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At least 1,207 records · Page 67Linked to original sources
PubMed2005

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

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

4-Aminobutyrate Transaminase↗
PubMed2002

Stereoselective synthesis of 3-substituted 2-aminocyclopentanecarboxylic acid derivatives and their incorporation into short 12-helical beta-peptides that fold in water.

A stereoselective synthetic route is reported for the introduction of side chains at the 3-position of trans-2-aminocyclopentanecarboxylic acid (ACPC). Ring opening of the aziridine 2-benzyloxymethyl-6-azabicyclo[3.1.0]hexane with selected nucleophiles occurs in a regioselective manner and provides ACPC precursors with functional groups at the 3-position, trans to the 2-amino group. Oligomers composed of the 3-substituted ACPC residues maintain the 12-helical conformation displayed by the nonsubstituted analogues, as shown by their similar circular dichroism signatures. The added diversity of the new residues provides good dispersion of NMR signals, allowing the assignment of nearly all the NOE signals of a selected hexamer in aqueous solution. The NOEs between protons on nonadjacent residues are characteristic of the 12-helix. 3-Substituted ACPC residues allow one to arrange specific functional groups in a geometrically defined fashion, which should facilitate the design of beta-peptides for biological applications.

Circular Dichroism↗
PubMed1991

Neurochemical effects of nicotine on glutamate and GABA mechanisms in the rat brain.

The effects of nicotine on gamma-aminobutyric acid (GABA) and glutamate mechanisms were studied in several rat brain regions both in vivo and in vitro. In vivo acute intermittent injections of nicotine decrease GABA utilization in the hypothalamus and glutamate levels within the nucleus caudatus and the subcortical limbic forebrain (mainly tuberculum olfactorium and nucleus accumbens). Glutamic acid decarboxylase activity was slightly increased in several regions, when the rats were treated with a single convulsant dose of nicotine and killed at the moment of the convulsions but it was not affected by a single injection nor by intermittent acute administration of non-convulsant doses of nicotine. In vitro nicotine elicited release of L-[3H]glutamate from synaptosomal preparations obtained from the frontoparietal cortex, nucleus caudatus and hypothalamus. The effect was dose-dependent and it was not blocked by mecamylamine. It was also Ca2+ independent. The possibilities are discussed that the decreased GABA utilization in the hypothalamus may be related to certain neuroendocrine actions of nicotine and that the nicotine-induced glutamate release might be involved in some of the physiological and toxicological effects of nicotine.

Animals↗
PubMed1982

The use of gabaculine-induced accumulation of GABA for an index of synthesis of GABA in the retina.

The characteristics of accumulation of gamma-aminobutyric acid (GABA) in the retina after an intravitreal injection of the GABA-T inhibitor, gabaculine, have been studied in rats. The accumulation of GABA after injection of gabaculine was both dosage- and time-dependent. In both dark- and light-adapted-retinas. GABA continued to increase linearly for at least 90 min after an injection of gabaculine and this increase (3-fold) was similar in dark- and light-adapted rats. The GABA agonist, muscimol, and the GABA antagonist, bicuculline methiodide, significantly inhibited and facilitated, respectively, the gabaculine-induced increase in GABA levels. Previous studies have shown that accumulation of GABA following the irreversible inhibition of GABA-T was useful for measuring the rate of synthesis of GABA in the central nervous system, and these studies suggest that this technique may also be useful in the retina.

Adaptation, Ocular↗
PubMed1998

Newer antiepileptic drugs: gabapentin, lamotrigine, felbamate, topiramate and fosphenytoin.

Twenty-five to 40 percent of patients with epilepsy continue to have seizures despite optimal treatment with traditional antiepileptic drugs. Treatment with standard anticonvulsants such as phenytoin, carbamazepine, valproic acid and phenobarbital is often complicated by side effects and by failure to adequately control seizures. Up to 61 percent of patients with seizures report having side effects with antiepileptic drugs. After a 15-year hiatus since the last new antiepileptic drug was marketed, five new drugs have been approved by the U.S. Food and Drug Administration for the control of seizures. Three of these, gabapentin, lamotrigine and topiramate, are approved for use in adults with partial seizures with or without generalization. Felbamate is approved for the above indication and also for use in children with Lennox-Gastaut syndrome, a rare childhood seizure disorder. Felbamate and lamotrigine have the potential of significant side effects and should be prescribed by physicians experienced in managing patients with complicated epilepsy. Fosphenytoin is a parenteral prodrug of phenytoin that is more tolerable than parenteral phenytoin.

