GABA In Central Nervous System Research Articles

In silico screening of GABA aminotransferase inhibitors from the constituents of Valeriana officinalis by molecular docking and molecular dynamics simulation study.

Modulation of γ-aminobutyric acid (GABA) levels has been required in various disorders. GABA itself cannot be directly introduced into central nervous system (CNS) because of the blood brain barrier; inhibition of GABA aminotransferase (GABA-AT), which degrades GABA in CNS, has been the target for the modulation of GABA levels in CNS. Given that root extract of valerian (Valeriana officinalis) has been used for millennia as anti-anxiolytic and sedative, in silico approach was carried out to investigate valerian compounds exhibiting GABA-AT inhibiting activity. The 3D structure of human GABA-AT was created from pig crystal structure via homology modeling. Inhibition of GABA-AT by 18 valerian compounds was analyzed using molecular docking and molecular dynamics simulations and compared with known GABA-AT inhibitors such as vigabatrin and valproic acid. Isovaleric acid and didrovaltrate exhibited GABA-AT inhibiting activity in computational analysis, albeit less potent compared with vigabatrin. However, multiple compounds with low activity may have additive effects when the total extract of valeriana root was used in traditional usage. In addition, isovaleric acid shares similar backbone structure to GABA, suggesting that isovaleric acid might be a valuable starting structure for the development of more efficient GABA-AT inhibitors for disorders related with low level of GABA in the CNS.

168 Social Stress Can Break Your Heart

Ischaemic heart disease (IHD) and Major Depressive Disorder (MDD) are two of the greatest health challenges of the 21st century. These disorders are also strongly linked, reciprocally promoting disease risks and worsening outcomes. At present, it is still largely unknown how MDD worsens the hearts response to ischaemia or infarction, or influences cardiac responses to protective therapy. We tested the impact of chronic social stress on the central nervous system (CNS), endocrine factors and the hearts response to simulated heart attack. Male C57Bl/6 male mice were subjected to 5 wks of social isolation, with twice daily episodes of ‘social defeat’ (return to group housing for 15 min) over the final 2 wks. Behaviour was tested pre- and post-experiment via open field and sucrose preference tests, and on sacrifice serum and CNS tissue was collected, while hearts were Langendorff perfused to assess ischaemic tolerance. Social stress was anxiogenic and induced anhedonia (reflecting a depressive phenotype) and significantly worsened myocardial tolerance to ischaemia-reperfusion (exaggerated diastolic contracture). These changes were associated with evidence of altered CNS GABA and dopamine signalling, and endocrine disruption (increased circulating leptin and ghrelin, reduced cardioprotective adiponectin). Interestingly, studies in female mice generally failed to produce these outcomes. Data reveal chronic social stress impairs mood and myocardial ischaemic tolerance, changes potentially linked to disturbed GABA, dopamine and adipokine signalling.

Glutamate versus GABA in neuron-oligodendroglia communication.

In the central nervous system (CNS), myelin sheaths around axons are formed by glial cells named oligodendrocytes (OLs). In turn, OLs are generated by oligodendrocyte precursor cells (OPCs) during postnatal development and in adults, according to a process that depends on the proliferation and differentiation of these progenitors. The maturation of OL lineage cells as well as myelination by OLs are complex and highly regulated processes in the CNS. OPCs and OLs express an array of receptors for neurotransmitters, in particular for the two main CNS neurotransmitters glutamate and GABA, and are therefore endowed with the capacity to respond to neuronal activity. Initial studies in cell cultures demonstrated that both glutamate and GABA signaling mechanisms play important roles in OL lineage cell development and function. However, much remains to be learned about the communication of glutamatergic and GABAergic neurons with oligodendroglia in vivo. This review focuses on recent major advances in our understanding of the neuron-oligodendroglia communication mediated by glutamate and GABA in the CNS, and highlights the present controversies in the field. We discuss the expression, activation modes and potential roles of synaptic and extrasynaptic receptors along OL lineage progression. We review the properties of OPC synaptic connectivity with presynaptic glutamatergic and GABAergic neurons in the brain and consider the implication of glutamate and GABA signaling in activity-driven adaptive myelination.

