Glutamic acid decarboxylase inhibition and ultrastructural changes by the convulsant drug allylglycine

Alberici, Martha; Arnaiz, Georgina Rodrı́guez de Lores; Robertis, E. De

doi:10.1016/0006-2952(69)90018-5

Cited by 85 publications

(10 citation statements)

References 14 publications

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“…This latency period was described previously in mice (44-240 min) and in rats (120-150 min) by Horton and Meldrum [41] and Alberici et al [64], respectively. A wide variation in seizure onset between test animals was also reported by these authors.…”

Section: Behavioral Response Of Zebrafish Larvae To Agsupporting

confidence: 69%

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

Leclercq

Afrikanova

Langlois

et al. 2015

Epilepsy & Behavior

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Treatment-resistant seizures affect about a third of patients suffering from epilepsy. To fulfill the need for new medications targeting treatment-resistant seizures, a number of rodent models offer the opportunity to assess a variety of potential treatment approaches. The use of such models, however, has proven to be timeconsuming and labor-intensive. In this study, we performed pharmacological characterization of the allylglycine (AG) seizure model, a simple in vivo model for which we demonstrated a high level of treatment resistance. (D,L)-Allylglycine inhibits glutamic acid decarboxylase (GAD) -the key enzyme in γ-aminobutyric acid (GABA) biosynthesis -leading to GABA depletion, seizures, and neuronal damage. We performed a side-by-side comparison of mouse and zebrafish acute AG treatments including biochemical, electrographic, and behavioral assessments. Interestingly, seizure progression rate and GABA depletion kinetics were comparable in both species. Five mechanistically diverse antiepileptic drugs (AEDs) were used. Three out of the five AEDs (levetiracetam, phenytoin, and topiramate) showed only a limited protective effect (mainly mortality delay) at doses close to the TD 50 (dose inducing motor impairment in 50% of animals) in mice. The two remaining AEDs (diazepam and sodium valproate) displayed protective activity against AG-induced seizures. Experiments performed in zebrafish larvae revealed behavioral AED activity profiles highly analogous to those obtained in mice. Having demonstrated crossspecies similarities and limited efficacy of tested AEDs, we propose the use of AG in zebrafish as a convenient and high-throughput model of treatment-resistant seizures.

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Section: Behavioral Response Of Zebrafish Larvae To Agsupporting

confidence: 69%

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

Leclercq

Afrikanova

Langlois

et al. 2015

Epilepsy & Behavior

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“…20 Conversely, the levels of released GABA decreased by ≈52.6% from untreated controls (Figure 3C), after exposure of the cells to LAG, a specific inhibitor of GABA synthesis. 19 In addition, immunostaining analysis utilizing monoclonal antibodies against GABA confirmed its presence in HUVEC under steady-state conditions ( Figure 3D) Figure 3. Thin-layer chromatography (TLC) analysis of (A) the human umbilical vein endothelial cell (HUVEC) extract and (B) the cultured media for the distribution of […”

Section: Cultured Huvec Synthesized and Released Gabamentioning

confidence: 79%

“…HUVEC was subjected to treatments such as LAG and Gc, which are specific inhibitors of GAD and GABA transaminase, respectively. 19,20 LAG was used at 300 µmol/L and Gc at 45 µmol/L concentrations for 24 hours. The concentrations utilized were based on concentrations that yielded optimum effects in predetermined trails (Online Figures I and II) and from those used by others.…”

Section: Detection Of Gaba By Elisamentioning

confidence: 99%

“…The concentrations utilized were based on concentrations that yielded optimum effects in predetermined trails (Online Figures I and II) and from those used by others. 19,20 The amount of GABA was corrected against the read-out of media without cells and then further against the total protein in the cells. The results represent the average of 6 independent experiments.…”

Section: Detection Of Gaba By Elisamentioning

confidence: 99%

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γ-Aminobutyric Acid Is Synthesized and Released by the Endothelium

