Seizures induced by hyperbaric oxygen and cerebral gamma-aminobutyric acid in chicks during development

Abstract— The susceptibility of chicks to convulsions induced by hyperbaric oxygen increased with age during the first few weeks of life. The sensitivity of the levels of cerebral GABA to change by oxygen at high pressure (OHP) also increased with age. There was correlation between the rate of decrease in concentration of cerebral GABA and the time to onset of OHP seizures. The anti-convulsant action of intraperitoneally administered GABA was greater in 6-9-day-old chicks than in 21-23-day-old chicks, consistent with decreasing permeability of the blood-brain barrier to the amino acid with increasing age.     

HYDRAZIDE-INDUCED SEIZURES AND CEREBRAL OF LEVELS γ-AMINOBUTYRIC ACID: A RE-EVALUATION

Data have been presented indicating that in chicks the time lag in the onset of seizures after the administration of hydrazides was not caused by a slow penetration of the convulsant agents into the brain. A correlation was evident between the rate of decrease in concentration of cerebral GABA and the susceptibility of chicks to hydrazide-induced seizures. Earlier studies precluding a role for GABA in hydrazide-induced convulsions were re-examined.     

Hyperbaric oxygen: effect of sodium dipropylacetate and dipropylacetamine on convulsion seizures and pulmonary lesions in the mouse]

It was shown that oxygen at high pressure (OHP) induced epileptic seizures and pulmonary damages on mice. Dipropylacetate protected mice against nervous syndrome better than did dipropylacetamide. No significant pulmonary protection was observed with both drugs.     

Effect of 6-hydroxydopamine on brain and blood catecholamine, ammonia, and amino acid metabolism in rats subjected to high pressure oxygen induced convulsions

Effects of 6-hydroxydopamine (6-OHDA) on rat brain and blood adrenaline (A), noradrenaline (NA), ammonia (NH3), gamma-aminobutyric acid (GABA), and amino acid metabolism prior to and after high pressure oxygen (OHP) induced convulsions have been studied. 6-OHDA reduces GABA and glutamate (Glu) rior to OHP exposure in rat brain so that the concentration is even equal to that seen in nondrugged animals after convulsion. Concomitantly, 6-OHDA reduces the latency of OHP-induced convulsion significantly, and increases brain NH3, glutamine, and asparagine significantly. Although 6-OHDA, in increasing dosage, elevates blood A concentration, convulsion produces a significant further increase in A. Blood NA was not significantly changed in drugged, convulsed animals and was much less than blood NA concentrations in nondrugged convulsed animals. Increasing doses of 6-OHDA also increase NH3 in the blood significantly and convulsion increases its concentration further. Latency of convulsion seems to be related to certain monoamine levels since in some drugged animals where A and total catecholamines are still reduced 96 h after the first of two doses of 6-OHDA, NA concentrations are recovered to relatively normal and the convulsion latency time is also increased although it remains significantly abbreviated from undrugged animals' convulsion time. Low brain GABA levels seem to be a prime effector of convulsive activity.     

Susceptibility to kainate-induced seizures under dietary zinc deficiency

Zinc homeostasis in the brain is altered by dietary zinc deficiency, and its alteration may be associated with the etiology and manifestation of epileptic seizures. In the present study, susceptibility to kainate-induced seizures was enhanced in mice fed a zinc-deficient diet for 4 weeks. When Timm's stain was performed to estimate zinc concentrations in synaptic vesicles, Timm's stain in the brain was attenuated in the zinc-deficient mice. In rats fed the zinc-deficient diet for 4 weeks, susceptibility to kainate-induced seizures was also enhanced. When the release of zinc and neurotransmitters in the hippocampal extracellular fluid of the zinc-deficient rats was studied using in vivo microdialysis, the zinc concentration in the perfusate was less than 50% of that of the control rats and the increased levels of zinc by treatment with kainate were lower than the basal level in control rats, suggesting that vesicular zinc is responsive to dietary zinc deficiency. The levels of glutamate in the perfusate of the zinc-deficient rats were more increased than in the control rats, whereas the levels of GABA in the perfusate were not at all increased in the zinc-deficient rats, unlike in the control rats. The present results demonstrate an enhanced release of glutamate associated with a decrease in GABA concentrations as a possible mechanism for the increased seizure susceptibility under zinc deficiency.     