Acetates↗
PubMed2006

The antiallodynic action target of intrathecal gabapentin: Ca2+ channels, KATP channels or N-methyl-d-aspartic acid receptors?

Gabapentin is a novel analgesic whose mechanism of action is not known. We investigated in a postoperative pain model whether adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channels, N-methyl-d-aspartic acid (NMDA) receptors, and Ca2+ channels are involved in the antiallodynic effect of intrathecal gabapentin. Mechanical allodynia was induced by a paw incision in isoflurane-anesthetized rats. Withdrawal thresholds to von Frey filament stimulation near the incision site were measured before and after incision and after intrathecal drug administration. The antiallodynic effect of gabapentin (100 mug) was not affected by intrathecal pretreatment with antagonists of K(ATP) channels, NMDA receptors or gamma-aminobutyric acid (GABA)(A) receptors. K(ATP) channel openers and GABA(A) receptor agonist, per se, had little effect on the postincision allodynic response. The Ca2+ channel blocker of N-type (omega-conotoxin GVIA, 0.1-3 microg), but not of P/Q-type (omega-agatoxin IVA), L-type (verapamil, diltiazem or nimodipine), or T-type (mibefradil), attenuated the incision-induced allodynia, as did gabapentin. Both the antiallodynic effects of gabapentin and omega-conotoxin GVIA were attenuated by Bay K 8644, an L-type Ca2+ channel activator. These results provide correlative evidence to support the contention that N-type Ca2+ channels, but not K(ATP) channels or NMDA or GABA(A) receptors, might be involved in the antiallodynic effect of intrathecal gabapentin.

Adenosine Triphosphate↗
PubMed2005

Gas chromatography-tandem mass spectrometry analysis of gabapentin in serum.

A new highly sensitive analytical method for determining gabapentin [1-(aminomethyl) cyclohexaneacetic acid; Neurontin] in serum using gas chromatography/tandem mass spectrometry (GC-MS/MS) was developed. GC-MS/MS was applied to determine the levels of gabapentin in serum samples of mice at 1 and 6 h after oral or intraperitoneal treatment (300 mg/kg). At 1 h, the concentrations of the drug were 4.02 +/- 0.42 and 4.32 +/- 0.28 microg/mL in mice treated orally and intraperitoneally, respectively. At 6 h, drug levels decreased by about 66% in both groups. The method, coupling two stages of mass analysis, could be very useful in identifying the drug in complex mixtures such as blood and urine. Moreover, it is easy and rapid to perform, and sensitive enough to allow the presence of the drug to be determined at very low detection limits. It is a very reliable method for both clinical and experimental monitoring of gabapentin.

Amines↗
PubMed2002

Long-term regulation of voltage-gated Ca(2+) channels by gabapentin.

Gabapentin (GBP) is a gamma-aminobutyric acid analog effective in the treatment of seizures. A high-affinity interaction between GBP and the alpha(2)delta subunit of the voltage-gated Ca(2+) channels has been documented. In this report, we examined the effects of the chronic treatment with GBP on neuronal recombinant P/Q-type Ca(2+) channels expressed in Xenopus oocytes. GBP did not affect significantly the amplitude or the voltage dependence of the currents. Exposure to the drug did, however, slow down the kinetics of inactivation in a dose-dependent fashion. In addition, biochemical analysis showed that the integrity of Ca(2+) channel complex is not apparently affected by GBP binding, suggesting that chronic treatment with the drug might cause the channel kinetic modification through subtle conformational changes of the protein complex.

Acetates↗
PubMed2000

Gabapentin, an antiepileptic drug, improves memory storage in mice.

