Structural Analogue Of GABA Research Articles

Repurposing of substances with lactone moiety for the treatment of γ-Hydroxybutyric acid and γ-Butyrolactone intoxication through modulating paraoxonase and PPARγ.

GHB and GBL are highly accessible recreational drugs of abuse with a high risk of adverse effects and mortality while no specific antidotes exist. These components can also be found in the clinical setting, beverages, and cosmetic products, leading to unwanted exposures and further intoxications. As the structural analogue of GABA, GHB is suggested as the primary mediator of GHB/GBL effects. We further suggest that GBL might be as critical as GHB in this process, acting through PPARγ as its receptor. Moreover, PPARγ and PON (i.e., the GHB-GBL converting enzyme) can be targeted for GHB/GBL addiction and intoxication, leading to modulation of the GHB-GBL balance and blockage of their effects. We suggest that repurposing substances with lactone moiety such as bacterial lactones, sesquiterpene lactones, and statins might lead to potential therapeutic options as they occupy the active sites of PPARγ and PON and interfere with the GHB-GBL balance. In conclusion, this hypothesis improves the GHB/GBL mechanism of action, suggests potential therapeutic options, and highlights the necessity of classifying GBL as a controlled substance.

Requirement of γ-Aminobutyric Acid Chemotaxis for Virulence of Pseudomonas syringae pv. tabaci 6605.

γ-Aminobutyric acid (GABA) is a widely distributed non-proteinogenic amino acid that accumulates in plants under biotic and abiotic stress conditions. Recent studies suggested that GABA also functions as an intracellular signaling molecule in plants and in signals mediating interactions between plants and phytopathogenic bacteria. However, the molecular mechanisms underlying GABA responses to bacterial pathogens remain unknown. In the present study, a GABA receptor, named McpG, was conserved in the highly motile plant-pathogenic bacteria Pseudomonas syringae pv. tabaci 6605 (Pta6605). We generated a deletion mutant of McpG to further investigate its involvement in GABA chemotaxis using quantitative capillary and qualitative plate assays. The wild-type strain of Pta6605 was attracted to GABA, while the ΔmcpG mutant abolished chemotaxis to 10‍ ‍mM GABA. However, ΔmcpG retained chemotaxis to proteinogenic amino acids and succinic semialdehyde, a structural analog of GABA. Furthermore, ΔmcpG was unable to effectively induce disease on host tobacco plants in three plant inoculation assays: flood, dip, and infiltration inoculations. These results revealed that the GABA sensing of Pta6605 is important for the interaction of Pta6605 with its host tobacco plant.

La toxicologie du baclofène

Baclofen is a structural analogue of GABA, used in the treatment of muscle spasticity that has seen its use expanded since 2008 in the treatment of alcohol addiction. With much higher dosage for this indication, overdose in treatment and acute intoxications are responsible of neurological disorders that can lead to a life-threatening prognosis. Management is essentially symptomatic and usually performed in hospital.The pharmacokinetic properties of baclofen explain the risk of its accumulation, as well as its “dialysable” characteristics useful in the management of an overdose in renal failure. In a much less well-known way, baclofen is at the origin of a risk of withdrawal.In these different situations, elimination monitoring of the drug can be carried out by its plasma and urinary assays in specialised toxicology laboratories. This monitoring can be used to assess the effectiveness of a scrubber treatment. Plasma concentrations in cases of acute intoxications are described in the literature between 700 and 3 300 ng/mL.No automated screening test is available to determine baclofen. Currently, the only methods for its identification and determination are targeted methods more commonly described in liquid chromatography coupled with mass spectrometry.

