Low Gamma-aminobutyric Acid Levels Research Articles

Interaction between interleukin-1 beta and angiotensin II receptor 1 in hypothalamic paraventricular nucleus contributes to progression of heart failure.

The central mechanisms by which interleukin-1 beta (IL-1β) and angiotension II receptor 1 (AT1-R) contribute to sympathoexcitation in heart failure (HF) are unclear. In this study, we determined whether an interaction between IL-1β and AT1-R in the paraventricular nucleus (PVN) contributes to progression of HF. Rats were implanted with bilateral PVN cannulae and subjected to coronary artery ligation or sham surgery (Sham). Subsequently, animals were treated for 4 weeks through PVN infusion with either vehicle, losartan (LOS, 200 μg/day), IL-1β (IL, 1 μg/day), or IL-1β along with LOS (LOS+IL). HF rats had higher levels of corticotropin-releasing hormone (CRH), norepinephrine (NE), and glutamate (Glu); lower levels of gamma-aminobutyric acid (GABA); and more positive fra-like activity in PVN when compared with Sham rats. HF rats also had higher levels of NE, epinephrine (EPI), and IL-1β in plasma. PVN infusion of LOS attenuated the decreases in GABA and the increases in CRH, NE, and Glu in the PVN of HF rats. IL-1β could further increase the expression of CRH, NE, Glu, EPI, and IL-1β and decrease GABA expression. Treatment with IL-1β along with LOS could eliminate the effects of IL-1β. These findings suggest that an interaction between AT1-R and IL-1β in the PVN contributes to progression in HF.

Altered Anterior Cingulate Neurochemistry in Emerging Adult Binge Drinkers with a History of Alcohol‐Induced Blackouts

Binge alcohol consumption is associated with multiple neurobiological consequences, including altered neurophysiology, brain structure, and functional activation. Magnetic resonance spectroscopy (MRS) studies have demonstrated neurochemical alterations in the frontal lobe of alcohol users, although most studies focused on older, alcohol-dependent subjects. In this study, neurochemical data were acquired using MRS at 4.0 Tesla from emerging adults (18 to 24 years old) who were binge alcohol drinkers (BD, n = 23) or light drinkers (LD, n = 31). Since binge drinking is also associated with increased prevalence of experiencing an alcohol-induced blackout, BD were stratified into alcohol-induced blackout (BDBO) and non-blackout (BDN) groups. Overall, BD had significantly lower gamma amino-butyric acid (GABA) and N-acetyl-aspartate (NAA) in the anterior cingulate cortex (ACC) than LD. When stratified by blackout history, BDBO also had lower ACC glutamate (Glu) than LD. No group differences in MRS metabolites were observed in the parietal-occipital cortex. Lower ACC GABA and Glu remained significant after accounting for lower gray matter content in BD, however, NAA differences were no longer evident. In addition, low ACC GABA levels were associated with greater alcohol use consequences, and worse response inhibition and attention/mental flexibility in BD. These data indicate that binge drinking affects frontal lobe neurochemistry, more so in those who had experienced an alcohol-induced blackout. Characterization of the neurochemical profiles associated with binge alcohol consumption and blackout history may help identify unique risk factors for the later manifestation of alcohol abuse and dependence, in young individuals who are heavy, frequent drinkers, but who do not meet the criteria for alcohol abuse disorders.

Exercise Training Attenuates Hypertension and Cardiac Hypertrophy by Modulating Neurotransmitters and Cytokines in Hypothalamic Paraventricular Nucleus