Male CF-1 mice were tested 48 h after training in a one-trial step-through inhibitory avoidance task. Immediately post-training i.p. injections of the antiepileptic drug gabapentin (1-aminomethyl cyclohexaneacetic acid) (GBP; 5, 10, 50, and 100 mg/kg) induced a dose-dependent enhancement of retention performance. Gabapentin did not affect response latencies in mice not given the footshock on the training trial, indicating that the actions of GBP on retention were not due to non-specific proactive effects on response latencies. The effects of GBP (10 mg/kg) were time-dependent, and the administration of GBP (10 mg/kg) 30 min before training also enhanced retention performance. However, the administration of GBP (10 mg/kg) 30 min prior to the retention test did not modify retention latencies of mice that had received either saline or GBP (10 mg/kg) immediately after training. Altogether, the results suggest that GBP influences retention by modulating time-dependent processes involved in memory storage, although the mechanism(s) of this action remain to be established.

Acetates↗
PubMed1996

Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study.

The effect of a single oral dose of various antiepileptic drugs on the excitability of the motor system was studied in healthy volunteers by means of transcranial magnetic stimulation. Motor threshold, duration of the cortical silent period, and intracortical excitability after double-shock transcranial stimulation were tested before and at defined intervals after drug intake. Antiepileptic drugs that support the action of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the neocortex (vigabatrin, baclofen) reduced intracortical excitability but had no effect on motor threshold. Gabapentin, whose mechanism of action has not yet been unequivocally identified, showed a similar profile. By contrast, sodium and calcium channel blockers without considerable neurotransmitter properties (carbamazepine, lamotrigine, losigamone) elevated motor threshold but did not change intracortical excitability. The cortical silent period was lengthened by gabapentin and carbamazepine. Changes in peripheral motor excitability (maximum M wave, peripheral silent period) were not observed. We conclude that the changes in intracortical excitability are caused by GABA-controlled interneuronal circuits in the motor cortex while changes in motor threshold are dependent on ion channel conductivity and may reflect membrane excitability. Transcranial magnetic stimulation may be a promising noninvasive approach to study the selective effects of antiepileptic drugs on brain function.

4-Aminobutyrate Transaminase↗
PubMed1988

Gabapentin augments whole blood serotonin in healthy young men.

It has been previously demonstrated that gabapentin, a gamma-amino butyric acid analogue, inhibits monoaminergic neurotransmitter release from rabbit caudate nucleus slices and from rat cortex. In humans this drug has been shown to have anti-epileptogenic activity. Serotonin may act as an inhibitory neurotransmitter and its interaction with blood platelets is thought to reflect its central actions. We investigated sleep stages, whole blood serotonin levels, and serum melatonin in healthy men after the administration of gabapentin. With increasing serum gabapentin levels six healthy subjects showed an increase in sleep stages 3 and 4 and in whole blood serotonin (P less than 0.05) Serum melatonin levels were not influenced. On account of these results we speculate that gabapentin modulates the release of serotonin from blood platelets. The increase in peripheral serotonin points paradigmatically to an increase in the bioavailability of serotonin which may account for the increase in sleep stages 3 and 4.

Acetates↗
PubMed1971

Constitutive mutants in a regulatory gene exerting positive control of quinic acid catabolism in Neurospora crassa.

In Neurospora crassa, evidence has recently been obtained for a cluster of four closely-linked genes controlling the inducible enzymes catalyzing the first three reactions in the catabolism of quinic acid. Three of these genes appear to be the structural genes for the three enzymes. The fourth gene, designated qa-1, has been interpreted as having a regulatory function, since qa-1 mutants are pleiotropic types, are noninducible for the three enzymes, and form heterocaryons which complement mutants in the structural genes. The present studies were undertaken to elucidate further the nature of the regulatory role of the qa-1 locus. A number of constitutive (qa-1(C)) mutants have been obtained from certain qa-1 mutants as revertants selected for their ability to grow on quinic acid as a sole source of carbon. These qa-1(C) mutants produce high levels of all three enzymes in the absence of an inducer, map within (or very close to) the qa-1 locus, and produce a catabolic dehydroquinase (EC 4.2.1.10) which is indistinguishable, on the basis of thermolability tests, from that of wild type. In addition, when grown in the absence of an inducer, heterocaryons between wild-type (qa-1(+)) and different qa-1(C) mutants exhibit markedly different levels of constitutivity (from 5 to 50% of the particular parental qa-1(C) mutant) for catabolic dehydroquinase, one of the enzymes under qa-1 control. These overall results are interpreted as supporting the hypothesis that the qa-1(+) gene product (presumably a multimeric protein) plays only a positive regulatory role in initiating synthesis of the three quinate catabolic enzymes.