In vitro effects of ethanol and gabapentin treatment

Background: The anticonvulsant drug gabapentin, a structural analogue of GABA, showed beneficial effects in the treatment of alcoholism and its consequences. Although the mechanisms of action of gabapentin are not fully understood, studies suggested that gabapentin’s neuroprotective effects could be achieved via GABA-A receptors. The aim of this study was to investigate the potential protective action of gabapentin on the well- known neurotoxic effects of chronic alcohol consumption and withdrawal. Methods: The dose– response relationship and the time course of ethanol and gabapentin treatment were established on human embryonic kidney (HEK) 293 cells, either non-transfected or stably expressing α1β2γ2S GABA-A receptors. A trypan blue exclusion assay and MTT test were performed to assess cell viability. Membrane preparations of stably transfected HEK 293 cells treated with 100 mM ethanol in combination with 1 µM gabapentin for 96 h were used in [3H]flunitrazepam and [3H]TBOB binding studies to determine the number and affinity of benzodiazepine and convulsant binding sites, and their allosteric interactions with GABA binding sites. 100 µM bicuculline, a GABA-A receptor antagonist, was used in other to counteract the effects of gabapentin. The levels of mRNA encoding the α1, β2 and γ2S receptor subunits in stably transfected HEK 293 cells following ethanol and gabapentin treatment were determined by semiquantitative RT-PCR analysis. Results: Treatment with ethanol at concentrations higher than 100 mM for 96 h reduced the number of HEK 293 cells, non- transfected or transfected with α1β2γ2S GABA-A receptors. The cytotoxic effect of ethanol was counteracted by co-administration of 1 µM gabapentin in transfected, but not in non- transfected cells. Exposure to 100 mM ethanol induced an increase in the number of binding sites for benzodiazepines and convulsants, while this effect was reversed by simultaneous exposure to 1 µM gabapentin, 100 µM bicuculline or their combination. Administration of ethanol, as well as bicuculline, induced functional allosteric uncoupling of the GABA and the benzodiazepine binding site, which was prevented by simultaneous gabapentin treatment. The mRNA expression levels of α1, β2 and γ2S GABAA receptor subunits were not influenced by the exposure to either ethanol or gabapentin, but only by their co-administration. Discussion: Although our results support the hypothesis of an involvement of GABA-A receptors in the actions of gabapentin, further research is needed to elucidate the mechanisms of gabapentin’s protective effects against ethanol-induced cytotoxicity.

Comparison of Analgesic Effect between Gabapentin and Diclofenac on Post-Operative Pain in Patients Undergoing Tonsillectomy

Dear Editor, We have examined attentively the latest manuscript by Yeganeh Mogadam et al. entitled “Comparison of Analgesic Effect between Gabapentin and Diclofenac on Post-Operative Pain in Patients Undergoing Tonsillectomy” available in Archives of Trauma Research (1). Ninety patients were included to receive 20 mg/kg oral gabapentin (n = 30), 1.0 mg/kg rectal diclofenac (n = 30) or placebo (n = 30) preoperatively. Pain was evaluated postoperatively at 2, 6, 12 and 24 hours. Authors concluded that gabapentin and diclofenac reduced postoperative pain and opioid consumption without any obvious side effects. Diclofenac is highly bound to serum proteins (≥ 99.5%) and has a relatively low volume of distribution (0.12 to 0.17 L/kg) (2, 3). Diclofenac easily penetrates the synovial fluid and crosses the placenta (2,3). However, diclofenac does not easily cross the blood-brain barrier. It has been proved that the diclofenac concentrations in cerebrospinal fluid is 8.22% compared to its value in plasma (4). There are reports wherein the anti-inflammatory and antinociceptive effect of diclofenac cannot be directly explained by circulating concentrations in humans (2, 3). Therefore, it has been suggested that diclofenac effects are mainly mediated via a local action in target tissues. In the present study, it is probable that diclofenac produced prostaglandins inhibition to oropharynx level and with that decreasing the sensitization of nociceptors at this level. On the other hand, although gabapentin is a structural analogue of GABA, which does not cross the blood-brain barrier, gabapentin penetrates into the central nervous system (5). Gabapentin binds to plasma proteins and it is not metabolized by nor inhibits hepatic enzymes that are responsible for the metabolism of other drugs (6). It is well known that gabapentin has analgesic and antihyperalgesic effects and is used in the control of clinical pain (6, 7). In this sense, the properties of gabapentin have been attributed to an action on the central and peripheral nervous system. Therefore, it is suggested that the gabapentin-induced analgesic effect in the present study was mediated by pain modulation at local level and on the descending pathways. In the present study, children and adult patients were evaluated together. It has been suggested that children may need moderately higher dosages of gabapentin to reach plasma concentrations comparable with those found in adults (8). Likewise, differences have been found in the volume of distribution, Cmax and clearance of diclofenac between children and adults (9, 10). Therefore, all the participants should have been evaluated separately to obtain a more consistent result. In the case of the pain intensity, authors stated on the background section that the post-operative pain in patients undergoing tonsillectomy may be as high as 70 in the scale of visual analog scale. However, the pain intensity in the present study was very low (from 1.53 to 3.43). Therefore, the effects of gabapentin and diclofenac appear very scarce or nil. On the other hand, the comparison of pain intensity in the three groups in the manuscript seems wrong. Whereas authors state that the patients’ pain in gabapentin group was significantly less than that of the placebo group (P < 0.05) and the mean pain intensity in diclofenac group at 6 hours after the surgery was significantly less than that of the placebo group (P < 0.05). Data shows that the pain intensities at 6, 12 and 24 hours in the gabapentin and diclofenac groups were bigger than in the placebo group. Only the pain intensities at 2 hours in the treated groups were lower than in the placebo group. This mistake was probably a measurement mistake, made by the authors.