AimsRegular exercise as an effective non-pharmacological antihypertensive therapy is beneficial for prevention and control of hypertension, but the central mechanisms are unclear. In this study, we hypothesized that chronic exercise training (ExT) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro-inflammatory cytokines (PICs) and restoring the neurotransmitters balance in the hypothalamic paraventricular nucleus (PVN) in young spontaneously hypertensive rats (SHR). In addition, we also investigated the involvement of nuclear factor-κB (NF-κB) p65 and NAD(P)H oxidase in exercise-induced effects.Methods and resultsModerate-intensity ExT was administrated to young normotensive Wistar-Kyoto (WKY) and SHR rats for 16 weeks. SHR rats had a significant increase in mean arterial pressure and cardiac hypertrophy. SHR rats also had higher levels of glutamate, norepinephrine (NE), phosphorylated IKKβ, NF-κB p65 activity, NAD(P)H oxidase subunit gp91phox, PICs and the monocyte chemokine protein-1 (MCP-1), and lower levels of gamma-aminobutyric acid (GABA) and interleukin-10 (IL-10) in the PVN. These SHR rats also exhibited higher renal sympathetic nerve activity (RSNA), and higher plasma levels of PICs, and lower plasma IL-10. However, ExT ameliorates all these changes in SHR rats.ConclusionThese findings suggest that there are the imbalances between excitatory and inhibitory neurotransmitters and between pro- and anti-inflammatory cytokines in the PVN of SHR rats, which at least partly contributing to sympathoexcitation, hypertension and cardiac hypertrophy; chronic exercise training attenuates hypertension and cardiac hypertrophy by restoring the balances between excitatory and inhibitory neurotransmitters and between pro- and anti-inflammatory cytokines in the PVN; NF-κB and oxidative stress in the PVN may be involved in these exercise-induced effects.

Interaction Between AT1 Receptor and NF-κB in Hypothalamic Paraventricular Nucleus Contributes to Oxidative Stress and Sympathoexcitation by Modulating Neurotransmitters in Heart Failure

Angiotensin II type 1 receptor (AT1-R) and nuclear factor-kappaB (NF-κB) in the paraventricular nucleus (PVN) play important roles in heart failure (HF); however, the central mechanisms by which AT1-R and NF-κB contribute to sympathoexcitation in HF are yet unclear. In this study, we determined whether interaction between AT1-R and NF-κB in the PVN modulates neurotransmitters and contributes to NAD(P)H oxidase-dependent oxidative stress and sympathoexcitation in HF. Rats were implanted with bilateral PVN cannulae and subjected to coronary artery ligation or sham surgery (SHAM). Subsequently, animals were treated for 4 weeks through bilateral PVN infusion with either vehicle or losartan (LOS, 10μg/h), an AT1-R antagonist; or pyrrolidine dithiocarbamate (PDTC, 5μg/h), a NF-κB inhibitor via osmotic minipump. Myocardial infarction (MI) rats had higher levels of glutamate (Glu), norepinephrine (NE) and NF-κB p65 activity, lower levels of gamma-aminobutyric acid (GABA), and more positive neurons for phosphorylated IKKβ and gp91(phox) (a subunit of NAD(P)H oxidase) in the PVN when compared to SHAM rats. MI rats also had higher levels of renal sympathetic nerve activity (RSNA) and plasma proinflammatory cytokines (PICs), NE and epinephrine. PVN infusions of LOS or PDTC attenuated the decreases in GABA and the increases in gp91(phox), NF-κB activity, Glu and NE, in the PVN of HF rats. PVN infusions of LOS or PDTC also attenuated the increases in RSNA and plasma PICs, NE and epinephrine in MI rats. These findings suggest that interaction between AT1 receptor and NF-κB in the PVN contributes to oxidative stress and sympathoexcitation by modulating neurotransmitters in heart failure.

Decreased Hepatocyte Growth Factor (HGF) and Gamma Aminobutyric Acid (GABA) in Individuals with Obsessive-Compulsive Disorder (OCD)

IntroductionThere is support for the role of gamma aminobutyric acid (GABA) in the etiology of mood disorders. Recent research has shown that hepatocyte growth factor (HGF) modulates GABAergic inhibition and seizure susceptibility. This study was designed to determine and correlate plasma levels of HGF and GABA as well as symptom severity in individuals with obsessive-compulsive disorder (OCD).Subjects and methodsPlasma from 15 individuals with OCD (9 males, 6 females;, mean age 38.7 years) and 17 neurotypical controls (10 males, 7 females; mean age 35.2 years) was assessed for HGF, GABA, urokinase plasminogen activator (uPA), and urokinase plasminogen activator receptor (uPAR) concentration using enzyme-linked immunosorbest assays ELISAs. Symptom severity was assessed in these OCD individuals and compared with HGF and GABA concentrations.ResultsIn this preliminary study, individuals with OCD had significantly decreased HGF levels, decreased plasma levels of GABA and decreased uPA. We found that both uPA and uPAR levels correlate with HGF. Both low uPA and low uPAR levels correlate with high symptom severity in individuals with OCD. Low GABA levels in OCD individuals also correlate with high symptom severity.DiscussionThese results demonstrate a preliminary association between HGF, GABA, uPA levels, and OCD and suggest that plasma GABA and uPA levels are related to symptom severity in individuals with OCD.