Measuring human brain GABA in vivo

Gamma-aminobutyric acid (GABA) plays a pivotal role in suppressing the origin and spread of seizure activity. Low occipital lobe GABA was associated with poor seizure control in patients with complex partial seizures. Vigabatrin irreversibly inhibits GABA-transaminase, raising brain and cerebrospinal fluid (CSF) GABA concentrations. The effect of vigabatrin on occipital lobe GABA concentrations was measured by in vivo nuclear magnetic-resonance spectroscopy. Using a single oral dose of vigabatrin, the rate of GABA synthesis in human brain was estimated at 17% of the Krebs cycle rate. As the daily dose of vigabatrin was increased to up to 3 g, the fractional elevation of brain GABA was similar to CSF increase. Doubling the daily dose from 3 to 6g failed to increase brain GABA further. Increased GABA concentrations appear to reduce GABA synthesis in humans as it does in animals. With traditional antiepileptic drugs, remission of the seizure disorder was associated with normal GABA levels. With vigabatrin, elevated CSF and brain GABA was associated with improved seizure control. Vigabatrin enhances the vesicular and nonvesicular release of GABA. The release of GABA during seizures may be mediated in part by transporter reversal that may serve as an important protective mechanism. During a seizure, this mechanism may be critical in stopping the seizure or preventing its spread.     

Cerebral Glutamic Acid Decarboxylase Activity and γ-Aminobutyric Acid Concentrations in Mice Susceptible or Resistant to Audiogenic Seizures

Abstract: DBA/2 mice between 21 and 28 days of age are highly susceptible to sound-induced seizures. Drug studies suggest a possible deficit of γ-Aminobutyric acid (GABA)-mediated neurotransmission may be involved. We have measured the whole brain GABA concentration and glutamic acid decar-boxylase activity in DBA/2 mice at various ages before, during, and after the period of maximal susceptibility to audiogenic seizures. Corresponding determinations were carried out on age-matched TO mice, a strain much less susceptible to audiogenic seizures than DBA/2 mice at all ages. No significant differences in GABA concentration or glutamic acid decarboxylase activity were found between strains at any age. The susceptibility of DBA/2 mice to audiogenic seizures does not result from a gross inability to synthesise or store GABA.     

Anticonvulsant activity of glycylglycine and delta-aminovaleric acid: evidence for glutamine exchange in amino acid transport

We have proposed that glutamine serves in a facilitated diffusion process, mediated by the enzyme gamma-glutamyl transferase (gamma-glutamyl transpeptidase; gamma GT) and that it leaves the brain in exchange for entering amino acids. Glutamine is also a precursor of gamma-aminobutyric acid (GABA). Thus, providing an alternate substrate for gamma GT should spare brain glutamine, raise GABA, and cause an anticonvulsant effect. We have found that glycylglycine, the best-known substrate for gamma GT, and delta-aminovaleric acid (DAVA), a structural analog, have anticonvulsant activity in DBA/2J mice. Both compounds can decrease the incidence and severity of seizures induced by L-methionine-RS-sulfoximine or electroconvulsive shock. DAVA was also tested and found to be active against seizures caused by pentylenetetrazol or picrotoxin. [14C]DAVA entered the brain at the rate of 18.7 nmol/g/min. The activity of DAVA as a substrate of gamma GT was intermediate to that of glycylglycine and glutamine. Preliminary studies have shown that brain glutamine and perhaps GABA are elevated 3 h after administration of DAVA (7.5 mmol/kg). These findings support the theory that glutamine exchange plays a role in amino acid transport across the blood-brain barrier and suggests a new concept in anticonvulsant therapy.     

The time course of brain and blood catecholamines, catechol O-methyltransferase, and amino acids in rats convulsed by oxygen at high pressure.

The time course of changes in blood and brain catecholamines, catechol O-methyltransferase (COMT), ammonia, and amino acids leading to convulsion by high pressure oxygen breathing (OHP) in rats has been investigated. Brain catecholamines were suppressed by OHP. They changed in phase with brain COMT concentration and consequently were not due to the action of this degrading enzyme. Convulsive actions seem not to be influenced by brain catecholamine concentration. Blood adrenaline concentrations are, however, significantly elevated both prior to and during convulsions. In both brain and blood, ammonia concentration increases, glutamate decreases, and glutamine-aspargine increases. It is proposed that the efficacy of the glutamate-glutamine ammonia buffering system in blood and brain is important in the prevention of the onset of convulsions but that when brain gamma-aminobutyric acid is depressed to critical levels, convulsions result.     