An open trial of pregabalin as an acute and maintenance adjunctive treatment for outpatients with treatment resistant bipolar disorder

BackgroundPregabalin is a structural analog of GABA, similar to gabapentin. It does not have a FDA indication for any psychiatric disorder in the USA. There has been one case report of the successful use of pregabalin as an augmenting agent in a patient with Bipolar Disorder (BD). In the present open label study, not subsidized by the manufacturer, the investigators prospectively evaluated the acute and maintenance efficacy of pregabalin as an adjunctive medication for a group of treatment refractory outpatients with BD. MethodsOlder adolescent and adult outpatients with any type of DSM-IV diagnosed BD, who were considered treatment nonresponders to multiple standard medications for BD, were treated with adjunctive pregabalin. The baseline mood state before initiation of pregabalin was compared to the mood state after an acute trial of pregabalin using the Clinical Global Impression-Bipolar Version Scale (CGI-BP). All acute responders were treated for a minimum of two months. Follow-up maintenance treatment data was obtained for the acute pregabalin responders for three years after the 18 month acute phase of the study. ResultsFifty-eight total patients were treated adjunctively with pregabalin. Twenty-four (41%) were rated as acute responders. For the acute responders, pregabalin produced either a mood stabilizing effect, antidepressant effect or antimanic effect. Intolerable side-effects were the most common reason (79%) for a failed acute trial of pregabalin. None of the side effects resulted in serious medical complications. No patient abused pregabalin, and there were no adverse drug-drug interactions despite an average of 3.3 concurrent other psychiatric medications. The maintenance data revealed that 10 (42%) of the original 24 acute pregabalin responders were still taking pregabalin as an add-on medicine for an average of 45.2 months (range 42–48, SD: 2.35). LimitationsThis study has an open label observation design. ConclusionsThe results of this preliminary open study suggest that pregabalin is a safe and effective acute and maintenance adjunctive treatment for a significant number of treatment-resistant outpatients with any type of BPD. It appears to have mood stabilizing and antidepressant properties in addition to antimanic effects. Similar studies using a double-blind, randomly controlled design would be useful to confirm the reliability and validity of the results of this study.

Suivi thérapeutique pharmacologique de la gabapentine

Gabapentin is a structural analogue of GABA used in the treatment of the partial epilepsies of adult and child of more than 12 years, in monotherapy or in association with other anticonvulsant drugs. In association, gabapentin presents the advantage of not interfering with the other anticonvulsant drugs. The interindividual pharmacokinetic variability and the saturable absorption are, with the adaptation in case of renal insufficiency, the only arguments in favor of TDM. During clinical studies, the plasma concentrations of gabapentin were generally included between 2 and 20 mg/L. For this molecule, the level of proof of the interest of therapeutic drug monitoring was estimated in: possibly useful.

Efficacy and tolerability of pregabalin in partial epilepsy

Pregabalin, the most recently approved antiepileptic drug, is a structural analog of GABA with a favorable pharmacokinetic profile. Pregabalin binds to the α2-δ subunit of a neuronal voltage-gated calcium channel and is believed to exert its anticonvulsant effect by modulating the release of specific neurotransmitters from hyperexcited presynaptic neurons. Animal models of epilepsy have suggested that this drug will be efficacious against partial-onset and generalized tonic–clonic seizures. Four pivotal, add-on clinical trials conducted in patients with partial-onset seizures demonstrated that pregabalin at daily doses of 150–600 mg is efficacious and associated with dose-dependent adverse events. Meta-analyses of efficacy and tolerability indicated that pregabalin is an efficacious and relatively well-tolerated antiepileptic drug.