NF-κB in the paraventricular nucleus modulates neurotransmitters and contributes to sympathoexcitation in heart failure.

Findings from our laboratory indicate that proinflammatory cytokines and their transcription factor, nuclear factor-kappaB (NF-κB), are increased in the hypothalamic paraventricular nucleus (PVN) and contribute towards the progression of heart failure. In this study, we determined whether NF-κB activation within the PVN contributes to sympathoexcitation via interaction with neurotransmitters in the PVN during the pathogenesis of heart failure. Heart failure was induced in rats by left anterior descending coronary artery ligation. Sham-operated control (SHAM) or heart failure rats were treated for 4weeks through bilateral PVN infusion with SN50, SN50M or vehicle via osmotic minipump. Rats with heart failure treated with PVN vehicle or SN50M (inactive peptide for SN50) had increased levels of glutamate, norepinephrine (NE), tyrosine hydroxylase (TH), superoxide, gp91(phox) (a subunit of NAD(P)H oxidase), phosphorylated IKKβ and NF-κB p65 activity, and lower levels of gamma-aminobutyric acid (GABA) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN compared with those of SHAM rats. Plasma levels of cytokines, norepinephrine, epinephrine and angiotensin II, and renal sympathetic nerve activity (RSNA) were increased in heart failure rats. Bilateral PVN infusion of SN50 prevented the decreases in PVN GABA and GAD67, and the increases in RSNA and PVN glutamate, norepinephrine, TH, superoxide, gp91(phox), phosphorylated IKKβ and NF-κB p65 activity observed in vehicle or SN50M-treated heart failure rats. A same dose of SN50 given intraperitoneally did not affect neurotransmitters concentration in the PVN and was similar to vehicle-treated heart failure rats. These findings suggest that NF-κB activation in the PVN modulates neurotransmitters and contributes to sympathoexcitation in rats with ischemia-induced heart failure.

Paraventricular nucleus corticotrophin releasing hormone contributes to sympathoexcitation via interaction with neurotransmitters in heart failure.

Recent studies indicate that systemic administration of tumor necrosis factor (TNF)-α induces increases in corticotrophin releasing hormone (CRH) and CRH type 1 receptors in the hypothalamic paraventricular nucleus (PVN). In this study, we explored the hypothesis that CRH in the PVN contributes to sympathoexcitation via interaction with neurotransmitters in heart failure (HF). Sprague-Dawley rats with HF or sham-operated controls (SHAM) were treated for 4 weeks with a continuous bilateral PVN infusion of the selective CRH-R1 antagonist NBI-27914 or vehicle. Rats with HF had higher levels of glutamate, norepinephrine (NE) and tyrosine hydroxylase (TH), and lower levels of gamma-aminobutyric acid (GABA) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN when compared to SHAM rats. Plasma levels of cytokines, NE, ACTH and renal sympathetic nerve activity (RSNA) were increased in HF rats. Bilateral PVN infusions of NBI-27914 attenuated the decreases in PVN GABA and GAD67, and the increases in RSNA, ACTH and PVN glutamate, NE and TH observed in HF rats. These findings suggest that CRH in the PVN modulates neurotransmitters and contributes to sympathoexcitation in rats with ischemia-induced HF.

