery of GABA to sites within the brain. Directions for future research regarding the efficacy and practical use of GABA-containing liposomes for extended periods of time as well as understanding and targeting neurological conditions are discussed.

Intervention effect of gamma aminobutyric acid on anxiety behavior induced by phthalate (2-ethylhexyl ester) in rats.

BACKGROUND: Di(2-ethylhexyl) phthalate (DEHP) is one of the most widely used phthalate esters. The application of DEHP has caused serious environmental pollution and posed a threat to human health. METHODS: A total of 30 male Sprague-Dawley rats were randomly divided into control group, DEHP group (500 mg/kg DEHP), low GABA (Gama-aminobutyric acid) group (500 mg/kg DEHP and 1 mg/kg GABA), medium GABA group (500 mg/kg DEHP and 2 mg/kg GABA) and high GABA group (500 mg/kg DEHP and 4 mg/kg GABA). The interventions continued for 30 consecutive days. Open-field test and elevated plus-maze test were used to detect behavioral changes of rats before and after interventions. RESULTS: The levels of nitric oxide and nitric oxide synthase in prefrontal cortex of rats were measured using enzyme-linked immunosorbent assay. DEHP and GABA treatment had no significant effects on the body weight of rats. GABA restored food utilization rate of rats impaired by DEHP to the level of healthy rats. According to open-field test and elevated plus-maze test, GABA alleviated the effects of DEHP on rat behaviors. Enzyme-linked immunosorbent assay showed that GABA was effective in reducing the levels of nitric oxide and nitric oxide synthase in rats treated with DEHP. CONCLUSION: DEHP exposure induced anxiety in rats, which may be achieved through elevating nitric oxide and nitric oxide synthase levels in prefrontal cortex of rats. However, the effects caused by DEHP could be alleviated by GABA.

Effectiveness of gabapentin as a postoperative analgesic in children undergoing appendectomy.

PURPOSE: Though gabapentin is increasingly used as a perioperative analgesic, data regarding effectiveness in children are limited. The purpose of this study was to evaluate gabapentin as a postoperative analgesic in children undergoing appendectomy. METHODS: A 12-month retrospective review of children undergoing appendectomy was performed at a two-hospital children's institution. Patients receiving gabapentin (GP) were matched (1:2) with patients who did not receive gabapentin (NG) based on age, sex and appendicitis severity. Outcome measures included postoperative opioid use, pain scores, and revisits/readmissions. RESULTS: We matched 29 (33.3%) GP patients with 58 (66.6%) NG patients (n = 87). The GP group required significantly less postoperative opioids than the NG group (0.034 mg morphine equivalents/kg (ME/kg) vs. 0.106 ME/kg, p < 0.01). Groups had similar lengths of time from operation to pain scores ≤ 3 (GP 12.21 vs. NG 17.01 h, p = 0.23). GP and NG had similar rates of revisit to the emergency department (13.8 vs. 10.3%, p = 0.73), readmission (6.9 vs. 1.7%, p = 0.26), and revisits secondary to surgical pain (3.4 vs. 3.4%, p = 1.00). CONCLUSION: In this single-center, retrospective cohort study, gabapentin is associated with a reduction in total postoperative opioid use in children with appendicitis. While promising, further prospective validation of clinical effectiveness is needed.

Gabapentine 300 mg vs. 450 mg as anesthetic premedication for reactive hypertension, anxiety and analgesia / Gabapentina a dosis de 300 vs. 450 mg como premedicación anestésica para hipertensión reactiva, ansiedad y analgesia.

Objective: Observe the behavior of gabapentin to reduce reactive hypertension secondary to anxiety and pain in patients undergoing ophthalmic surgery as well as opioid consumption between groups. Method: Clinical randomized double blind controlled trial that analyzed 125 patients divided into three groups: Group A, gabapentin 300 mg; Group B, gabapentin 450 mg; and Group C, amaranth dragees as a control 2 h before the surgical procedure. Chi-squared test was used in sociodemographic variables and one-way ANOVA for continuous numeric variables. It was considered as significant a p < 0.05 for a study of two tails with a power of 80% beta. Results: Anxiety and analgesia intraoperative and postoperative had significant differences between groups. Lower consumption of opioid was found in the groups that used gabapentin. Conclusions: Gabapentin orally 300 or 450 mg h prior to surgery reduces pain, anxiety and postoperative opioid consumption in patients undergoing ophthalmic surgery.

