Brain Gamma-aminobutyric Acid Levels Research Articles

Charting brain GABA and glutamate levels across psychiatric disorders by quantitative analysis of 121 1H-MRS studies.

Psychiatric diagnosis is based on categorical diagnostic classification, yet similarities in genetics and clinical features across disorders suggest that these classifications share commonalities in neurobiology, particularly regarding neurotransmitters. Glutamate (Glu) and gamma-aminobutyric acid (GABA), the brain's primary excitatory and inhibitory neurotransmitters, play critical roles in brain function and physiological processes. We examined the levels of Glu, combined glutamate and glutamine (Glx), and GABA across psychiatric disorders by pooling data from 121 1H-MRS studies and further divided the sample based on Axis I disorders. Statistically significant differences in GABA levels were found in the combined psychiatric group compared with healthy controls (Hedge's g = -0.112, p = 0.008). Further analyses based on brain regions showed that brain GABA levels significantly differed across Axis I disorders and controls in the parieto-occipital cortex (Hedge's g = 0.277, p = 0.019). Furthermore, GABA levels were reduced in affective disorders in the occipital cortex (Hedge's g = -0.468, p = 0.043). Reductions in Glx levels were found in neurodevelopmental disorders (Hedge's g = -0.287, p = 0.022). Analysis focusing on brain regions suggested that Glx levels decreased in the frontal cortex (Hedge's g = -0.226, p = 0.025), and the reduction of Glu levels in patients with affective disorders in the frontal cortex is marginally significant (Hedge's g = -0.172, p = 0.052). When analyzing the anterior cingulate cortex and prefrontal cortex separately, reductions were only found in GABA levels in the former (Hedge's g = - 0.191, p = 0.009) across all disorders. Altered glutamatergic and GABAergic metabolites were found across psychiatric disorders, indicating shared dysfunction. We found reduced GABA levels across psychiatric disorders and lower Glu levels in affective disorders. These results highlight the significance of GABA and Glu in psychiatric etiology and partially support rethinking current diagnostic categories.

Green supported of silver nanoparticles on the surface of reduced graphene oxide: Investigation of its anti-epileptic activity on experimental models of epilepsy in mice

This research demonstrated a novel, simple and environmentally safe process for the fabrication of graphene/silver composite using Malva sylvestris flower extract as a capping and reducing agent. Initially, the Malva sylvestris flower was used to make modified reduced graphene oxide that was coated by extract. The phytochemical groups of extract that have poylphenolic function can act as the green reducing agent for capping and reducing Ag ions on the surface of rGO (Reduced Graphene Oxide) to make the desired rGO/M.S./Ag NPs nanocomposite. The FT-IR, TEM, FE-SEM-EDX and XRD results confirmed the successful fabrication of the desired nanocomposite. The efficacy of the rGO/M.S./Ag NPs was first tested using the 6-Hz-induced seizure model. Subsequently, its effectiveness was assessed against maximal electroshock (MES) and pentylenetetrazole (PTZ)-induced convulsions. Additionally, the impact of the potent rGO/M.S./Ag NPs nanocomposite on Gamma amino butyric acid (GABA) levels in the brain was investigated to elucidate its potential mechanism of action. Furthermore, the effective rGO/M.S./Ag NPs nanocomposite underwent an actophotometer test to evaluate its potential to induce deficits in locomotor activity. During the 6-Hz seizure test, the rGO/M.S./Ag NPs nanocomposite demonstrated a significant and dose-dependent reduction in 6-Hz-induced seizures at doses of 30 and 90 µg/kg. Subsequently, the rGO/M.S./Ag NPs nanocomposite was assessed in MES and PTZ models. Interestingly, rGO/M.S./Ag NPs provided substantial and dose-dependent protection against MES (P < 0.01) and PTZ-induced (P < 0.01) seizures in mice. The rGO/M.S./Ag NPs nanocomposite exhibited a notable increase in brain GABA levels (P < 0.01) compared to the control, while showing no significant change in locomotor activity across all tested doses. Notably, a higher dose of rGO/M.S./Ag NPs nanocomposite (90 µg/kg, p.o.) and Diazepam (5 mg/mg, p.o.) completely prevented convulsions in all anticonvulsant tests. These results indicate that the rGO/M.S./Ag NPs nanocomposite possesses significant anticonvulsant properties, with one potential mechanism being the enhancement of GABA levels in the brain.