Individual Differences in Subconscious Motor Control Predicted by GABA Concentration in SMA

Subliminal visual stimuli affect motor planning, but the size of such effects differs greatly between individuals. Here, we investigated whether such variation may be related to neurochemical differences between people. Cortical responsiveness is expected to be lower under the influence of more of the main inhibitory neurotransmitter, GABA. Thus, we hypothesized that, if an individual has more GABA in the supplementary motor area (SMA)--a region previously associated with automatic motor control--this would result in smaller subliminal effects. We measured the reversed masked prime--or negative compatibility--effect, and found that it correlated strongly with GABA concentration, measured with magnetic resonance spectroscopy. This occurred specifically in the SMA region, and not in other regions from which spectroscopy measurements were taken. We replicated these results in an independent cohort: more GABA in the SMA region is reliably associated with smaller effect size. These findings suggest that, across individuals, the responsiveness of subconscious motor mechanisms is related to GABA concentration in the SMA.

Characterization of CGRP protein expression in “satellite‐like” cells and dendritic arbours of the mouse olfactory bulb

The main olfactory bulb (OB) is made up of several concentric layers, forming circuitries often involving dendro-dendritic synapses. Important interactions between OB neurons occur in the external plexiform layer (EPL), where dendrites of tufted and Van Gehuchten cells form synapses with dendrites of deeper lying mitral, tufted, and granule cells. OB neurons display a variety of neurotransmitters. Here, the focus is on calcitonin gene-related peptide (CGRP), a 37-amino acid neuropeptide transmitter that is widely distributed in the central and peripheral nervous system. In the OB, CGRP-immunoreactive (ir) cell bodies were mostly observed in the mitral cell layer (MCL) of normal mice, and their number increased following colchicine treatment. Sparsely distributed CGRP-ir cell bodies were also found in the EPL and granular cell layer. Double-immunofluorescence experiments revealed a lack of co-localization between CGRP-like immunoreactivity (LI) and corticotropin-releasing factor- or galanin-LI, two markers for mitral cells, and no CGRP-LI was found in cholecystokinin-, parvalbumin-, or vasoactive intestinal polypeptide-ir tufted/Van Gehuchten cells. CGRP-ir cell bodies were not found to co-localize glutamic acid decarboxylase 67 (GAD67)-green fluorescence protein, gamma-aminobutyric acid (GABA)-, or calretinin-LI, although the possibility remains that CGRP-ir cells may contain low levels of GABA and/or GAD67 not detected by our methodology. Dendrites of CGRP-ir cells extensively ramified deep in the EPL and double-immunofluorescence revealed them to be adjacent with, often apparently contacting, dendrites of granule, mitral, tufted, and Van Gehuchten cells. We propose that these CGRP-ir cell bodies in the mouse OB are "satellite-like" cells within and, occasionally, close to the MCL.

TNF-.ALPHA. in Hypothalamic Paraventricular Nucleus Contributes to Sympathoexcitation in Heart Failure by Modulating AT1 Receptor and Neurotransmitters

Proinflammatory cytokines, including tumor necrosis factor (TNF)-α, augment the progression of heart failure (HF) that is characterized by sympathoexcitation. In this study, we explored the role of TNF-α in hypothalamic paraventricular nucleus (PVN) in the exaggerated sympathetic activity observed in HF. Heart failure rats were made by ligating the left anterior descending coronary artery. The expression levels of angiotensin type 1 receptor (AT1-R) and neurotransmitters were analyzed in the PVN of HF rats that received direct PVN infusion of a TNF-α blocker (pentoxifylline or etanercept) or vehicle. Sham-operated control (SHAM) or HF rats were treated for 4 weeks through PVN infusion with each TNF-α blocker or vehicle. Rats with HF had higher levels of glutamate, norepinephrine, AT1-R and tyrosine hydroxylase (TH), and lower levels of gamma-aminobutyric acid (GABA), neuronal nitric oxide synthase (nNOS) and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN when compared to SHAM rats. Plasma levels of cytokines, norepinephrine and angiotensin II and renal sympathetic nerve activity (RSNA) were increased in HF rats. PVN infusion of pentoxifylline or etanercept attenuated the decreases in PVN GABA, nNOS and GAD67, and the increases in RSNA and PVN glutamate, norepinephrine, TH and AT1-R observed in HF rats. We have developed a novel method for chronic and continuous infusion of drugs directly into the PVN and provided evidence that TNF-α in the PVN modulates neurotransmitters and the expression of AT1 receptor, which could account for exaggerated sympathetic activity in HF.