Effect of Repeated Convulsive Seizures on Brain γ-Aminobutyric Acid Metabolism in Three Sublines of Mice Differing by Their Response to Acoustic Stimulations

The turnover rates and steady-state levels of gamma-aminobutyric acid (GABA) have been determined in 15 brain areas of three sublines of inbred mice differing in their susceptibility to audiogenic seizures: Rb3, which is seizure resistant; Rb2, which develops clonic seizures; and Rb1, which develops tonic-clonic seizures. In the Rb1 subline, GABA steady-state levels are lower than in the Rb3 subline in three of the 15 areas examined (cerebellum, anterior colliculus, and amygdala), whereas in the Rb2 subline, steady-state levels are either higher (posterior colliculus and hippocampus) or lower (amygdala) than in the Rb3 subline. GABA turnover rates differ in three brain areas in Rb1 (amygdala, raphe, and hypothalamus) and in a single area (amygdala) in Rb2 when compared with Rb3. Only one area has similar variations of GABA turnover rate and steady-state levels in the two susceptible sublines: the amygdala. After 2 weeks of repeated auditory stimulations (two times a day, 8,000 Hz, 100 dB), additional alterations in GABA metabolism are observed: mainly large increases in GABA turnover rates (from 40% to three- to fourfold). The Rb2 subline displays a greater number of alterations (increases of turnover rates in pons, cerebellum, anterior and posterior colliculus, amygdala, olfactory bulbs and tubercles, striatum, and frontal cortex) than the Rb1 subline (increases of turnover rates in cerebellum, posterior colliculus, olfactory tubercles, raphe, and frontal cortex and a decrease in hypothalamus). In the Rb3 subline, increases of the turnover rate in amygdala and olfactory tubercles and decreases in olfactory bulbs and hippocampus are observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta adrenergic receptors and glucagon in seizures from exposure to oxygen at high pressure (OHP)

Previous studies have shown that sympathetic factors and blood glucose are of importance in the development of seizures and lung damage from OHP. In the present study we examined the influence of beta sympathetic agonists and blocking agents and glucagon on OHP toxicity. Rats were exposed to 6 ATA OHP and examined for time-to-seizure and lung damage. Pretreatment with propranolol increased the time-to-seizure by 70% and practolol by 50% without altering gross lung appearance or lung wet wt/dry wt. Propranolol and practolol also prevented brain glycogen depletion prior to seizure which otherwise occurred in subconvulsive exposure to OHP. Isoproterenol and glucagon pretreatment had no effect on time-to-seizure but isoproterenol did increase lung injury. Both practolol and propranolol block the beta-receptor influence on adenyl cyclase-stimulated second messenger production, while both isoproterenol and glucagon activate adenyl cyclase to produce second messenger. Our results may suggest a possible role for second messenger in mediating some of the acute toxic effects of OHP on the CNS.     

Gas Exchange of Algae: II. Effects of Oxygen, Helium, and Argon on the Photosynthesis of Chlorella pyrenoidosa

Changes in the oxygen partial pressure of air over the range of 8 to 258 mm of Hg did not adversely affect the photosynthetic capacity of Chlorella pyrenoidosa. Gas exchange and growth measurements remained constant for 3-week periods and were similar to air controls (oxygen pressure of 160 mm of Hg). Oxygen partial pressures of 532 and 745 mm of Hg had an adverse effect on algal metabolism. Carbon dioxide consumption was 24% lower in the gas mixture containing oxygen at a pressure 532 mm of Hg than in the air control, and the growth rate was slightly reduced. Oxygen at a partial pressure of 745 mm of Hg decreased the photosynthetic rate 39% and the growth rate 37% over the corresponding rates in air. The lowered metabolic rates remained constant during 14 days of measurements, and the effect was reversible after this time. Substitution of helium or argon for the nitrogen in air had no effect on oxygen production, carbon dioxide consumption, or growth rate for 3-week periods. All measurements were made at a total pressure of 760 mm of Hg, and all gas mixtures were enriched with 2% carbon dioxide. Thus, the physiological functioning and reliability of a photosynthetic gas exchanger should not be adversely affected by: (i) oxygen partial pressures ranging from 8 to 258 mm of Hg; (ii) the use of pure oxygen at reduced total pressure (155 to 258 mm of Hg) unless pressure per se affects photosynthesis, or (iii) the inclusion of helium or argon in the gas environment (up to a partial pressure of 595 mm of Hg).     