Gamma-aminobutyric acid (GABA) levels in the midcingulate cortex and clozapine response in patients with treatment-resistant schizophrenia: A proton magnetic resonance spectroscopy (1 H-MRS) study.

Gamma-Aminobutyric Acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABAergic dysfunction has been implicated in the pathophysiology of schizophrenia. Clozapine, the only approved drug for treatment-resistant schizophrenia (TRS), involves the GABAergic system as one of its targets. However, no studies have investigated the relationship between brain GABA levels, as measured by proton magnetic resonance spectroscopy (1 H-MRS), and clozapine response in patients with TRS. This study enrolled patients with TRS who did not respond to clozapine (ultra-resistant schizophrenia: URS) and who responded to clozapine (non-URS), patients with schizophrenia who responded to first-line antipsychotics (first-line responders: FLR), and healthy controls (HCs). We measured GABA levels in the midcingulate cortex (MCC) using 3T 1 H-MRS and compared these levels among the groups. The associations between GABA levels and symptom severity were also explored within the patient groups. A total of 98 participants (URS: n=22; non-URS: n=25; FLR: n=16; HCs: n=35) completed the study. We found overall group differences in MCC GABA levels (F(3,86)=3.25, P=0.04). Specifically, patients with URS showed higher GABA levels compared to those with non-URS (F(1,52)=8.40, P=0.03, Cohen's d=0.84). MCC GABA levels showed no associations with any of the symptom severity scores within each group or the entire patient group. Our study is the first to report elevated GABA levels in the MCC in patients with schizophrenia resistant to clozapine treatment compared with those responsive to clozapine. Longitudinal studies are required to evaluate if GABA levels are a suitable biomarker to predict clozapine resistance.

Evaluation of repeated ghrelin administration on seizures, oxidative stress and neurochemical parameters in pentyleneterazole induced kindling in rats.

Epileptic seizures are thought to be caused by the impaired balance between excitatory (glutamate) and inhibitor [gamma amino butyric acid (GABA)] neurotransmitters in the brain. Neuropeptides have potent modulator properties on these neurotransmitters. Ghrelin exerts anticonvulsant effects in an acute pentylenetetrazole (PTZ) model. However, the effect of repeated ghrelin injections in chronic pentylenetetrazole kindling model is not known. In this study, the effects of repeated ghrelin administration on seizure scores, working memory, locomotor activity, oxidative biomarkers, and neurochemical parameters in PTZ kindling in rats was examined. For this purpose, 35 mg/kg of PTZ was administered intraperitoneally to the experimental groups. The rats also received physiological saline/diazepam or ghrelin before each PTZ injection. After behavioral analysis (Y-maze, rotarod, and locomotor activity tests), biochemical and neurochemical analysis were conducted using ELISA. PTZ administration induced progression in the seizure scores and all of the rats in the PS + PTZ group were kindled with the 20th injection. Ghrelin treatment significantly reduced the seizure scores. The difference among the groups in terms of the Y-maze, locomotor activity, and rotarod tests was nonsignificant. PTZ administration significantly decreased the brain GABA, CAT, and AChE levels, and increased the MDA, NO, and protein carbonyl levels. Repeated ghrelin treatment ameliorated the GABA, AChE, CAT, MDA, NO, and protein carbonyl levels. Taken together, the results indicated that repeated ghrelin treatment had antioxidant, and anticonvulsant activity on PTZ kindling in rats.

P550. GABA Alteration in Patients With Treatment-Resistant Schizophrenia: A 1H-MRS Study

Gamma-Aminobutyric Acid (GABA) is the primary inhibitory neurotransmitter in the central nervous system. GABAergic dysfunction has been implicated in the pathophysiology of schizophrenia. Clozapine, the only approved drug for treatment-resistant schizophrenia (TRS), involves the GABAergic system as one of its targets. However, no studies have investigated the relationship between brain GABA levels, measured by proton magnetic resonance spectroscopy (1H-MRS), and clozapine response in patients with TRS.