Alcohol Oxidoreductases↗
PubMed1994

Mechanisms of action of currently prescribed and newly developed antiepileptic drugs.

Clinically available antiepileptic drugs (AEDs) decrease membrane excitability by interacting with neurotransmitter receptors or ion channels. AEDs developed before 1980 appear to act on sodium (Na) channels, gamma-aminobutyric acid A (GABAA) receptors, or calcium (Ca) channels. Benzodiazepines and barbiturates enhance GABAA-receptor-mediated inhibition. Phenytoin, carbamazepine and, possibly, valproate (VPA) decrease high-frequency repetitive firing of action potentials by enhancing Na channel inactivation. Ethosuximide and VPA reduce a low threshold (T-type) Ca-channel current. The mechanisms of action of recently developed AEDs are less clear. Lamotrigine may decrease sustained high-frequency repetitive firing of voltage-dependent Na action potentials, and gabapentin (GBP) appears to bind to a specific binding site in the CNS with a restricted regional distribution. However, the identity of the binding site and the mechanism of action of GBP remain uncertain. The antiepileptic effect of felbamate may involve interaction at the strychnine-insensitive glycine site of the N-methyl-D-aspartate receptor, but the mechanism of action is not yet proven.

Acetates↗
PubMed1990

Effect of gabaculine on metabolism and release of gamma-aminobutyric acid in synaptosomes.

Synaptosomes isolated from mouse brain were incubated with [14C]glutamate and [3H]gamma-amino-butyric acid ([3H]GABA), and then [14C]GABA (newly synthesized GABA) and [3H]GABA (newly captured GABA) in the synaptosomes were analysed. (1) the [3H]GABA was rapidly degraded in the synaptosomes, (2) when the synaptosomes were treated with gabaculine (a potent inhibitor of GABA aminotransferase), the degradation of [3H]GABA was strongly inhibited, (3) the gabaculine treatment brought about a significant increase in Ca2(+)-independent release of [3H]GABA with no effect on Ca2(+)-dependent release, (4) no effects of gabaculine on degradation and release of [14C]GABA were observed. The results indicate that there are at least two pools of GABA in synaptosomes and support the possibilities that GABA taken up into a pool which is under the influence of GABA aminotransferase is released Ca2(+)-independently and that GABA synthesized in another pool which is not under the influence of GABA aminotransferase is released Ca2(+)-dependently.

4-Aminobutyrate Transaminase↗
PubMedDate not supplied

[The safety and tolerability profile of gabapentin in optimal doses].

INTRODUCTION: Gabapentin (GBP) is an amino acid that is structurally analogous to GABA with the capacity to cross the blood-brain barrier and an antiepileptic action. It is indicated in the treatment of partial seizures with or without secondary generalisation. It has been suggested that the dosages used in pilot studies were not suitable to achieve optimal efficiency. AIMS: The aims of this study were to investigate the safety and tolerability of GBP with doses above those initially advocated in the literature. DEVELOPMENT: We review its pharmacological characteristics and analyse the results of different placebo-controlled, open, short and long-term trials, both in monotherapy and associated to other antiepileptic drugs. CONCLUSION: Enough evidence was found to allow us to state that the efficiency of GBP can be increased with the utilisation of higher doses than those recommended to date, without the risk of generating unacceptable side effects at the same time.

Adult↗
PubMed1993

Advances in the pharmacotherapy of epilepsy.

Three new antiepileptic drugs (AEDs) are likely to be approved in the United States by the Food and Drug Administration in the near future. In general, all three have good safety profiles, causing only mild, well-tolerated side effects. Felbamate (FBM) is effective in the treatment of partial seizures and Lennox-Gastaut epilepsy. FBM appears to have a broader spectrum of antiepileptic activity than carbamazepine (CBZ) or phenytoin (PHT). Gabapentin (GBP) was designed to be a structured analogue of gamma-aminobutyric acid (GABA). GBP is most effective in the maximal electroshock model of seizures but may have a different mechanism of action than CBZ and PHT. Unique pharmacokinetic properties (no hepatic metabolism and no protein binding) may make GBP especially useful for certain patients, such as those with hepatic disease and elderly patients who are receiving multiple medications. The overall profile of activity of lamotrigine (LTG) is similar to that of PHT and may act on voltage-sensitive sodium channels to stabilize neuronal membranes. LTG is effective in partial seizures, and there is some indication that LTG may be helpful in primary generalized seizures. The long half-life and lack of effect on other AEDs will make LTG easy to dose and add to a patient's existing regimen. These new agents will provide physicians with more effective medications from which to choose in the treatment of the patient with epilepsy.

