Influence of short-lasting bilateral clamping of carotid arteries (BCCA) on GABA turnover in rat brain structures

We have previously shown that short-lasting reduction of cerebral blood flow by bilateral clamping of carotid arteries (BCCA) results in long-lasting increase in regional GABA concentration and decrease in seizure susceptibility in rats. In the present experiments, the effect of BCCA on GABA turnover and the enzymes involved in GABA synthesis and degradation were studied in rats. Regional GABA turnover was measured by means of GABA accumulation induced by the GABA-transaminase (GABA-T) inhibitor aminooxyacetic acid (AOAA). Fourteen days after BCCA, GABA turnover was significantly increased in hippocampus, substantia nigra and cortex, but not different from sham-operated controls in several other brain regions, including striatum, hypothalamus and cerebellum. The activity of glutamate decarboxylase (GAD) measured ex vivo did not show any changes in investigated structures, while the activity of GABA-T was slightly increased in hippocampus. The increased GABA turnover in some brain regions may explain our previous findings of increased GABA content in these brain regions and decreased sensitivity of BCCA treated animals to the GABA_A-receptor antagonist bicuculline.     

Effect of the nitro analog of tetrapeptidamide and morphine on the cerebral blood supply

A tetrapeptidamide nitroanalog and morphine produced an unmarked and short-lived increase in cerebral circulation, determined by the reduction of the vascular tone in both arterial brain systems. The tetrapeptidamide nitroanalog and morphine exerted a pronounced depressant effect on the nervous regulation of cerebral circulation by inhibiting the reflex constriction of the cerebral vessels. These effects of the drugs also occurred under blockade of GABA receptors. This indicates no relationship between the properties of the tetrapeptidamide nitroanalog and morphine and bicuculline-sensitive GABAergic processes.     

Mechanism of the cerebrovascular effect of piracetam

Piracetam produces a more pronounced effect on cerebral circulation disturbed by hemorrhagic shock as compared with intact animals. Piracetam has a depressant effect on the nervous regulation of cerebral circulation by suppressing the reflex constriction of the vessels in both arterial systems of the brain. The cerebrovascular effects of piracetam are not mediated through the GABAergic bicuculline-sensitive mechanisms, which is supported by experiments where the drug exhibits its effects under the blockade of GABA receptors.     

Effects of GABA and piracetam on the development of experimental cerebral infarction in rats and platelet aggregation in patients with cerebrovascular disorders

GABA and Piracetam caused the improvement of the morphological state of cerebral infarction, due to intracarotid infusion of Arachidonic acid. The effect of GABA was more pronounced. The diminishing of antiaggregatory effect of Piracetam arose in patients with acute cerebrovascular disturbances, compared with the donor group. In contrast, the antiaggregatory activity of GABA increased in the patients group. The improvement of cerebral circulation under influence of GABA can be ascribed to its rheological changes.     

Cerebrovascular effects of met- and leu-enkephalins

Met- and leu-enkephalines have a two-phase influence on the brain blood supply: initial short-term blood flow increase is replaced by the decrease of cerebral blood flow. Enkephalines are established to possess a pronounced depressive influence on neurogenic spasms of cerebral vessels and somatosympathetic and vasomotor reflex both under systemic administration and administration into brain lateral ventricles. Bicucullin has no effect on leuenkephaline action on cerebral circulation and its nervous control, while naloxone either removes or reduces the effects. Hence, opiate receptors take part in the realization of cerebrovascular effects of opioid peptides. The data obtained show the brain opioid system involvement in the regulation of brain circulation.     

Effect of microwave radiation on regional blood flow and tissue oxygenation in the brain

The effect of irradiation of the central nervous system by microwaves (MW) at a frequency of 2450 MHz and power 5-40 W on the regulation of cerebral circulation and oxygen supply to the nervous tissue were studied in rabbits. Local irradiation of the exposed cerebral cortex resulted in hyperemia and hyperoxia in the zone of exposure induced by the hyperthermal effect of MW. When the region of the medulla oblongata was irradiated even with low MW power (not leading to hyperthermia), the local circulation and oxygen tension increased in the whole brain, apparently due to the impairment of the regulation of the cerebral blood flow and oxygen supply to the brain tissue.     