Decreased Brain GABA Levels in Patients with Migraine Without Aura: An Exploratory Proton Magnetic Resonance Spectroscopy Study

Increasing neurophysiological studies had revealed that regional excitation-inhibition imbalance in the brain played a key role in the pathogenesis of migraine. This study aimed to explore the alterations in gamma-aminobutyric acid (GABA) and glutamate/glutamine complex (Glx) levels in the anterior cingulate gyrus (ACC) and medial prefrontal lobe (mPFC) of patients with migraine without aura (MWoA) and investigate the correlation between neurotransmitter levels and clinical indicators. A total of 28 patients with MWoA and 28 sex-, age-, and education level–matched healthy controls (HCs) underwent single-voxel proton magnetic resonance spectroscopy scanning at 3.0 Tesla. MEscher-Garwood Point RESolved Spectroscopy (MEGA-PRESS) sequence was performed to acquire the spectral data of GABA and Glx in the ACC and mPFC. The clinical indicators and anxiety-depression states of all participants were assessed. The acquired GABA signal contained the overlapping signals of macromolecules and homocarnosine, hence expressed as GABA+. The creatine (Cr) signal was applied as an endogenous reference. We observed that GABA+/Cr levels were significantly lower in ACC and mPFC of patients with MWoA than of HCs, with no significant difference in Glx levels. Negative correlations between GABA+/Cr levels and attack frequency were found in the ACC and mPFC regions of patients. These results suggested that there might be a close relationship between ACC and mPFC GABAergic neurons abnormalities and the pathophysiological mechanisms of MWoA. It might be beneficial to targeted treatment for patients with MWoA.

Elevation of brain gamma‐aminobutyric acid levels is associated with vigabatrin‐associated brain abnormalities on magnetic resonance imaging

ObjectiveVigabatrin (VGB) is an effective antiseizure medication for West syndrome. It works by irreversibly inhibiting gamma-aminobutyric acid (GABA) transaminase and increasing central GABA levels. Vigabatrin-associated brain abnormalities on magnetic resonance imaging (VABAM) are an adverse effect of VGB that has only been reported in children, but the pathophysiology of this effect is unknown. In this study, we evaluated the relationship of VGB and brain GABA levels as well as the association between VABAM and GABA. MethodsFor the 15 consecutive pediatric patients treated with VGB, free GABA, glutamine, and glutamate in cerebrospinal fluid (CSF) and plasma, GABA to creatine and phosphocreatine (Cr) peak ratio (GABA/Cr), glutamine (Gln)/Cr, and glutamate (Glu)/Cr as quantified by proton MR spectroscopy (1H-MRS) were retrospectively examined. GABA/Cr was compared with in-house normal pediatric controls. Differences in the levels of each metabolite in VABAM and non-VABAM cases were also examined. ResultsThirteen of the included subjects underwent magnetic resonance imaging (MRI) and 1H-MRS, and two of them presented VABAM; both cases were very-low-birth-weight preterm infants with post-hemorrhagic hydrocephalus. CSF levels of free GABA were significantly higher in VABAM (5.26 ± 1.95 μmol/L) than in non-VABAM (0.59 ± 0.63 μmol/L) cases (P = 0.03). The GABA/Cr was significantly higher in patients with VGB (0.34 ± 0.16) than in pediatric controls (0.20 ± 0.05) (P = 0.02). The GABA/Cr tended to be higher in VABAM (0.48 ± 0.10) than in non-VABAM cases (0.31 ± 0.15) (P = 0.31). SignificanceElevated brain GABA levels were observed in VABAM patients, suggesting its involvement in the pathogenesis of this condition. In particular, a marked increase in CSF-free GABA was characteristic. Although the elevation of the GABA/Cr is mild, it may be useful for early identification of patients with risk of VABAM.

GABA concentrations in the anterior cingulate and dorsolateral prefrontal cortices: Associations with chronic cigarette smoking, neurocognition, and decision making.

Chronic cigarette smoking is associated with regional metabolite abnormalities in choline-containing compounds, creatine-containing compounds, glutamate, and N-acetylaspartate. The effects of cigarette smoking on anterior frontal cortical gamma-aminobutyric acid (GABA) concentration are unknown. This study compared chronic smokers (n = 33) and nonsmokers (n = 31) on anterior cingulate cortex (ACC) and right dorsolateral prefrontal cortex (DLPFC) GABA+ (the sum of GABA and coedited macromolecules) concentrations and associations of GABA+ levels in these regions with seven neurocognitive domains of functioning, decision making, and impulsivity measures. Smokers had significantly lower right DLPFC GABA+ concentration than nonsmokers, but groups were equivalent on ACC GABA+ level. Across groups, greater number of days since end of menstrual cycle was related to higher GABA+ level in the ACC but not right DLPFC GABA+ concentration. In exploratory correlation analyses, higher ACC and right DLPFC GABA+ levels were associated with faster processing speed and better auditory-verbal memory, respectively, in the combined group of smokers and nonsmokers; in smokers only, higher ACC GABA+ was related to better decision making and auditory-verbal learning. This study contributes additional novel data on the adverse effects of chronic cigarette smoking on the adult human brain and demonstrated ACC and DLPFC GABA+ concentrations were associated with neurocognition and decision making/impulsivity in active cigarette smokers. Longitudinal studies on the effects of smoking cessation on regional brain GABA levels, with a greater number of female participants, are required to determine if the observed metabolite abnormalities are persistent or normalize with smoking cessation.