Torin 1 partially corrects vigabatrin‐induced mitochondrial increase in mouse

Recent findings in mice with targeted deletion of the GABA-metabolic enzyme succinic semialdehyde dehydrogenase revealed a new role for supraphysiological GABA (4-aminobutyric acid) in the activation of the mechanistic target of rapamycin (mTOR) that results in disruption of endogenous mitophagy. Employing biochemical and electron microscopic methodology, we examined the hypothesis that similar outcomes would be observed during intervention with vigabatrin, whose antiepileptic capacity hinges on central nervous system GABA elevation. Vigabatrin intervention was associated with significantly enhanced mitochondrial numbers and areas in normal mice that could be selectively normalized with the rapalog and mechanistic target of rapamycin inhibitor, Torin 1. Moreover, short-term administration of vigabatrin induced apoptosis and enhanced phosphorylation of mechanistic target of rapamycin Ser 2448 in liver. Our results provide new insight into adverse outcomes associated with vigabatrin intervention, and the first evidence that its administration is associated with increased mitochondrial number in central and peripheral tissues that may associate with mechanistic target of rapamycin function and enhanced cell death.

Selected Correction of Vigabatrin‐Related Toxicity in Mice with Adjuvant Rapalog Intervention

Vigabatrin (γ-vinyl GABA; SabrilR), an antiepileptic drug that irreversibly inhibits GABA-transaminase, enhances central nervous system GABA. VGB is employed therapeutically for infantile spasms, secondary generalized and complex partial seizures. However, VGB has a well-defined retinal toxicity that significantly impacts its long-term use. We administered VGB (35 and 250 mg/kg/d) to mice for 7 days. GABA was quantified by isotope dilution mass spectrometry, and redox parameters (malondialdehyde (MDA), glutathione (GSH)) determined using spectrometric assays. Transmission electron microscopy (TEM) was employed to quantify mitochondrial abundance. VGB induced a dose-dependent increase in GABA in the brain (1,717.5+109.7 nmol/mg vehicle; 5,236.9+1,223.4 VGB (35 mg/kg); 10,559.0+968.9 VGB (250 mg/kg)) and eye (158.5 +21.9 vehicle; 680.6 +63.1 VGB (35 mg/kg); 939.0+161.3, VGB (250 mg/kg); ANOVA, p<0.0001). TEM micrographs revealed significantly increased mitochondrial abundance along the retinal pigmented epithelium (vehicle 60+20 mitochondria/micrograph; VGB (35 mg/kg) 73+18; p<0.01), hippocampus and liver. MDA levels were 3.1-fold elevated with VGB intervention (p<0.05) and total GSH levels showed a trend toward depletion in eye, indicative of oxidative stress associated with enhanced mitochondrial number. Torin 1 application (5mg/kg) for 7 days corrected mitochondrial accumulation in hippocampus (figure 1). Our data highlight the potential of adjuvant rapalog intervention with VGB. Support NIH R21 NS 85369.

Murine succinate semialdehyde dehydrogenase deficiency.

Inherited succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria) is one of the few neurogenetic disorders of GABA metabolism, and one in which tonic-clonic seizures associate with increased central nervous system GABA and gamma-hydroxybutyrate (GHB). To explore pathomechanisms and develop new preclinical treatment approaches, we developed a murine knockout model of SSADH deficiency. In the absence of intervention, SSADH(-/-) mice suffer 100% mortality at week 3 to 4 of life from generalized tonic-clonic seizures. In this report, we summarize earlier studies indicating disruption of the GABA/glutamine axis in SSADH(-/-) mouse brain, effective pharmacotherapeutic approaches, preliminary gene-therapy results, and electrophysiological analyses of mutant mice. We also present new evidence for oxidative stress in SSADH(-/-) mice, significant alterations of dopamine metabolism, and abnormal neurosteroid levels in brain, potentially implicating the GABA(A) receptor in pathogenesis. In SSADH deficiency, the accumulation of two neuroactive species, GABA and GHB, is significant because GABA is one of the earliest transmitters expressed in mammals, with key roles in synaptogenesis and myelination, whereas GHB displays a vast array of pharmacological actions. The SSADH(-/-) mouse may represent a useful model in which to explore the effect of GABA and GHB accumulation on central nervous system development and function.

Sexual behavior and copulatory thrusting patterns in male rabbits treated with GABA transaminase inhibitors

The effects of enhanced central nervous system GABA levels on sexual behavior and copulatory pelvic thrusting were evaluated in male New Zealand white rabbits. The GABA transaminase inhibitors sodium valproate and γ-acetylen GABA (GAG), in doses of 100 and 200 mg/kg and 50 and 100 mg/kg, respectively, were intraperitoneally administered and sexual behavior recorded at several intervals after drug administration. At the same time, copulatory thrusting was registered using a polygraphic technique. Tests for gross motor functions were also performed. None of the drugs had any effect in these latter tests. Sodium valproate, in a dose of 100 mg/kg, had a slight inhibitory effect on sexual behavior at 280 min postinjection. A dose of 200 mg/kg inhibited sexual activity already 15 min postinjection, and the effect lasted for at least 280 min. GAG, 100 mg/kg, inhibited mounting behavior at 8 h postinjection, and ejaculation was reduced from 2 to at least 8 h postinjection. Copulatory thrusting patterns were not affected by the drug ments. These data suggest that increased GABAergic activity reduces sexual arousal in the rabbit. GABA does not seem to be critically involved in the regulation of the motor patterns underlying pelvic thrusting. There are important quantitative and qualitative differences between rats and rabbits with regard to the actions of GABA transaminase inhibitors upon sexual functions.