Cellular and behavioral interactions of gabapentin with alcohol dependence.

Gabapentin is a structural analog of GABA that has anticonvulsant properties. Despite the therapeutic efficacy of gabapentin, its molecular and cellular mechanisms of action are unclear. The GABAergic system in the central nucleus of the amygdala (CeA) plays an important role in regulating voluntary ethanol intake. Here, we investigated the effect of gabapentin on GABAergic transmission in CeA slices, on ethanol intake, and on an anxiety measure using animal models of ethanol dependence. Gabapentin increased the amplitudes of evoked GABA receptor-mediated IPSCs (GABA-IPSCs) in CeA neurons from nondependent rats, but decreased their amplitudes in CeA of ethanol-dependent rats. Gabapentin effects were blocked in the presence of a specific GABA(B) receptor antagonist. The sensitivity of the GABA-IPSCs to a GABA(B) receptor antagonist and an agonist was decreased after chronic ethanol, suggesting that ethanol-induced neuroadaptations of GABA(B) receptors associated with ethanol dependence may account for the differential effects of gabapentin after chronic ethanol. Systemic gabapentin reduced ethanol intake in dependent, but not in nondependent, rats and reversed the anxiogenic-like effects of ethanol abstinence using an acute dependence model. Gabapentin infused directly into the CeA also blocked dependence-induced elevation in operant ethanol responding. Collectively, these findings show that gabapentin reverses behavioral measures of ethanol dependence and, in turn, dependence reverses the effects of gabapentin on CeA neurons, and suggest that gabapentin represents a potential medication for treatment of alcoholism.

Newer N-Phthaloyl GABA Derivatives with Antiallodynic and Antihyperalgesic Activities in Both Sciatic Nerve and Spinal Nerve Ligation Models of Neuropathic Pain

Background: There is considerable research evidence supporting a palliative role for γ-aminobutyric acid (GABA)-ergic neurotransmission and voltage-gated sodium channel blockade in neuropathic pain conditions. Hence, the present study was undertaken to assess the peripheral analgesic, antiallodynic and antihyperalgesic activities of the synthesized structural analogues of GABA. Methods: The screening study included acute tissue injury, chronic constriction injury (CCI), and spinal nerve ligation (SNL) models of neuropathic pain. Results: All of the tested compounds sup-pressed the acetic acid-induced writhing response significantly in comparison to the control. In particular, compound JVP-8 was observed to be the most active compound with percent inhibition greater than that of the standard drug aspirin (97.8% inhibition of writhing response as against 97.0% shown by aspirin). In neuropathic pain studies, compound JVP-5 (100 mg/kg i.p.) emerged as the most active compound affording maximum protection against dynamic allodynia and mechanical hyperalgesia in the CCI model, and against spontaneous pain and mechanical hyperalgesia in SNL rats. Conclusion: In this study, we have demonstrated that combining phthalimide pharmacophore with GABA has evolved compounds effective for the treatment of neuropathic pain.

Pregabalin

Pregabalin, the pharmacologically active S-enantiomer of 3-aminomethyl-5-methyl-hexanoic acid, is a structural analogue of GABA, although it is not active at GABA receptors, nor does it acutely alter GABA uptake or degradation.black triangle Pregabalin binds with high affinity to the alpha2-delta subunit protein of voltage-gated calcium channels in CNS tissues and acts as a presynaptic modulator of the excessive release, in hyperexcited neurons, of various excitatory neurotransmitters. Binding of pregabalin to the alpha2-delta subunit appears necessary for its demonstrable anxiolytic, analgesic and anticonvulsant activities in animal models.black triangle Oral pregabalin, typically at dosages of 300-600 mg/day, was superior to placebo and similar to lorazepam 6 mg/day, alprazolam 1.5 mg/day and venlafaxine 75 mg/day in improving anxiety and depressive symptoms in patients with moderate-to-severe generalised anxiety disorder (GAD). Pregabalin had a rapid onset of anxiolytic activity relative to alprazolam and venlafaxine, which was evident after 1 week. Additionally, pregabalin (initial dosage 450 mg/day) was effective for the prevention of relapse of GAD over 34 weeks. Pregabalin was well tolerated during dosage escalation to fixed dosages (maximum 600 mg/day) over 7 days. Dizziness and somnolence, usually of mild to moderate severity, were the most common adverse events.black triangle The drug was not associated with a clinically significant medication withdrawal syndrome during a 1-week taper following 4 or 6 weeks' double-blind treatment.