Retrospective Chart Review of Intravenous Valproate Sodium as a Preventive Treatment for Patients With Chronic Migraine.

This is a small pilot study to evaluate the effectiveness of an intravenous (IV) valproate sodium therapy protocol for migraine prevention in a population of patients with chronic migraine refractory to multiple preventive medications. Valproate sodium is an anti-epileptic and mood stabilizer that has been shown to prevent migraine when used daily in oral form. The specific mechanism of action in migraine is unknown, but it may be related to suppressing inflammation and increasing brain Gamma-aminobutyric acid levels. It also may relate to its ability to suppress cortical spreading depression. Multiple studies have suggested that valproic acid and its derivatives may inhibit Calcitonin gene-related peptide. In the present work, we undertook a small pilot study to evaluate the effectiveness of an IV valproate sodium therapy for migraine prevention in a population of patients with chronic migraine refractory to multiple preventive medications. Fourteen adult patients with chronic migraine were admitted for a 4-day course of IV valproate sodium. Patients received 250mg of valproate sodium over a standard infusion time of 60minutes every 8hours. Most patients received 9 doses over the 4-day course of treatment. One patient had to discontinue after 1 dose of 250-mg valproate sodium, as this patient experienced an increase in his previous symptoms of nausea, vomiting, and vertigo with his first dose. To avoid positive selection bias, we evaluated the first admission for valproate IV therapy in patients with multiple admissions; there was 1 patient with 2 admissions and 1 with 3 admissions for IV valproate sodium. Of note - all admission outcomes for these patients were similar. Headache diaries were reviewed from 1 month before, during, and approximately 2 months after their admission. Due to the observational nature of the study and small sample size, we did not think that quantitative statistical analysis would add more meaning to this pilot study. Formal quantitative statistical analysis was not performed in this study and descriptive statistical analysis was used due to this being a pilot proof of concept study. Physician clinical judgment in combination with patient reports were used to assign a dichotomous conclusion on clinical improvement for each patient. In the future, we plan to create a larger study, including additional treatment groups for control, such as IV Dihydroergotamine or IV Chlorpromazine, in order to quantify improvement of symptoms. A total of 9 out of 13 (69%) patients had an improvement in their headache post-admission and reported a reduction in headache frequency, intensity, and/or use of acute medications 4-6 weeks following their admissions. A total of 5 out of 13 (38%) patients also reported an improvement in headache intensity during the 4-day period of inpatient admission. The other 8 out of 13 (62%) patients reported stable headache pattern. One patient had feelings of restlessness, which improved with prolongation of infusion time to 120minutes. These results indicate that this repetitive dosing valproate sodium protocol is a safe and well-tolerated intervention for the treatment of chronic migraine resistant to oral medications. Given the promising outcomes on patient headache improvement with this small pilot study, studies to confirm this benefit in a larger cohort of chronic migraine patients are warranted, preferable with the addition of a blinded control group for comparison.

The Effect of Visual Stimulation on GABA and Macromolecule Levels in the Human Brain in vivo