Acetates↗
PubMed2001

Requirement of additional adenylate cyclase activation for the inhibition of human eosinophil degranulation by phosphodiesterase IV inhibitors.

Human eosinophils contain predominantly phosphodiesterase type IV, but selective inhibitors of this isoenzyme fail to inhibit certain eosinophil responses such as degranulation. In this study, the effect of activation of adenylate cyclase on the ability of several highly selective PDE IV inhibitors to inhibit complement C5a-induced O2- release and degranulation of human eosinophils in vitro was investigated. All four selective PDE IV inhibitors, N-(3,5-dichloropyrid-4-yl)-3-cyclopentyl-oxy-4-methoxybenzamide (RP 73401), rolipram, N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indol-3-yl]glyoxylacidamide (AWD 12-281) and c-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl-r-1-cyclohexane carboxylic acid) (SB 207499) potently inhibited C5a-induced O2- generation (IC50 = 0.03, 0.42, 0.55 and 0.86 microM, respectively), but generally failed to inhibit degranulation. The only exception was AWD 12-281, which inhibited degranulation (IC50 = 16.2 microM). In the presence of different AC activators (histamine, salbutamol, prostaglandin E2 and forskolin), the PDE IV inhibitors became potent inhibitors of degranulation. The interaction between the PDE IV inhibitors and the AC activators resulted in a synergistic increase in intracellular levels of adenosine 3', 5'-monophosphate (cAMP). These results show that PDE IV inhibitors generally require an additional cAMP signal to be able to inhibit eosinophil degranulation, and that this signal can be generated via both membrane receptors and direct AC activation. This may be relevant to the in vivo effectiveness of PDE IV inhibitors in eosinophilic inflammation.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2002

Gabapentin inhibits high-threshold calcium channel currents in cultured rat dorsal root ganglion neurones.

1. This study examined the action of gabapentin (gabapentin,1-(aminomethyl) cyclohexane acetic acid (Neurontin) on voltage-gated calcium (Ca(2+)) channel influx recorded in cultured rat dorsal root ganglion (DRG) neurones. 2. Voltage-gated Ca(2+) influx was monitored using both fura-2 based fluorescence Ca(2+) imaging and the whole-cell patch clamp technique. 3. Imaging of intracellular Ca(2+) transients revealed that gabapentin inhibited KCl (30 mM)-evoked voltage-dependent Ca(2+) influx. Both the duration for 50% of the maximum response (W50) and total Ca(2+) influx were significantly reduced by approximately 25-30% in the presence of gabapentin (25 microM). 4. Gabapentin potently inhibited the peak whole-cell Ca(2+) channel current (I(Ba)) in a dose-dependent manner with an estimated IC(50) value of 167 nM. Block was incomplete and saturated at a maximal concentration of 25 microM. 5. Inhibition was significantly decreased in the presence of the neutral amino acid L-isoleucine (25 microM) but unaffected by application of the GABA(B) antagonist, saclofen (200 microM), suggesting a direct action on the alpha(2)delta subunit of the Ca(2+) channel. 6. Gabapentin inhibition was voltage-dependent, producing an approximately 7 mV hyperpolarizing shift in current voltage properties and reducing a non-inactivating component of whole-cell current activated at relatively depolarized potentials. 7. The use of specific Ca(2+) channel antagonists revealed a mixed pharmacology of the gabapentin-sensitive current (N-, L- and P/Q-type), which is dominated by N-type current. 8. The present study is the first to demonstrate that gabapentin directly mediates inhibition of voltage-gated Ca(2+) influx in DRG neurones, providing a potential means for gabapentin to effectively mediate spinal anti-nociception.

Acetates↗