Reduced Density of Calbindin Immunoreactive GABAergic Neurons in the Occipital Cortex in Major Depression: Relevance to Neuroimaging Studies

Several lines of evidence suggest dysfunction of the gamma-aminobutyric acid (GABA)ergic system in major depressive disorder. Neuroimaging studies report reduced levels of GABA in the dorsolateral prefrontal and occipital cortex of depressed patients. Our previous postmortem study revealed a reduction in the density and size of calbindin-immunoreactive (CB-IR) GABAergic neurons in the prefrontal cortex in major depressive disorder. The goal of this study was to test whether the changes in CB-IR neurons can also be detected in the occipital cortex, where neuroimaging studies report a prominent GABA decrease. A three-dimensional cell counting probe was used to assess the cell-packing density and size of CB-IR neurons in layer II of the occipital cortex in 10 major depressive disorder subjects and 10 psychiatrically healthy control subjects. The density of CB-IR neurons was significantly decreased by 28% in major depressive disorder subjects compared with the control group. The size of CB-IR neurons was unchanged in major depressive disorder subjects when compared with control subjects. The reduction in the density of CB-IR GABAergic neurons in the occipital cortex in depression is similar to that observed previously in the prefrontal cortex. Deficit in cortical GABAergic interneurons may contribute to the low GABA levels detected in neuroimaging studies in major depressive disorder patients.

Brain tumour necrosis factor- modulates neurotransmitters in hypothalamic paraventricular nucleus in heart failure

Increased proinflammatory cytokines after myocardial infarction augment the progression of heart failure (HF) and are of prognostic significance. Recently, we demonstrated that increased proinflammatory cytokines in the brains of HF rats increased paraventricular nucleus (PVN) superoxide and down-regulated neuronal nitric oxide synthase (nNOS), contributing to sympathoexcitation. In this study, we explored the possible roles of brain proinflammatory cytokines and their effects on modulating PVN neurotransmitters in the exaggerated sympathetic activity in HF. Sprague-Dawley rats with HF or sham-operated control (SHAM) rats were treated for 4 weeks with a continuous intracerebroventricular (ICV) infusion of the cytokine blockers-pentoxifylline (PTX, 10 microg/h and 40 microg/h), etanercept (ETN, 5 microg/h and 10 microg/h), or vehicle. Another set of HF and SHAM rats were treated with intraperitoneal (ip) infusion of a similar dose of PTX or ETN. HF rats had increased neuronal excitation accompanied by higher levels of glutamate, norepinephrine (NE), and tyrosine hydroxylase (TH), and lower levels of gamma-aminobutyric acid (GABA), nNOS, and 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN when compared with SHAM rats. Plasma cytokines, NE, epinephrine, angiotensin II, and renal sympathetic nerve activity (RSNA) were also increased in HF rats. ICV treatment with low doses of PTX or ETN attenuated, and high doses prevented, increases in levels of glutamate, NE, and TH, and decreases in levels of GABA, nNOS, and GAD67 in the PVN in HF rats. The same ICV treatments also attenuated the increased RSNA seen in HF rats. IP treatment with similar doses of PTX or ETN did not affect glutamate, NE, TH, GABA, nNOS, and GAD67 in the PVN and had no effect on RSNA of HF rats. This study, for the first time, demonstrates that proinflammatory cytokines modulate neurotransmitters in the PVN and contribute to sympathoexcitation in HF.