Cellular Actions of Gabapentin and Related Compounds on Cultured Sensory Neurones

In this review we outline the actions of gabapentin and pregabalin on the excitability of sensory dorsal root ganglion (DRG) neurones in culture and compare these effects with those seen in other neuronal and cultured cell preparations. We also consider the potential mechanisms of action of gabapentin and pregabalin that may contribute to their anti-nociceptive effects. Gabapentin and pregabalin have similar actions and at saturating concentrations do not have additive effects suggesting that they act at the same or closely associated sites. The only high affinity binding sites yet identified for these drugs are α2δ-subunits (types 1 and 2 but not 3 and 4) of voltage-activated Ca2+ channels. Consistent with this are the findings that gabapentin and pregabalin both attenuate Ca2+ influx through voltage-activated channels and these inhibitory actions may in part provide a mechanism by which multiple firing of action potentials in sensory neurones is reduced. However, it is clear that gabapentin and pregabalin have a number of novel characteristics. Although structural analogues of GABA they appear to act independently of GABA receptor activation in sensory neurones. The actions of gabapentin and pregabalin on sensory neurones are not consistent with selective effects on particular high voltage-activated Ca2+ channel subtypes (L, N, P, Q and R) yet a significant proportion (at least 50%) of the whole cell Ca2+ current is insensitive to these drugs. Cell culture conditions can alter Ca2+ channel subunit expression in such a way as to reduce sensitivity to gabapentin and this can be used to identify potential sites of action of this drug. Analysis of subunit mRNA in cell populations with different sensitivities to gabapentin surprisingly indicated that Ca2+ channel b2-subunits as well as α2δ-subunits may determine Ca2+ channel sensitivity to gabapentin in DRG neurones. In addition to Ca2+ channels, gabapentin and pregabalin modulate other whole cell currents, and in particular a delayed enhancement of voltage-dependent K+ conductances has been observed in cultured DRG neurones. The delayed and prolonged features of this enhancement of voltage-activated K+ currents may reflect gabapentin and pregabalin modulating channel activity via intracellular signalling pathways either via a surface receptor interaction leading to the production of a second messenger or by directly acting at intracellular sites. The wide variety of therapeutic effects achieved with gabapentin and pregabalin offer a considerable challenge when trying to determine cellular mechanisms of action of these apparently simple synthetic compounds. Keywords: gabapentin, sensory dorsal root, pregabalin, anti-nociceptive effects

Gabapentin In The Treatment Of Neuropathic Pain After Spinal Cord Injury: A Prospective, Randomized, Double-Blind, Crossover Trial

Background: Neuropathic pain is a common complaint after traumatic spinal cord injury (SCI). Gabapentin, a synthetic structural analogue of GABA, has been shown to have beneficial effects in the treatment of neuropathic pain in other diagnostic groups; however, no standardized clinical trial has been performed to evaluate its efficacy after SCI.Design: A 1 0-week, prospective, randomized, double-blind, crossover, and placebo-controlled clinical trial.Objective: To determine the efficacy of gabapentin in the treatment of SCI-related neuropathic pain.Methods: Seven subjects with neuropathic pain, who were more than 30 days post-SCI, completed the study. Two groups received a 4-week course of gabapentin and placebo in a randomized crossover design with a 2-week washout period. The Neuropathic Pain Scale was used to record daily pain levels. Data were analyzed using the Wilcoxon signed rank test.Results: Gabapentin has some beneficial effects on certain types of neuropathic pain. There was a significant decrease of "unpleasant feeling" and a trend toward a decrease in both the "pain intensity" and "burning sensation" at the fourth week of gabapentin treatment compared with those on the placebo. No significant difference was found among other pain descriptors during the gabapentin and placebo treatment, although this may have been limited by the small sample size and low maximum dosage of gabapentin.Conclusions: Gabapentin reduces certain types of neuropathic pain in the SCI population. Future studies with larger sample sizes, higher dosages, and quicker titration will help further determine the efficacy of gabapentin in the treatment of SCI-related neuropathic pain.

Gamma-hydroxybutyric acid: an endogenous neuromodulator with abuse potential?