Objetivo: Observar el comportamiento de la gabapentina para aminorar la hipertensión reactiva secundaria a ansiedad y dolor en pacientes sometidos a cirugía oftálmica, así como el consumo de opiáceos entre los grupos. Método: Ensayo clínico controlado aleatorizado y doble ciego que analizó a 125 pacientes divididos en tres grupos: grupo A, gabapentina 300 mg; grupo B, gabapentina 450 mg; grupo C, amaranto en grageas como control 2 horas antes del procedimiento quirúrgico. Se utilizó la prueba de ji al cuadrado para variables sociodemográficas y ANOVA de un factor para variables numéricas continuas. Se consideró como significativo un valor de p < 0.05 para un estudio de dos colas con un poder beta del 80%. Resultados: La ansiedad y la analgesia transoperatoria y posoperatoria tuvieron diferencias significativas entre los grupos. Se encontró menor consumo de opiáceos en los grupos que usaron gabapentina. Conclusiones: La gabapentina por vía oral, 300 o 450 mg, 2 horas antes de la cirugía, reduce el dolor, la ansiedad y el consumo de opiáceos durante el posoperatorio en pacientes sometidos a cirugía oftalmológica.

The Actions of Drug Combinations on the GABAA Receptor Manifest as Curvilinear Isoboles of Additivity.

Drug interactions are often analyzed in terms of isobolograms. In the isobologram, the line connecting the axial points corresponding to the concentrations of two different drugs that produce an effect of the same magnitude is termed an isobole of additivity. Although the isobole of additivity can be a straight line in some special cases, previous work has proposed that it is curvilinear when the two drugs differ in their maximal effects or Hill slopes. Modulators of transmitter-gated ion channels have a wide range of maximal effects as well as Hill slopes, suggesting that the isoboles for drug actions on ion channel function are not linear. In this study, we have conducted an analysis of direct activation and potentiation of the human α1ß2γ2L GABAA receptor to demonstrate that: 1) curvilinear isoboles of additivity are predicted by a concerted transition model where the binding of each GABAergic drug additively and independently reduces the free energy of the open receptor compared with the closed receptor; and 2) experimental data for receptor activation using the agonist pair of GABA and propofol or potentiation of responses to a low concentration of GABA by the drug pair of alfaxalone and propofol agree very well with predictions. The approach assuming independent energetic contributions from GABAergic drugs enables, at least for the drug combinations tested, a straightforward method to accurately predict functional responses to any combination of concentrations.

Rescuing fluoride-induced damages in liver with gamma aminobutyric acid.

Fluorine poisoning affects human health all over the world and an urgent task is to develop alleviative medicine to recover or ameliorate the damages to the body. Here we studied the effects of gamma-aminobutyric acid (GABA), a liver protector reported previously, on fluoride-induced damage in the mouse liver. Through microscope imaging of the liver tissue, TUNEL immunostaining, real-time RT-PCR, enzyme immunoassay and colorimetric method, we found that GABA supplementation prevented the metabolic toxicity caused by fluoride treatment in mice. This detoxification was reflected by the reduced oxidative stress and apoptosis, enhanced neuron protection and liver function. Collectively, this study provided evidence of the beneficial effects of GABA supplement on liver damage, implicating its therapeutic potential in fluorosis.

The Effects of Acute GABA Treatment on the Functional Connectivity and Network Topology of Cortical Cultures.

γ-Aminobutyric acid (GABA) is an inhibitory transmitter, acting on receptor channels to reduce neuronal excitability in matured neural systems. However, electrophysiological responses of whole neuronal ensembles to the exposure to GABA are still unclear. We used micro-electrode arrays (MEAs) to study the effects of the increasing amount of GABA on functional network of cortical neural cultures. Then the recorded data were analyzed by the cross-covariance analysis and graph theory. Results showed that after the GABA treatment, the activity parameters of firing rate, bursting rate, bursting duration and network burst frequency in neural cultures decreased as expected. In addition, the functional connectivity also decreased in similarity, network density, and the size of the largest component. However, small-worldness was not found to be influenced by the acute GABA treatment. Our results support the position that using graph theory to evaluate the functional connectivity of neural cultures may enhance understanding of the pharmacological impact of neurotransmitters on neuronal networks.