A Computational Model of the Fetal Circulation to Quantify Blood Redistribution in Intrauterine Growth Restriction

Intrauterine growth restriction (IUGR) due to placental insufficiency is associated with blood flow redistribution in order to maintain delivery of oxygenated blood to the brain. Given that, in the fetus the aortic isthmus (AoI) is a key arterial connection between the cerebral and placental circulations, quantifying AoI blood flow has been proposed to assess this brain sparing effect in clinical practice. While numerous clinical studies have studied this parameter, fundamental understanding of its determinant factors and its quantitative relation with other aspects of haemodynamic remodeling has been limited. Computational models of the cardiovascular circulation have been proposed for exactly this purpose since they allow both for studying the contributions from isolated parameters as well as estimating properties that cannot be directly assessed from clinical measurements. Therefore, a computational model of the fetal circulation was developed, including the key elements related to fetal blood redistribution and using measured cardiac outflow profiles to allow personalization. The model was first calibrated using patient-specific Doppler data from a healthy fetus. Next, in order to understand the contributions of the main parameters determining blood redistribution, AoI and middle cerebral artery (MCA) flow changes were studied by variation of cerebral and peripheral-placental resistances. Finally, to study how this affects an individual fetus, the model was fitted to three IUGR cases with different degrees of severity. In conclusion, the proposed computational model provides a good approximation to assess blood flow changes in the fetal circulation. The results support that while MCA flow is mainly determined by a fall in brain resistance, the AoI is influenced by a balance between increased peripheral-placental and decreased cerebral resistances. Personalizing the model allows for quantifying the balance between cerebral and peripheral-placental remodeling, thus providing potentially novel information to aid clinical follow up.     

Changes in regional levels of putative neurotransmitter amino acids in brain under unilateral forebrain ischemia

The levels of the neurotransmitter amino acids glutamate, aspartate, and GABA were determined in different brain regions during ischemia and post-ischemic recirculation periods using the unilateral carotid artery occlusion model of stroke in gerbils. The levels of glutamate, aspartate and GABA in ischemic hemisphere were increased significantly by 10 min of ischemia and later declined with time. Reperfusion for 30 min following 10 min. of ischemia further enhanced the levels of glutamate and aspartate. Increase in GABA levels were found during early periods of reperfusion. Regional variations in the changes of amino acids' levels were noticed following ischemia. Hippocampus showed the highest increase in glutamate levels followed by striatum and cerebral cortex. Aspartate levels in striatum and hippocampus increased during 10 min ischemia (46% and 30%) and recirculation (70% and 79%), whereas in cerebral cortex the levels were doubled only during recirculation. Ischemia induced elevations of GABA levels were observed in cerebral cortex (68%) and in hippocampus (30%), and the levels were normalized during recirculation. No changes in GABA levels were found in striatum. It is suggested that the large increase in the levels of excitatory neurotransmitter amino acids in brain regions specially in hippocampus during ischemia and recirculation may be one of the causal factors for ischemic brain damage.     

THE EFFECT OF AMINO-OXYACETIC ACID ON BRAIN CATECHOLAMINES

Abstract— —Administration of amino-oxyacetic acid (AOAA) to rats induced a pronounced decrease of midbrain norepinephrine (NE) and adrenal epinephrine (E) after 30 min, at which time the GABA level of midbrain had increased to 117 per cent of the initial value. The concentrations of NE in the pons-medulla and of dopamine (DA) in the cerebral hemispheres were not changed.
Further increases in brain GABA were accompanied by a rise of NE in midbrain and pons-medulla beginning 1 hr after AOAA administration. A rise of cerebral DA level was observed only after 4 hr. Six hours after AOAA administration the levels of both NE and DA in brain were reduced.
From the results of these and other studies, where administration of small amounts of GABA were shown to affect brain NE and serotonin levels, it is suggested that monoamines may be involved in the physiological action of GABA in the brain.     

Chronic blockade of N-methyl-D-aspartate receptors alters gamma-aminobutyric acid type A receptor peptide expression and function in the rat

Chronic in vivo or in vitro application of GABA(A) receptor agonists alters GABA(A) receptor peptide expression and function. Furthermore, chronic in vitro application of N-methyl-D-aspartate (NMDA) agonists and antagonists alters GABA(A) receptor function and mRNA expression. However, it is unknown if chronic in vivo blockade of NMDA receptors alters GABA(A) receptor function and peptide expression in brain. Male Sprague-Dawley rats were chronically administered the noncompetitive NMDA receptor antagonist MK-801 (0.40 mg/kg, twice daily) for 14 days. Chronic blockade of NMDA receptors significantly increased hippocampal GABA(A) receptor alpha4 and gamma2 subunit expression while significantly decreasing hippocampal GABA(A) receptor alpha2 and beta2/3 subunit expression. Hippocampal GABA(A) receptor alpha1 subunit peptide expression was not altered. In contrast, no significant alterations in GABA(A) receptor subunit expression were found in cerebral cortex. Chronic MK-801 administration also significantly decreased GABA(A) receptor-mediated hippocampal Cl- uptake, whereas no change was found in GABA(A) receptor-mediated cerebral cortical Cl- uptake. Finally, chronic MK-801 administration did not alter NMDA receptor NR1, NR2A, or NR2B subunit peptide expression in either the cerebral cortex or the hippocampus. These data demonstrate heterogeneous regulation of GABA(A) receptors by glutamatergic activity in rat hippocampus but not cerebral cortex, suggesting a new mechanism of GABA(A) receptor regulation in brain.     