THE ANTICONVULSANT ACTION OF GABA-ELEVATING AGENTS: A RE-EVALUATION

Abstract— The GABA-elevating agents, aminooxyacetic acid, hydrazine, and hydroxylamine, all possessed anticonvulsant properties, although to a widely varying degree. Aminooxyacetic acid was the most efficacious in delaying drug-induced seizures in mice whereas hydroxylamine brought about only a slight delay in the onset of seizures. The anticonvulsant action was observed against various convulsant agents regardless of whether the convulsant mechanism might involve a deranged GABA metabolism (allylglycine, isonicotinic acid hydrazide, hydrazine), an interference with GABA function (picrotoxin) or some other mechanism (pentylenetetrazol). The anticonvulsant action was not related in a simple manner to either GABA levels or glutamic acid decarboxylase (GAD) activities but the anomalous situation whereby seizures occurred when the GABA content of brain was above normal could be resolved on the basis of an expression which included changes in both GABA levels and GAD activity. The possibility was proposed that the anticonvulsant action of aminooxyacetic acid involved two separate mechanisms.     

Desensitization of gamma-aminobutyric acid receptor from rat brain: two distinguishable receptors on the same membrane

Transmembrane chloride flux mediated by gamma-aminobutyric acid (GABA) receptor can be measured with a mammalian brain homogenate preparation containing sealed membrane vesicles. The preparation can be mixed rapidly with solutions of defined composition. Influx of 36Cl- tracer initiated by mixing with GABA was rapidly terminated by mixing with bicuculline methiodide. The decrease in the isotope influx measurement due to prior incubation of the vesicle preparation with GABA, which increased with preincubation time and GABA concentration, was attributed to desensitization of the GABA receptor. By varying the time of preincubation with GABA between 10 ms and 50 s with quench-flow technique, the desensitization rates could be measured over their whole time course independently of the chloride ion flux rate. Most of the receptor activity decreased in a fast phase of desensitization complete in 200 ms (t 1/2 = 32 ms) at saturation with GABA. Remaining activity was desensitized in a few seconds (t 1/2 = 533 ms). These two phases of desensitization were each kinetically first order and were shown to correspond with two distinguishable GABA receptors on the same membrane. The receptor activities could be estimated, and the faster desensitizing receptor was the predominant one, giving on average ca. 80% of the total activity. The half-response concentrations were similar, 150 and 114 microM for the major and minor receptors, respectively. The dependence on GABA concentration indicated that desensitization is mediated by two GABA binding sites. The fast desensitization rate was approximately 20-fold faster than previously reported rates while the slower desensitization rate was slightly faster than previously reported rates.     

Extracellular GABA in the Ventrolateral Thalamus of Rats Exhibiting Spontaneous Absence Epilepsy: A Microdialysis Study

Abstract: There is compelling evidence that excessive GABA-mediated inhibition may underlie the abnormal electrical activity, initiated in the thalamus, associated with epileptic absence seizures. In particular, the GABA_B receptor subtype seems to play a critical role, because its antagonists are potent inhibitors of absence seizures, whereas its agonists exacerbate seizure activity. Using a validated rat model of absence epilepsy, we have previously found no evidence of abnormal GABA_B receptor density or affinity in thalamic tissue. In the present study, we have used in vivo microdialysis to monitor changes in levels of extracellular GABA and other amino acids in this brain region. We have shown that basal extracellular levels of GABA and, to a lesser extent, taurine are increased when compared with values in nonepileptic controls. However, modifying GABAergic transmission with the GABA_B agonist (−)-baclofen (2 mg/kg i.p.), the GABA_B antagonist CGP-35348 (200 mg/kg i.p.), or the GABA uptake inhibitor tiagabine (100 µ M ) did not produce any further alteration in extracellular GABA levels, despite the ability of these compounds to increase (baclofen and tiagabine) or decrease (CGP-35348) seizure activity. These findings suggest that the increased basal GABA levels observed in this animal model are not simply a consequence of seizure activity but may contribute to the initiation of absence seizures.     

BRAIN ENERGETICS IN OXYGEN-INDUCED CONVULSIONS

Mice were exposed to 6 ATA of 100% oxygen. The effect of high oxygen pressure (OHP), disulphiram and both disulphiram and oxygen as a function of the length of oxygen exposure on cerebral cortical ATP, phosphocreatine, lactate, pyruvate and glucose was determined. Neither OHP nor disulphiram altered ATP prior to the onset of convulsions. The combination of OHP and disulphiram appeared to elevate cerebral ATP, particularly during the early exposure period. OHP had no effect on phosphocreatine, however, disulphiram, both alone and in combination with OHP increased cerebral cortical phosphocreatine. ATP and phosphocreatine were unchanged in mice sacrificed either at the onset or 9 s after the onset of oxygen convulsions. Lactate and pyruvate increased as the length of time the mice were exposed to OHP increased although neither lactate nor pyruvate levels differed significantly from control levels at either the onset or 9 s after the onset of convulsions. Disulphiram by itself lowered cerebral lactate, and prevented the increase in lactate and pyruvate in mice exposed to OHP. OHP and disulphiram increased cerebral glucose with the combination of both OHP and disulphiram appearing to have an additive effect. Glucose also remained elevated at the onset or 9 s after the onset of oxygen convulsions.     