Abstract—Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain; it plays an important role in various types of synaptic plasticity and pathology. In the present work, proton magnetic resonance spectroscopy (1H-MRS) and two modified MEGA-PRESS pulse sequences, that is, –GABAMEGA-PRESS and +GABAMEGA-PRESS, were used to investigate the effect of visual stimulation on the GABA level in the human visual cortex in vivo. With –GABAMEGA-PRESS, it was possible to acquire the 1H-NMR signal of methylated protons of GABA with the chemical shift δ = 3.01 ppm without the signals from macromolecules. When +GABAMEGA-PRESS was used, the GABA signal was a superposition of resonances of methylene protons of GABA and macromolecules. The effect of constant visual stimulation on the level of N-acetylaspartate and total level of glutamate and glutamine was also estimated. Constant visual stimulation had no effect on the levels of N-acetylaspartate and glutamine in the visual cortex. The –GABA signal intensity decreased with a statistically significant decrease in the level of GABA signal intensity leading to inactivation of GABA synthesis. No statistically significant changes in the intensity of the +GABA resonance were found, probably due to the effect of visual stimulation on macromolecules. In order to test this hypothesis, a signal from macromolecules was acquired using a specifically designed inversion-recovery pulse sequence. It was shown that the intensity of this signal is unaffected by visual stimulation and the absence of changes in the intensity of the +GABA signal during the stimulation has to be considered as the masking effect of macromolecular signal.

Anticonvulsant Activity of Hydroalcoholic Phoenix dactylifera Fruit Extract and Pimpinella anisum Oil in Mice

Epilepsy is a group of long-term neurological disorders characterized by epileptic seizures. The present study sought to investigate the anticonvulsant and neuroprotective Activity of Hydroalcoholic Phoenix dactylifera fruit extract (HAPD) and Pimpinella Anisum Oil (PAO) against Pentylenetetrazole (PTZ) and Maximal Electric Shock (MES) induced a seizure in mice. Mice groups were treated with HAPD1000 mg/kg, PAO 4 ml/kg. The onset of a seizure and generalized seizure were measured, followed by Gamma-Aminobutyric Acid (GABA) and antioxidant enzymes assessments. The potential of these substances to induce any neurological toxicity was also evaluated by using rotarod, forced swim test and horizontal screen test. The current study demonstrates that HAPD and PAO delay onset of the seizure and generalized seizure, also elevated GABA and antioxidant enzymes level and haven’t any neurological toxicity. The current study suggests that hydroalcoholic Phoenix dactylifera extract and Pimpinella anisum oil have anticonvulsant, neuroprotective and antioxidant activity and can increase brain GABA level.

Pyridoxine for the treatment of isoniazid-induced seizures in intentional ingestions: The experience of a national poison center

BackgroundPyridoxine (vitamin B6) is used as an antidote for isoniazid (INH) overdose, especially in intentional ingestions. The active form of pyridoxine is pyridoxal 5′-phosphate (P5P), a cofactor for glutamic acid decarboxylase in gamma aminobutyric acid (GABA) synthesis. INH inhibits this enzymatic pathway causing a decrease in brain levels of GABA, the major inhibitory neurotransmitter in the central nervous system, with resultant increase in susceptibility to seizures. The aim of this study was to evaluate and document the role of pyridoxine in the treatment of patients with intentional ingestion of INH and to report our experience. MethodsMedical records of affected patients were reviewed; data collected included exposure history, clinical manifestations, physical examination, laboratory values and clinical outcomes. ResultsThere were 16 cases of INH intoxication associated with intentional ingestions, 11 were associated with substantial ingestions with the maximum dose ingested being 15 g. In 9 cases the patients suffered seizures while other clinical manifestations included hypertension, drowsiness and vomiting. Pyridoxine was administered prophylactically in only 3 patients, none of whom developed seizures. ConclusionIntentional ingestion of INH is one of the causes of drug-induced seizures. Early recognition and specific treatment with pyridoxine can prevent mortality. Our series suggests that patients with large-dose intentional ingestions have a substantial risk of multiple seizures that can be treated successfully with 1 g of pyridoxine intravenously or 1 g of pyridoxine per gram of isoniazid ingestion. This antidote is safe and effective. Consideration can be given to administering pyridoxine prophylactically in some circumstances.

Sex- and age-specific modulation of brain GABA levels in a mouse model of Alzheimer's disease

Age and sex are risk factors of Alzheimer's disease (AD). Among the neurotransmitter systems, gamma-aminobutyric acid (GABA) has been implicated in AD pathogenesis but the relevance of sex-specific GABAergic dysfunction during AD progression remains unknown. In the present study, we utilized state-of-the-art high-resolution magic angle spinning nuclear magnetic resonance to systematically monitor the brain region-, age-, and sex-specific modulation of GABA levels in wild-type and Tg2576 mice with amyloid pathology. In addition, we followed the possible role of reactive astrocytes in sex-specific GABA modulation. In female Tg2576 mice, hippocampal GABA levels were significantly elevated, along with higher number of reactive astrocytes and amyloid deposition. The elevated GABA was found to be produced via the monoamine oxidase-B route from putrescine in reactive astrocytes, more substantially in female than male mice, thus suggesting a role of astrocytes in memory impairment and sex-related differences in AD. Our results paint a coherent model of memory impairment in AD and signify that dynamic changes in regional GABA may be at the root of marked sex disparities observed in AD.