Differential expression of γ-aminobutyric acid receptor A (GABAA) and effects of homocysteine

gamma-Aminobutyric acid (GABA) is a known inhibitory neurotransmitter in the mammalian central nervous system, and homocysteine (Hcy) behaves as an antagonist for GABA(A) receptor. Although the properties and functions of GABA(A) receptors are well studied in mouse neural tissue, its presence and significance in non-neural tissue remains obscure. The aim of the present study was to examine the expression of GABA(A) receptor and its subunits in non-neural tissue. The mice were analyzed. The presence of GABA(A) receptor and its subunits was evaluated using Western blot and reverse transcription polymerase chain reaction. We report that GABA(A) receptor protein is abundant in the renal medulla, cortex, heart, left ventricle, aorta and pancreas. Low levels of GABA(A) receptor protein were detected in the atria of the heart, right ventricle, lung and stomach. The mRNA protein expression of GABA(A) receptor subunit shows that alpha1, beta1, beta3 and gamma1 subunits are present only in brain. The mRNA protein expression levels of GABA(A) receptor alpha2, alpha6, beta2 and gamma3 subunits were highly expressed in brain compared to other tested tissue, while GABA(A) receptor gamma2 subunit was expressed only in brain and kidney. Treatment of microvascular endothelial cells with Hcy decreased GABA(A) receptor protein level, which was restored to its baseline level in the presence of GABA(A) receptor agonist, muscimol. The distribution of GABA(A) and GABA(B) receptors in wild type mice was determined and tissue-specific expression patterns were found showing that several receptor subtypes were also expressed in the central nervous system. Hcy, a GABA(A) agonist, was found to decrease GABA(A) expression levels. These data enlarge knowledge on distribution of GABA receptors and give novel ideas of the effects of Hcy on different organs.

Relationship Between Posttrauma GABA Plasma Levels and PTSD at 1-Year Follow-Up

Gamma-aminobutyric acid (GABA) exerts a prominent effect on central adrenergic stress responses in times of high stress and has been associated with acute posttraumatic stress disorder (PTSD). The authors examined the association between low posttrauma plasma GABA levels and long-term PTSD.Plasma GABA levels were measured in 78 victims of road traffic accidents who met criteria for trauma exposure on arrival at a trauma department and were admitted for at least 3 days. Patients were assessed for PTSD and major depressive disorder at 6-week and 1-year follow-ups.At 6 weeks and at 1 year, mean posttrauma GABA levels were significantly lower among subjects who met all or nearly all criteria for PTSD than among those who did not. Among patients who met all or nearly all criteria for PTSD at 6 weeks, 75% of those with posttrauma GABA levels above 0.20 mmol/ml no longer met criteria at 1 year. By contrast, among patients whose GABA levels were below 0.20 mmol/ml, 80% met all or nearly all criteria for PTSD at 1 year. Two-thirds of patients who met all or nearly all criteria for PTSD at 1 year also met criteria for major depressive disorder.A plasma GABA level above 0.20 mmol/ml may protect against chronic PTSD and may represent a marker of recovery from trauma.

Relationship Between Posttrauma GABA Plasma Levels and PTSD at 1-Year Follow-Up

Gamma-aminobutyric acid (GABA) exerts a prominent effect on central adrenergic stress responses in times of high stress and has been associated with acute posttraumatic stress disorder (PTSD). The authors examined the association between low posttrauma plasma GABA levels and long-term PTSD. Plasma GABA levels were measured in 78 victims of road traffic accidents who met criteria for trauma exposure on arrival at a trauma department and were admitted for at least 3 days. Patients were assessed for PTSD and major depressive disorder at 6-week and 1-year follow-ups. At 6 weeks and at 1 year, mean posttrauma GABA levels were significantly lower among subjects who met all or nearly all criteria for PTSD than among those who did not. Among patients who met all or nearly all criteria for PTSD at 6 weeks, 75% of those with posttrauma GABA levels above 0.20 mmol/ml no longer met criteria at 1 year. By contrast, among patients whose GABA levels were below 0.20 mmol/ml, 80% met all or nearly all criteria for PTSD at 1 year. Two-thirds of patients who met all or nearly all criteria for PTSD at 1 year also met criteria for major depressive disorder. A plasma GABA level above 0.20 mmol/ml may protect against chronic PTSD and may represent a marker of recovery from trauma.