Interactions of Oxygen at High Pressure and Radiation in Drosophila

Oxygen at high pressure (OHP) and X-irradiation can interact in the fruit fly Drosophila melanogaster to potentiate toxic actions characteristic of one agent alone. 1000 kvp X-irradiation in doses of 30, 60, and 75 kr accelerated the acute immobilization of young male Drosophila by oxygen at 7.8 atm, up to rates twice that observed with such oxygen pressure alone. X-irradiation alone in these dosages did not acutely immobilize the Drosophila. X-irradiation during exposure to 7.8 atm pO₂ was more effective and consistent in producing this potentiation than was X-irradiation that preceded exposure to OHP. Acute OHP toxicity in young female Drosophila was not potentiated by 75 kr of X-irradiation. On the other hand, shortening of the life span of young male Drosophila by the above doses of X-irradiation was augmented significantly by a concurrent 40 min exposure to OHP (which alone did not significantly decrease life span). This shows, for the first time, that oxygen can affect not only the acute effects of radiation, but also the residual irreversible effects indicated by the life span shortening.     

The γ-Aminobutyrate Content of Nerve Endings (Synaptosomes) in Mice After the Intramuscular Injection of γ-Aminobutyrate-Elevating Agents: A Possible Role in Anticonvulsant Activity

Abstract: The intramuscular administration of L-cycloserine, gabaculine, and aminooxyacetic acid caused significant, time-dependent increases in the γ-aminobutyric acid (GABA) content of both whole brain and synaptosomalenriched preparations obtained from the tissue, a linear relationship being observed between the two parameters. In contrast, the administration of hydrazine resulted in a large increase in whole brain GABA level, with little change in the synaptosomal GABA content. The key factor in these different responses appeared to be the degree of inhibition of glutamic acid decarboxylase by the drugs. Pretreatment of mice with the GABA-elevating agents resulted in a delay in the onset of seizures, which was related directly to the increase in synaptosomal GABA content. Although the seizures were delayed, they occurred while the GABA content of nerve endings (synaptosomes) was above that in preparations from untreated animals. The decrease in GABA content at the onset of seizures, expressed as a percentage of the level at the time of injection of the convulsant agent, was, however, reasonably constant. A hypothesis to explain these results is proposed.     

Oral intake of γ-aminobutyric acid affects mood and activities of central nervous system during stressed condition induced by mental tasks

γ-Aminobutyric acid (GABA) is a kind of amino acid contained in green tea leaves and other foods. Several reports have shown that GABA might affect brain protein synthesis, improve many brain functions such as memory and study capability, lower the blood pressure of spontaneously hypertensive rats, and may also have a relaxation effect in humans. However, the evidence for its mood-improving function is still not sufficient. In this study, we investigated how the oral intake of GABA influences human adults psychologically and physiologically under a condition of mental stress. Sixty-three adults (28 males, 35 females) participated in a randomized, single blind, placebo-controlled, crossover-designed study over two experiment days. Capsules containing 100?mg of GABA or dextrin as a placebo were used as test samples. The results showed that EEG activities including alpha band and beta band brain waves decreased depending on the mental stress task loads, and the condition of 30?min after GABA intake diminished this decrease compared with the placebo condition. That is to say, GABA might have alleviated the stress induced by the mental tasks. This effect also corresponded with the results of the POMS scores.     

局部高频电刺激海马对海人酸致痫大鼠海马细胞外谷氨酸和γ-氨基丁酸释放的影响

目的：通过高频电刺激海人酸癫痫模型大鼠海马,观察海马细胞外谷氨酸（Glu）和γ-氨基丁酸（GABA）的动态变化。方法：将SD大鼠分成4大组（n=10）：①空白组;②海人酸组;③假刺激组：植入刺激电极未予电刺激;④电刺激组：海人酸注射后予130 Hz电刺激。利用微透析技术收集不同时段海马细胞外液,应用高效液相-荧光检测法测定收集液Glu、GABA的浓度。结果：注射海人酸后Glu明显升高,并持续至第14天,电刺激使Glu明显下降;而注射海人酸后GABA呈短暂性升高,后逐渐下降于第4天后保持稍高于正常水平,电刺激并无明显改变GABA的水平。结论：海马细胞外Glu下降在海马电刺激治疗癫痫中起到重要作用;高频电刺激海马选择性地减少谷氨酸能神经元活动,但不影响GABA的释放。