Cerebral infarction--a general-medical problem]

A knowledge of events accompanying the acute coronary failure may help understanding the acute cerebral blood flow insufficiency leading to brain infarction. Cerebral blood flow should be treated as an integral part of the systemic blood circulation. It is of importance when the disease produces lesions to the vascular wall, and the brain looses its autoregulation functions. In such a situation every extracerebral disorders--even slight--may produce extensive lesions to nervous tissue. Therefore, the treatment of the acute cerebral circulation failure requires proper functioning of all factors which may affect hemodynamics and tissue metabolism. Duration of cerebral flow disorders plays an important role in the avoidance of unfavourable complications such as brain infarction. Therefore, every physician is obliged to undertake any possible actions preventing such complications.     

Enhanced GABA release in cerebral cortical slices derived from rats with thioacetamide-induced hepatic encephalopathy

The release of newly loaded [³H]GABA was studied in slices of different brain regions derived from rats in which acute hepatic encephalopathy (HE) was induced with a hepatotoxin thioacetamide. HE increased both spontaneous and high (50 mM) ammonium chloride-evoked GABA release in cerebral cortical slices by 38% and 50%, respectively. No effects of HE were noted in cerebellar or striatal slices. An increased release of GABA in the cerebral cortex may contribute to the endogenous benzodiazepine-mediated enhancement of GABAergic tone, which is thought to be partly responsible for the pathophysiological mechanism of HE.     

Acute and short term effects of ethanol on the metabolism of glutamic acid and GABA in rat brain

Although alcoholic intoxication is attributed to its pharmacological effects on the cell membranes in brain, the rapid metabolic utilisation of the same alters the metabolism of brain affecting the metabolism of glutamate and GABA which have varied metabolic roles besides serving a major proportion of synaptic activity. A study on the effects of ethanol, both acute and short-term, on glutamate (glu) and GABA metabolism in various regions of rat brain was carried out. Increased activities of glutamic acid decarboxylase (GAD) and aspartic acid aminotransferase (AST) in all brain regions, but decreased activity of glutamic acid dehydrogenase (GDH) in cerebral cortex (CC) and cerebellum (CB) following ethanol administration in brain was observed. Differential effects of ethanol were also obtained on the contents of glu and aspartate (asp), which were increased in CC, CB, and brain stem (BS) regions, as opposed to GABA content, which, although found to increase in acute toxicity, showed a decrease in all of the above brain regions in short-term toxicity. It is concluded that the above changes in glu, asp and GABA represent the consequences of metabolic utilization of alcohol in the brain, probably more a state of cerebral excitation than depression, and the changes may be a compensatory phenomenon.     

小鼠惊厥时孕烯醇酮及其硫酸盐对GABAA受体的调制作用

在建立稳定的红藻氨酸(KA)诱发小鼠惊厥模型的基础上,用放射配体受体结合分析法,研究孕烯醇酮(Pe)及其拮抗剂孕烯醇酮硫酸盐(Pes)对小鼠下丘脑、大脑皮层、海马和小脑四个脑区γ-氨基丁酸A(GABAA)受体的调制作用.结果显示,Pe能增加某些脑区3H-GABA与GABAA受体的结合量,下丘脑、海马和小脑差异显著(P＜0.05或P＜0.001),而大脑皮层差异不显著(P＞0.05).Pe对GABAA受体的调制作用能被印防己毒素(Pic)阻断,对KA的致惊效应具有抑制作用.Pes 能显著降低各脑区GABAA受体的结合量(P＜0.01或P＜0.001),对惊厥有促进作用.实验结果提示:孕烯醇酮具有明显的镇静和抗惊厥效应,并且可能是通过GABAA受体介导的.     