Cerebrospinal fluid GABA levels in chronic migraine with and without depression

Psychiatric comorbidity is one of the key elements in chronic migraine (CM) management. Depression is particularly common in these patients, occurring in up to 85%. Preclinical studies have suggested that gamma-aminobutyric acid (GABA) levels may be decreased in animal models of depression. Also, clinical studies have reported low level in mood disorder patients for both plasma and cerebrospinal fluid (CSF) GABA. We hypothesized that low GABA levels in the brain might be related to the depression associated with CM. We studied 14 chronic migraine patients, with or without depression, compared to age-and sex-matched controls. CSF GABA levels were measured by HPLC. CSF GABA levels showed significant lower levels in depressed patients than those without depression. No difference was found when comparing patients versus controls. A GABA deficiency may be the underlying mechanism of depression in CM. Hence, preventive therapies modulating GABA neurotransmission could be used in CM associated with depression.

GAT1 and GAT3 expression are differently localized in the human epileptogenic hippocampus

The gamma amino butyric acid (GABA) transporters GAT-1 and GAT-3 were localized by immunohistochemistry in hippocampi removed for the control of medically intractable temporal lobe epilepsy (TLE). The study aimed to determine the relationship of GABA transporter expression to known patterns of hippocampal hyperexcitability and extracellular GABA levels. GAT-1 was localized in axon terminals and small neuronal cell bodies, and in non-sclerotic hippocampi was strongly expressed throughout all regions of the hippocampal formation. In the epileptogenic hippocampus exhibiting Ammon's horn sclerosis, immunoreactivity was reduced in the sclerotic regions CA3 and CA1, and around the cell bodies of dentate granule cells, but was increased along granule cell dendrites. GAT-3 was weakly expressed, if at all, in non-sclerotic hippocampi, but more prominently expressed in sclerotic hippocampi. GAT-3 expression was confined to cells resembling protoplasmic astrocytes, which were located in regions of relative neuronal sparing such as the dentate gyrus and hilus of the sclerotic hippocampus. The reduction in GAT-1 around granule cells in the sclerotic hippocampus could explain the prolonged GABA responses in this region. The loss of GAT-1 (a marker of GABAergic terminals) would also suggest a reduced GABAergic input to the granule cells, thus facilitating hyperexcitability. The increased GAT-3 expression in astrocytes in regions of relative neuronal sparing in the sclerotic hippocampus may be related to the overall low levels of extracellular GABA observed in the sclerotic hippocampus and their increased excitability.

An Update on GABA Analogs for CNS Drug Discovery

GABA (gamma-aminobutyric acid) is one of the major inhibitory transmitters in the central nervous system of mammals. GABA is not transported efficiently into the brain from the bloodstream (i.e. GABA does not effectively cross the blood-brain barrier). Consequently, brain cells provide virtually all of the GABA found in the brain i.e. GABA is biosynthesized by decarboxylation of glutamic acid with pyridoxal phosphate. The implication of low GABA levels in a number of common CNS disease states and/or common medical disorders has stimulated intensive interest in preparing GABA analogs, which have superior pharmaceutical properties in comparison to GABA. Accordingly, a number of GABA analogs, with considerable pharmaceutical activity have been synthesized in the art. This review includes some of the important recent patents on novel GABA analogs and some pharmaceutical compositions there of.

Brain Imaging in Idiopathic Generalized Epilepsies

While it is generally accepted that there is no neuroimaging abnormality in idiopathic generalized epilepsy (IGE), image processing and quantitative magnetic resonance imaging (MRI) studies suggest that there may be subtle structural abnormalities. Magnetic resonance spectroscopy indicates neuronal dysfunction with differing abnormalities in the IGE subsyndromes, and high concentrations of glutamate and glutamine have been inferred in the frontal lobes, and low gamma-aminobutyric acid levels in the occipital lobe. Studies of cerebral blood distribution at the time of absences have given complex results. The general consensus is of an increase in the thalamus and broad decreases in the neocortex, reflecting a suppression of neuronal activity, but with some increases, that may indicate focal areas of activation. Positron emission tomography (PET) ligand studies with an opioid tracer have inferred neocortical release of endogenous opioids at the time of serial absences. In combination with neurophysiological methods, PET studies with specific ligands have the potential to clarify the functional anatomy and neurochemical circuits that underlie IGE.

Idiopathic Generalized Epilepsies: A Review and Modern Approach

Idiopathic Generalized Epilepsies: A Review and Modern Approach