Gamma-hydroxybutyrate (GHB) is an endogenous constituent of mammalian brains, synthesized locally from GABA that might play a role as a central neuromodulator (Box 1) 1 Bowery N.G. Hudson A.L. Price G.W. Neuroscience. 1987; 20: 365-383 Crossref PubMed Scopus (775) Google Scholar , 2 Mathivet P. Bernasconi R. de Barry J. Marescaux C. Bittiger H. Eur. J. Pharmacol. 1997; 321: 67-75 Crossref PubMed Scopus (122) Google Scholar , 3 Maötre M. Prog. Neurobiol. 1997; 51: 337-361 Crossref PubMed Scopus (409) Google Scholar . GHB freely crosses the blood–brain barrier and has been used in anaesthesia, sleep disorders and alcohol and opioid dependence. Recently, the ability of GHB to induce euphoria has resulted in a growing number of illicit self-administrations. Acute overdoses induce confusion, epileptic seizures and coma. Chronic exposure can lead to physical dependence, as evidenced by withdrawal symptoms. The mechanisms by which GHB affects neural functioning and acts as a drug of abuse are still under study. Box 1. Biosynthesis and degradation of γ-hydroxybutyrate in the rat brain GABA is deaminated through GABA transaminase (EC 2.6.19) (a) into succinic semialdehyde (SSA). Oxidation of SSA by the mitochondrial SSA dehydrogenase (b) produces succinic acid, whereas its reduction by the cytosolic SSA reductase (EC 1.1.1.1.2) (c) gives rise to Γ-hydroxybutyric acid (GHB). Less than 0.15% of the metabolic flux coming from GABA takes the reductive pathway and forms GHB. Depending on species, anatomical structures, level of brain maturation and methods of detection, GHB levels range from 0.5–25 pmol mg−1 tissue. The substantia nigra, thalamus and hypothalamus contain the greatest amounts of GHB, whereas the cerebellum and some cortical areas contain the lowest. Degradation of GHB involves its oxidation to SSA, through GHB dehydrogenase (EC 1.1.1.19), (d) followed by entry intro Krebs cycle via succinic acid. A small part of SSA coming from GHB might be retransformed into GABA (e). Substances structurally related to GHB bind to both high- and low-affinity sites and display agonistic (trans-γ-hydroxycrotonic acid, THCA) or antagonistic (NCS382) properties. γ-Butyrolactone (GBL) does not bind to GHB binding sites and is inactive per se. However, as GBL is rapidly and irreversibly hydrolysed into GHB by peripheral gamma-lactonase (f) and as it is more rapidly and more reproducibly absorbed, GBL is often used as a GHB precursor in animal experiments. r(−)-Baclofen is a structural analogue of GABA and a specific agonist of GABAB receptors; it is inactive at GABAA and GHB binding sites. (See 1 Mathivet P. Bernasconi R. de Barry J. Marescaux C. Bittiger H. Eur. J. Pharmacol. 1997; 321: 67-75 Crossref PubMed Scopus (97) Google Scholar , 2 Maı̂tre M. Prog. Neurobiol. 1997; 51: 337-361 Crossref PubMed Scopus (319) Google Scholar for review.) aSee 3 Bowery N.G. Hudson A.L. Price G.W. Neuroscience. 1987; 20: 365-383 Crossref PubMed Google Scholar . (Online: Fig. I) GABA is deaminated through GABA transaminase (EC 2.6.19) (a) into succinic semialdehyde (SSA). Oxidation of SSA by the mitochondrial SSA dehydrogenase (b) produces succinic acid, whereas its reduction by the cytosolic SSA reductase (EC 1.1.1.1.2) (c) gives rise to Γ-hydroxybutyric acid (GHB). Less than 0.15% of the metabolic flux coming from GABA takes the reductive pathway and forms GHB. Depending on species, anatomical structures, level of brain maturation and methods of detection, GHB levels range from 0.5–25 pmol mg−1 tissue. The substantia nigra, thalamus and hypothalamus contain the greatest amounts of GHB, whereas the cerebellum and some cortical areas contain the lowest. Degradation of GHB involves its oxidation to SSA, through GHB dehydrogenase (EC 1.1.1.19), (d) followed by entry intro Krebs cycle via succinic acid. A small part of SSA coming from GHB might be retransformed into GABA (e). Substances structurally related to GHB bind to both high- and low-affinity sites and display agonistic (trans-γ-hydroxycrotonic acid, THCA) or antagonistic (NCS382) properties. γ-Butyrolactone (GBL) does not bind to GHB binding sites and is inactive per se. However, as GBL is rapidly and irreversibly hydrolysed into GHB by peripheral gamma-lactonase (f) and as it is more rapidly and more reproducibly absorbed, GBL is often used as a GHB precursor in animal experiments. r(−)-Baclofen is a structural analogue of GABA and a specific agonist of GABAB receptors; it is inactive at GABAA and GHB binding sites. (See 1 Mathivet P. Bernasconi R. de Barry J. Marescaux C. Bittiger H. Eur. J. Pharmacol. 1997; 321: 67-75 Crossref PubMed Scopus (97) Google Scholar , 2 Maı̂tre M. Prog. Neurobiol. 1997; 51: 337-361 Crossref PubMed Scopus (319) Google Scholar for review.) aSee 3 Bowery N.G. Hudson A.L. Price G.W. Neuroscience. 1987; 20: 365-383 Crossref PubMed Google Scholar . (Online: Fig. I) 3-N[1{(s)-3,4-dichlorophenyl}-ethylamino]-2-(s)hydroxypropylcyclo-hexylmethyl phosphinic acid 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid ethyl-8-azido-6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]-[1,4]benzodiazepine-3-carboxylate