Blocking actions of heptachlor at an insect central nervous system GABA receptor

The actions of the polychlorocycloalkane insecticide heptachlor, and its epoxide metabolite, were examined on GABA receptors in insects and vertebrates. Electrophysiological experiments on the cell body of the cockroach (Periplaneta americana) fast coxal depressor motor neuron (Df), and GABA-activated 36Cl- uptake experiments on microsacs prepared from cockroach ventral nerve cords showed that both heptachlor and heptachlor epoxide blocked functional GABA receptors. The block appeared to be non-competitive and was voltage-independent over the membrane potential range -75 mV to -110 mV. There was no significant difference between the potencies of heptachlor and heptachlor epoxide in the functional assays for insect GABA receptors. Both compounds inhibited [35S]-t-butylbicyclophosphorothionate [( 35S]TBPS) binding in insects and vertebrates. The findings provide further evidence for block of an insect GABA receptor/Cl- channel by the cyclodiene class of polychlorocycloalkanes, and reveal differences in the insecticide-[35S]TBPS binding site interactions of insects and vertebrates.

Review: Normal and abnormal central nervous system GABA metabolism in childhood

The metabolism and function of central nervous system GABA is briefly reviewed. Hereditary disorders of the GABA metabolism presenting in childhood are discussed with particular emphasis on the recently identified succinic semialdehyde dehydrogenase deficiency and GABA-transaminase deficiency, and on diseases associated with low CSF GABA which await further unravelling. Low CSF GABA concentrations are not always associated with convulsions. A separate section is devoted to the CSF as a tool in the diagnosis of these disorders. Finally, we present a few diagnostic and therapeutic guidelines.

Block of an insect central nervous system GABA receptor by cyclodiene and cyclohexane insecticides

The effects of a cyclodiene (endrin) and a cyclohexane (lindane) insecticide have been tested on gamma-aminobutyric acid (GABA) receptors in the central nervous system of the cockroach (Periplaneta americana), by using electrophysiological methods and an in vitro functional receptor assay. In electrophysiological experiments on an identified motor neuron (Df), endrin blocked the GABA response with a 50% inhibition concentration of 5.0 x 10(-7) M in a non-competitive manner. The actions of endrin were irreversible under the experimental conditions adopted. Increasing the intracellular chloride concentration reduced the effectiveness of endrin, whereas a change in the potassium concentration failed to influence the block by endrin of GABA responses. Lindane exhibited similar actions to endrin on insect GABA receptors, but was approximately an order of magnitude less effective. In a microsac preparation from cockroach nerve cords, endrin, at a concentration of 1.0 x 10(-5) M, completely blocked GABA-stimulated 36Cl- uptake, whereas the same concentration of lindane was less potent, only blocking about 40% of uptake under similar conditions. Neither insecticide had any effect on L-glutamate-activated chloride channels. The results demonstrate that endrin and lindane block functional insect neuronal GABA receptors.

Noncompetitive inhibition of GABA receptors in insect and vertebrate CNS by endrin and lindane

γ-Aminobutyric acid (GABA) receptors have been recognized as a possible primary site of action for polychlorocycloalkane insecticides (cyclodienes and cyclohexanes). The mechanism of action of endrin and lindane on functional insect central nervous system (CNS) GABA receptors was studied by applying electrophysiological techniques to the cell body of an identified motor neuron, the fast coxal depressor motor neuron ( D f) of the cockroach Periplaneta americana. The technique of monitoring GABA-regulated 36 Cl − influx into rat brain membranes, which provides a functional assay for vertebrate CNS GABA A receptors, was also used to study the actions of these two polychlorocycloalkane insecticides. Endrin and lindane inhibited in a dose-dependent, noncompetitive manner both insect and vertebrate GABA receptors. Lindane was at least an order of magnitude less potent than endrin. The results demonstrate that endrin and lindane act in a similar manner on the GABA receptors of both insect and mammalian central nervous systems. Their blocking actions may involve noncompetitive binding to an allosteric site associated with the receptor's chloride channel. Toxicity of these insecticides to both vertebrates and insects appears to be mediated by their inhibitory actions on GABA receptors.