Sen

Roy

Bandyopadhyay

et al. 2016

Circulation Research

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Rationale: Gamma aminobutyric acid (GABA), a neurotransmitter of the central nervous system, is found in the systemic circulation of humans at a concentration between 0.5 and 3 μmol/L. However, the potential source of circulating GABA and its significance on the vascular system remains unknown. We hypothesized that endothelial cells (ECs) may synthesize and release GABA to modulate some functions in the EC and after its release into the circulation.Objective: To assess whether GABA is synthesized and released by the EC and its potential functions. Methods and Results: Utilizing the human umbilical vein ECs and aortic ECs, we demonstrated for the first time that ECs synthesize and release GABA from [1-14 C]glutamate. Localization of GABA and the presence of the GABA-synthesizing enzyme, glutamic acid decarboxylase in EC were confirmed by immunostaining and immunoblot analysis, respectively. The presence of GABA was further confirmed by immunohistochemistry in the EC lining the human coronary vessel. EC-derived GABA regulated the key mechanisms of ATP synthesis, fatty acid, and pyruvate oxidation in EC. GABA protected EC by inhibiting the reactive oxygen species generation and prevented monocyte adhesion by attenuating vascular cell adhesion molecule -1 and monocyte chemoattractant protein-1 expressions. GABA had no relaxing effect on rat aortic rings. GABA exhibited a dose-dependent fall in blood pressure. However, the fall in BP was abolished after pretreatment with pentolinium. from Perkin Elmer, MA, catalog NEC290E050UC, NEC255050UC, and NEC559010UC. All other chemicals unless specified were obtained from Sigma. Conclusions: Cell CultureHuman umbilical vein endothelial cells (HUVECs) were freshly isolated from umbilical cords from different donors after normal delivery (with approval from the Institutional Review Board of University of California at Los Angeles, LA, CA). Primary cultures of HUVEC were prepared as described 14 and used at passages 1 or 2. Primary cultures of human aortic endothelial cells (HAEC) at passage 2 or 3 were a generous gift from Dr M. Navab in the Department of Medicine, University of California, Los Angeles, 90095-1732, USA. Both HAEC and HUVEC were cultured in endothelial cell basal medium-2 (Lonza), and the medium was supplemented with Endothelial Growth Medium-2 Bullet kit (CC3162; Lonza) as per the manufacturer's instructions as described previously. 15PC12 cells were a generous gift from Dr E. Schweitzer, Semel Institute of Neuroscience and Human Behavior, University of California, Los Angeles. PC12 cells were cultured in DMEM supplemented with 5% FCS and 5% Horse serum. Human skin fibroblast (HSF) cells were a gift from Dr H. Coller, Molecular Cell and Developmental Biology, University of California, Los Angeles. HSF and THP1 were cultured in DMEM supplemented with 10% FBS. All cells were cultured until 70% confluent before downstream manipulations. Cell culture treatments were done under sterile conditions, for 24 hours unless specified. Glutamic acid decarboxylase (GAD) doubl...

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“…Pyridoxal phosphate antagonists may influence the activity of other cerebral decarboxylases and transaminases: the other biochemical effects of allylglycine and 3-mercaptopropionic acid have not been extensively investigated, but allylglycine appears to have little effect on cerebral transaminases but does produce slight inhibition of glutamine synthetase (Alberici et al, 1969). 3-Mercaptopropionic acid is also a competitive inhibitor of bacterial GABA-transaminase, but does not affect glutamine synthetase (Lamar, 1970).…”

Section: Discussionmentioning

confidence: 99%

Seizures induced by allylglycine, 3‐mercaptopropionic acid and 4‐deoxypyridoxine in mice and photosensitive baboons, and different modes of inhibition of cerebral glutamic acid decarboxylase

Horton

Meldrum

1973

British J Pharmacology

151

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Summary 1. DL-C-Allylglycine, 4-deoxypyridoxine hydrochloride and 3-mercaptopropionic acid have been studied with reference to their convulsant effects in mice and in baboons (Papio papio) with photosensitive epilepsy, and their action on the cerebral enzyme synthesizing y-aminobutyric acid (L-glutamate-1-carboxy-lyase).2. In mice, the EI)0 values for seizures following intraperitoneal injection were allylglycine 1-0 mmol/kg body weight, 4-deoxypyridoxine 141 mmol/kg and 3-mercaptopropionic acid 027 mmol/kg. Latency to seizure onset was longest after allylglycine (44-240 min), intermediate after 4-deoxypyridoxine (9-114 min) and shortest after 3-mercaptopropionic acid (2 5-8 min). 3. In Papio papio intravenous administration of subconvulsant doses of allylglycine (0O87-3-1 mmol/kg), or of 4-deoxypyridoxine (0 21 0-53 mmol/kg) enhanced the occurrence and persistence of myoclonic responses to intermittent photic stimulation, and augmented the associated electroencephalographic abnormalities, without modifying their character or distribution. Higher doses produced brief seizures recurring at regular intervals, between 2-14 h after allylglycine (4-0-4-3 mmol/kg) or 1-4 h after 4-deoxypyridoxine (0-53-0{87 mmol/kg). Electroencephalographically these seizures originated unilaterally in the occipital or posterior parietal cortex. 4. In Papio papio photically-induced epileptic responses were enhanced 5-10 min after the intravenous injection of 3-mercaptopropionic acid (009-028 mmoi/kg). A sequence of brief generalized seizures followed bv complete recovery occurred 4-17 min after the injection of 3-mercaptopropionic acid (0 28-0-38 mmol/kg). Fatal status epilepticus followed the injection of 3-mercaptopropionic acid (0 57-0 75 mmol/kg). E.E.G. records showed generalized cortical involvement at the onset of the seizures. 5. L-Glutamate 1-carboxy-lyase (GAD) activity was determined in whole brain homogenates from mice killed at various intervals after receiving i.p. a convulsant dose of one of the compounds. Inhibition of GAD activity was evident 30-60 min before seizure onset following allylglycine or 4-deoxypyridoxine administration, and was maximal (40-60%) just before or during seizure activity. Addition of pyridoxal phosphate to the brain homogenate relieved inhibition produced by 4-deoxypyridoxine but not that produced by allylglycine. Inhibition of GAD activity in brain homogenates from animals killed 2 or * Present address:

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Glutamic acid decarboxylase inhibition and ultrastructural changes by the convulsant drug allylglycine

Cited by 85 publications

References 14 publications

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

Cross-species pharmacological characterization of the allylglycine seizure model in mice and larval zebrafish

γ-Aminobutyric Acid Is Synthesized and Released by the Endothelium

Seizures induced by allylglycine, 3‐mercaptopropionic acid and 4‐deoxypyridoxine in mice and photosensitive baboons, and different modes of inhibition of cerebral glutamic acid decarboxylase

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