Rand Lecture, ASCEPT. GABA receptors: as complex as ABC? Australaisian Society for Clinical and Experimental Pharmacologists and Toxicologists.

1. Receptors for the inhibitory neurotransmitter GABA are currently classified pharmacologically into two major subtypes. 2. GABAA receptors are antagonized by the convulsant alkaloid bicuculline, and are insensitive to activation by the GABA analogue baclofen. GABAB receptors are insensitive to bicuculline and activated stereoselectively by baclofen. 3. There is increasing evidence for 'novel' GABA receptors that pharmacologically fall outside that defined by the GABAA/B classification. 4. GABA receptors insensitive to both baclofen and bicuculline have been described in the spinal cord, optic tectum, retina, cerebellum and hippocampus. In addition such novel GABA receptors may be widespread in insects and bacteria. These novel receptors have been given a variety of descriptions: GABAC, GABANANB (non-A, non-B) and GABA rho (cloned from retina). 5. cis-4-Aminocrotonic acid (CACA), a structural analogue of GABA in a folded conformation, is considered to be a selective agonist of the putative GABAC receptors. Tritiated CACA binds to cerebellar membranes in a GABA-sensitive, baclofen-insensitive manner. It can be displaced only by relatively high concentrations of bicuculline. 6. Autoradiographic studies show pronounced differences in regional distribution between the binding of CACA, the GABAA agonist muscimol and the GABAB agonist baclofen. 7. Novel GABA receptors may represent important new pharmacological targets.

Glutaric Aciduria Type 1: First Reported Cases in Three Saudi Patients

The clinical and biochemical findings in three patients with glutaric aciduria Type 1 (GAT1) are presented. They had a normal postnatal period of three to 14 months. They developed sudden and severe encephalopathy following an infection or trauma (patient 3) that gradually progressed to severe dystonia, choreoathetosis, spastic quadriplegia and mental retardation. Neuroradiologic studies of the brain revealed white matter disease and frontotemporal lobe hypoplasia. The urine findings by gas chromatography/mass spectrometry (GC)/(MS) were characteristic of GAT1. Since GAT1 is an organic acidemia without intermittent acidotic attacks, but primarily manifests with progressive encephalopathy, it is important to recognize the potential of its existence among handicapped children in chronic care facilities. The good clinical response in two of the patients urges early diagnosis in subsequent newborn siblings of the families with the disease. The diagnosis of three patients in less than two years indicates the need for neonatal screening for the recognition of this disease, among other treatable metabolic diseases, in Saudi Arabia.