The aging brain and changes in GABA concentrations

The aging brain and changes in GABA concentrations

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.

Brain GABA levels across psychiatric disorders: A systematic literature review and meta-analysis of (1) H-MRS studies.

The inhibitory gamma-aminobutyric acid (GABA) system is involved in the etiology of most psychiatric disorders, including schizophrenia, autism spectrum disorder (ASD) and major depressive disorder (MDD). It is therefore not surprising that proton magnetic resonance spectroscopy ((1) H-MRS) is increasingly used to investigate in vivo brain GABA levels. However, integration of the evidence for altered in vivo GABA levels across psychiatric disorders is lacking. We therefore systematically searched the clinical (1) H-MRS literature and performed a meta-analysis. A total of 40 studies (N = 1,591) in seven different psychiatric disorders were included in the meta-analysis: MDD (N = 437), schizophrenia (N = 517), ASD (N = 150), bipolar disorder (N = 129), panic disorder (N = 81), posttraumatic stress disorder (PTSD) (N = 104), and attention deficit/hyperactivity disorder (ADHD) (N = 173). Brain GABA levels were lower in ASD (standardized mean difference [SMD] = -0.74, P = 0.001) and in depressed MDD patients (SMD = -0.52, P = 0.005), but not in remitted MDD patients (SMD = -0.24, P = 0.310) compared with controls. In schizophrenia this finding did not reach statistical significance (SMD = -0.23, P = 0.089). No significant differences in GABA levels were found in bipolar disorder, panic disorder, PTSD, and ADHD compared with controls. In conclusion, this meta-analysis provided evidence for lower brain GABA levels in ASD and in depressed (but not remitted) MDD patients compared with healthy controls. Findings in schizophrenia were more equivocal. Even though future (1) H-MRS studies could greatly benefit from a longitudinal design and consensus on the preferred analytical approach, it is apparent that (1) H-MRS studies have great potential in advancing our understanding of the role of the GABA system in the pathogenesis of psychiatric disorders. Hum Brain Mapp 37:3337-3352, 2016. © 2016 Wiley Periodicals, Inc.

Evaluation of anti-epileptic activity of leaf extracts of Punica granatum on experimental models of epilepsy in mice.

Objectives:This study was aimed to examine the anti-epileptic activity of leaf extracts of Punica granatum in experimental models of epilepsy in Swiss albino mice.Materials and Methods:Petroleum ether leaf extract of P. granatum (PLPG), methanolic LPG (MLPG), and aqueous LPG (ALPG) extracts of P. granatum leaves was initially evaluated against 6-Hz-induced seizure model; the potent extract was further evaluated against maximal electroshock (MES) and pentylenetetrazole (PTZ)-induced convulsions. Further, the potent extract was evaluated for its influence on Gamma amino butyric acid (GABA) levels in brain, to explore the possible mechanism of action. In addition, the potent extract was subjected to actophotometer test to assess its possible locomotor activity deficit inducing action.Results:In 6-Hz seizure test, the MLPG has alleviated 6-Hz-induced seizures significantly and dose dependently at doses 50, 100, 200, and 400 mg/kg. In contrast, PLPG and ALPG did not show any protection, only high dose of ALPG (400 and 800 mg/kg, p.o.) showed very slight inhibition. Based on these observations, only MLPG was tested in MES and PTZ models. Interestingly, the MLPG (50, 100, 200 and 400 mg/kg) has offered significant and dose-dependent protection against MES (P < 0.01) and PTZ-induced (P < 0.01) seizures in mice. Further, MLPG showed a significant increase in brain GABA levels (P < 0.01) compared to control and showed insignificant change in locomotor activity in all tested doses (100, 200 and 400 mg/kg). Interestingly, higher dose of MLPG (400 mg/kg, p.o.) and Diazepam (5 mg/mg, p.o.) have completely abolished the convulsions in all the anticonvulsant tests.Conclusion:These findings suggest that MLPG possesses significant anticonvulsant property, and one of the possible mechanisms behind the anticonvulsant activity of MLPG may be through enhanced GABA levels in the brain.