Insect central nervous system γ-aminobutyric acid

Specific saturable binding of radiolabelled γ-aminobutyric acid (GABA) has been demonstrated in central nervous system (CNS) extracts of the cockroach, Periplaneta americana. The pharmacological properties of these putative insect CNS GABA receptors differ from those of both the vertebrate GABA A and GABA B receptor sites. Autoradiographical techniques have been used to examine the localization of these [ 3H]GABA binding sites in a cockroach ganglion and have shown that they are found predominantly in the neuropile, the region where the majority of synaptic connections occur. The results suggest that these insect CNS [ 3H]GABA binding sites may represent a novel class of GABA receptors.

Prolactin control by the tubero-infundibular gabaergic system: role of anterior pituitary GABA receptors

Anterior pituitary (AP) GABA receptors have been shown to play a functional role in the inhibitory control of prolactin (PRL) secretion by this amino acid. However, the physiological significance and the pharmacological characteristics of these receptors have yet to be determined. In normal male rat AP's incubated in vitro, GABA (10 −6M) is effective in decreasing PRL release only when incubated in the presence of ethanolamine-O-sulphate (EOS), a potent GABA-transaminase (GABA-T) blocker. The failure of GABA alone to inhibit PRL release in vitro could be explained by the rapid degradation of the amino acid when added to the medium by AP-GABA-T. Central nervous system (CNS)- and AP-GABA receptors present similar affinity constants when evaluated by Scatchard analysis. However, displacement studies show that AP-GABA receptors have 10- and 100-times less affinity for muscimol (M), a GABA agonist, and for bicuculline, a GABA antagonist, respectively, than have CNS GABA receptors. The low affinity of the agonist towards the AP receptors could also account for the relatively poor sensitivity of lactotrophs to GABA-mimetic compounds. Failure of chronic treatment with aminooxyacetic acid, a GABA-T inhibitor, to modify the PRL-lowering effect of GABA-mimetic compounds, despite the decrease in the number of AP-GABA receptors, indicates that in normal conditions only a reduced number of receptors are operative. These studies of AP-GABA receptors provide insight for a better understanding of the mechanisms involved in the regulation of PRL secretion by the hypothalamic GABAergic system.

Changes in [3H]muscimol binding in substantia nigra, entopeduncular nucleus, globus pallidus, and thalamus after striatal lesions as demonstrated by quantitative receptor autoradiography

A quantitative autoradiographic technique for measuring the binding of [3H]muscimol to central nervous system GABA receptors is described using tritium-sensitive film. [3H]Muscimol binding was studied in primary and secondary striatal projection areas of rat brain following kainic acid lesions of the striatum. Seven days after the lesion, binding affinities in the striatum and its projection areas were not altered significantly. There was a loss of [3H]muscimol receptors in the striatum. Receptors increased in numbers in the ipsilateral globus pallidus (19%), entopeduncular nucleus (22%), and substantia nigra pars reticulata (38%). [3H]Muscimol binding was decreased in the ipsilateral anteroventrolateral and ventromedial (8%) thalamic nuclei. [3H]Muscimol binding in other brain areas (layer IV of the cerebral cortex, central gray, superior colliculus, and stratum moleculare of hippocampus) was not affected. The findings suggest that a loss of striatal innervation resulted in increased numbers of GABA receptors in striatal projection sites. It is further suggested that loss of inhibitory striatal inputs to neurons in the entopeduncular nucleus and substantia nigra pars reticulata may activate GABAergic projections to thalamus and thus result in decreased numbers of thalamic GABA receptors.

Alterations in brain GABA fail to influence morphine withdrawal body shakes

Discontinuation of chronic morphine infusion in rats resulted in the reliable occurrence of withdrawal body shakes. Valproic acid (2.5–160 mg/kg) or gamma-vinyl GABA (500 and 1000 mg/kg) failed to significantly effect this sign of morphine withdrawal. Etomidate (5 and 10 mg/kg) reduced body shakes, however, these doses produced marked sedation. Similarly, chlordiazepoxide (2.5–40 mg/kg) and flurazepam (2.5–40 mg/kg) decreased the withdrawal body shakes but only at doses which produced sedation. Bicuculline (0.16-0.64 mg/kg) did not alter the occurrence of body shakes whereas picrotoxin (0.64 mg/kg) produced a decrease. These results indicate that central nervous system GABA mechanisms are not important in the mediation of morphine withdrawal body shakes.