U-14C]glucose metabolism of the perfused cat brain with blood flow disturbances

—In order to study changes of the glycolytic-respiratory system and amino acid metabolism associated with blood flow disturbance, the cat brain perfusion was conducted with artificial blood containing [U-¹⁴C]glucose and the results were compared with those of standard perfusion keeping the cerebral blood flow at constant rate. The findings of the present study are briefly summarized: (1) In blood flow disturbance there was observed an accumulation of lactate just as seen in the low functional state observable in the standard perfusion. However the increase in relative specific activity of lactate was not so marked as the rise in cerebral lactate content, and this indicates that there is an increase of lactate production from substrates other than glucose as well as an increase of net flow of glucose carbon to lactate. (2) In blood flow disturbance relative specific activities of glutamate, aspartate, glutamine and respiratory CO₂ were decreased as compared with those in the brain of high functional state. The relative specific activity of GABA in the reduced blood flow brain was at the same level as that of the brain at high functional state and it was higher than the relative specific activity of glutamate. (3) The relative specific activity and content of alanine were increased in the low function brain with standard perfusion.     

Long-term course of the cerebral circulatory function after brain irradiation in rats

Long-term evolution of radioisotope indices, evaluating respectively the cerebral blood flow (CBF), the cerebral blood volume (CBV) and the cephalic specific distribution space of iodoantipyrine (delta IAP) of rat, was studied after brain irradiation at 20 Gy. Radioinduced hemodynamic alterations evidenced by this approach are biphasic and support the prominent role of circulation impairment in the genesis of delayed brain radionecrosis.     

Difference in the cerebrovascular effects of phenoxybenzamine]

The isotope, electromagnetic and resistographic investigation showed phenoxybenzamine to be capable of producing different effects on the blood supply of different regions of the brain. The preparation enhanced the circulation of the vertebro-basilar system and decreased it in the carotic one. Phenoxybenzamine also significantly inhibited the nervous control of the cerebral circulation. It inhibited the reflex reaction of cerebral vessels, changed the cerebral blood flow by stimulation of cervical sympathetic nerves and was capable of protecting against experimental cerebrovascular disorders. These data allow one to recommend phenoxybenzamine in neurological and neurosurgical clinics for the treatment of cerebrovascular disorders in the vertebro-basilar arterial system.     

Regional levels of glucose,amino acids,high energy phosphates,and cyclic nucleotides in the central nervous system during hypoglycemic stupor and behavioral recovery

The effects of insulin-induced hypoglycemic stupor and subsequent treatment with glucose on mouse cerebral cortical, cerebellar and brain stem levels of glucose, glycogen, ATP, phosphocreatine, glutamate, aspartate and GABA and on cerebral cortical and cerebellar levels of cyclic AMP and cyclic GMP have been measured. Hypoglycemia decreased glucose, glycogen and glutamate levels and had no effect on ATP levels in all three regions of brain. GABA levels were decreased only in cerebellum. Aspartate levels rose in cerebral cortex and brain stem, and creatine phosphate increased in cerebral cortex and cerebellum. In the hypoglycemic stuporous animals, cyclic GMP levels were elevated in cerebral cortex and depressed in cerebellum whereas cyclic AMP levels were unchanged from control values. Intravenous administration of 2.5-3.5 mmol/kg of glucose to the hypoglycemic stuporous animals produced recovery of near normal neurological function within 45 s. Only brain glucose and aspartate levels returned to normal prior to behavioral recovery. These results suggest that of the several substances examined in this study, only glucose and perhaps aspartate have important roles in the biochemical mechanisms producing neurological abnormalities in hypoglycemic animals.     

Acute metabolic effects of taurine on the enzymes metabolizing glutamate and gaba

100 mg of taurine per kg body weight had been administered intraperitoneally and 30 min after the administration the animals were sacrificed. Glutamate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, glutaminase, glutamine synthetase, glutamate decarboxylase and GABA aminotransferase along with the content of glutamate and GABA in cerebral cortex, cerebellum and brain stem were studied and compared with the same obtained in the rats treated with normal saline in place of taurine. The results indicated a significant decrease in the activity of glutamate dehydrogenase in cerebral cortex and cerebellum and a significant increase in brain stem. Glutaminase and glutamine synthetase were found to increase significantly both in cerebral cortex and cerebellum. The activities of glutamate decarboxylase was found to increase in all the three regions along with a significant decrease in GABA aminotransferase while the content of glutamate showed a decrease in all the three brain regions, the content of GABA was observed to increase significantly. The above effects of taurine on the metabolism of glutamate and GABA are discussed in relation to the functional role of GABA and glutamate. The results indicate that taurine administration would result in a state of inhibition in brain.