Edited Magnetic Resonance Spectroscopy Detects an Age-Related Decline in Nonhuman Primate Brain GABA Levels

Recent research had shown a correlation between aging and decreasing Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain. However, how GABA level varies with age in the medial portion of the brain has not yet been studied. The purpose of this study was to investigate the GABA level variation with age focusing on the posterior cingulate cortex, which is the “core hub” of the default mode network. In this study, 14 monkeys between 4 and 21 years were recruited, and MEGA-PRESS MRS was performed to measure GABA levels, in order to explore a potential link between aging and GABA. Our results showed that a correlation between age and GABA+/Creatine ratio was at the edge of significance (r = −0.523, p = 0.081). There was also a near-significant trend between gray matter/white matter ratio and the GABA+/Creatine ratio (r = −0.518, p = 0.0848). Meanwhile, the correlation between age and grey matter showed no significance (r = −0.028, p = 0.93). Therefore, age and gray matter/white matter ratio account for different part of R-squared (adjusted R-squared = 0.5187) as independent variables for predicting GABA levels. Adjusted R-squared is about 0.5 for two independent variables. These findings suggest that there is internal neurochemical variation of GABA levels in the nonhuman primates associated with normal aging and structural brain decline.

Neurotransmitters as food supplements: the effects of GABA on brain and behavior.

Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human cortex. The food supplement version of GABA is widely available online. Although many consumers claim that they experience benefits from the use of these products, it is unclear whether these supplements confer benefits beyond a placebo effect. Currently, the mechanism of action behind these products is unknown. It has long been thought that GABA is unable to cross the blood–brain barrier (BBB), but the studies that have assessed this issue are often contradictory and range widely in their employed methods. Accordingly, future research needs to establish the effects of oral GABA administration on GABA levels in the human brain, for example using magnetic resonance spectroscopy. There is some evidence in favor of a calming effect of GABA food supplements, but most of this evidence was reported by researchers with a potential conflict of interest. We suggest that any veridical effects of GABA food supplements on brain and cognition might be exerted through BBB passage or, more indirectly, via an effect on the enteric nervous system. We conclude that the mechanism of action of GABA food supplements is far from clear, and that further work is needed to establish the behavioral effects of GABA.

Antiepileptic and antipsychotic activities of standardized Śilājatu (Shilajit) in experimental animals.

Background:Śilājatu (Shilajit; SJ) is claimed in traditional Indian medical practice to be useful in the treatment of nervous disorders, epilepsy and as antistress.Aim:To investigate whether SJ possesses antiepileptic and antipsychotic activities in rodents.Materials and Methods:Isonicotinyl hydrazine (INH), pentylenetetrazole (PTZ), apomorphine, phenytoin, diazepam, haloperidol and other chemicals of analytical grade were procured from standard companies. The antiepileptic activity of SJ was assessed using maximal electro shock (MES)-induced seizures in rats, INH and PTZ-induced seizures in mice. The antipsychotic effect of SJ was evaluated using apomorphine-induced climbing and stereotyped behaviours respectively, in mice and rats.Settings and Designs:SJ (25 and 50 mg/kg, p.o.) was given orally once daily for 15 days in all the rodent models. On the test day, SJ was administered 1 h prior to electric shock or chemical inducers (INH/PTZ/apomorphine) in experimental animals; the animals were then observed for different phases of seizures and psychotic behaviours. In addition, gamma-aminobutyric acid (GABA) content in the brain of rats and mice was estimated in seizure models.Statistical Analysis:The data were expressed as mean ± standard error of mean. Statistical comparisons were performed by one-way ANOVA followed by Tukey's post-test using Graph Pad Prism version 5.0, USA. A P < 0.05 was considered significant.Results and Conclusions:SJ pretreatment significantly inhibited the seizures induced by MES, INH and PTZ in a dose dependent manner. Further, SJ augmented brain GABA levels to normal, decreased by INH and PTZ in mice brain. SJ pretreatment also significantly inhibited the climbing and stereotyped behaviours induced by apomorphine. The present data seems to confirm the antiepileptic activity of SJ which may be because of enhancing the GABAergic system. The antipsychotic activity observed may be due to anti-dopaminergic and/or GABA-mimetic actions.