Central receptor binding and cardiovascular effects of GABA analogues in the cat

1. 1. Several structural analogues of GABA were shown to be inhibitors of GABA A receptor binding in membranes from cat cerebral cortex. 2. 2. These compounds were 3-aminopropanesulfonic acid (APS; IC 50 = 0.04 μM), imidazoleacetic acid (IMA; IC 50 = 0.4 μM), morpholinopropanesulfonic acid (MOPS; IC 50 = 1.6 μM), 5-phenylpyrrolepropionic acid (PPP; IC 50 = 15 μM), aminoethanethiosulfonic acid (AETS; IC 50 = 22 μM), 3-amino-3-phenylpropionic acid (APP; IC 50 = 35 μM), meta-aminobenzoic acid (MABA; IC 50 = 58 μM) and urocanic acid (UCA; IC 50 = 354 μM). The IC 50 value for GABA was 0.03 μM. 3. 3. GABA, PPP, AETS, MABA and UCA were previously shown to reduce arterial pressure in the cat after intracerebroventricular infusion. 4. 4. In the present study MOPS (ED 50 = 0.26 nmol/kg), APS (ED 50 = 4.7 nmol/kg), APP (ED 50 = 49 nmol/kg), and IMA (ED 50 = 350 nmol/kg) were also found to be able to decrease blood pressure when infused into the fourth ventricle. 5. 5. All nine compounds reduced blood pressure to the same extent, but in some cases their relative potencies (ED 50 values) exhibited significant differences. 6. 6. When the IC 50 values for receptor binding were plotted against the ED 50 values for the cardiovascular effects, no significant correlation emerged. 7. 7. This lack of a correlation does not necessarily imply that the reductions in blood pressure elicited by the drugs are not related to an activation of central GABA A receptors. 8. 8. Instead, it highlights the difficulties that are sometimes encountered in attempting to obtain quantitative measurements after intracerebroventricular infusion.

Uptake of γ-aminobutyric acid by catfish brain

1. Using homogenates of catfish whole-brain in an isotonic medium, we observed an accumulation of [ 3H]GABA that was temperature-sensitive and was dependent on the presence of sodium ions, the optimum concentration of which was 75 mM. 2. A kinetic analysis showed that the [ 3H]GABA uptake mechanism became saturated with increasing GABA concentrations. A high-affinity system, only, was evident whose K m was calculated as 12 μM. 3. Four structural analogues of GABA were found to be competitive inhibitors of uptake, and K i values were determined. Nipecotic acid ( K i = 1.8 μM) and guvacine ( k i = 3.9 μM) were the most potent compounds, however 2,4-diaminobutyric acid ( K i = 8.9 μM) and β-alanine ( K i = 55 μM) also had an effect. 4. The characteristics of the uptake mechanism in catfish brain that we have studied are similar to those reported for uptake by mammalian brain except that in the latter, both a high- and a low-affinity transport processes are present. Our data, taken together with what is already known, strongly suggest that the biochemistry of the GABA system in lower vertebrates does not differ significantly from that in mammals.

Pharmacological analysis of the central cardiovascular effects of four GABA analogues

The central cardiovascular effects of 4 structural analogues of GABA were investigated. The drugs were injected intracerebroventricularly (i.c.v.) in cumulative doses into pentobarbital-anaesthetized normotensive rats. Muscimol (0.01-10 micrograms/kg), THIP (0.01-100 micrograms/kg), kojic amine (0.1-100 micrograms/kg) and isoguvacine (0.1-100 micrograms/kg) produced dose-dependent hypotension and bradycardia. The maximal fall in the mean blood pressure was of about 35% of the initial values. These effects appears to be of central origin since the intravenous (i.v.) injection of the same doses of the drugs did not produce any similar cardiovascular modifications. The hypotensive effects of muscimol and kojic amine were antagonized partly by i.c.v. bicuculline. The combination of bicuculline and kainic acid almost completely prevented the blood pressure lowering effects of muscimol, kojic amine and isoguvacine. THIP however was only slightly antagonized by bicuculline and kainic acid. Atropine i.v. also prevented partly the cardiovascular effects of all these drugs. Thus, the mechanisms of the central cardiovascular actions of GABA analogues appear to be more complex than expected and variable from one drug to another. The involvement of GABA receptors of the A and B types and of cholinergic mechanisms in the hypotensive effect of the drugs is discussed.

Effect of muscimol, a central GABA receptor agonist, on the catalepsy, striatal homovanillic acid increase, and analgesia induced by pilocarpine in rats

Muscimol, a structural analog of GABA, significantly potentiated pilocarpine-induced analgesia in rats, but failed to alter pilocarpine-induced catalepsy. It also failed to affect pilocarpine-elicited increase in homovanillic acid levels in the striatum. These findings suggest that the potentiation of pilocarpine-induced analgesia by muscimol is unrelated to an interaction of the GABAergic system with the striatal cholinergic or dopaminergic systems.