Search PubMed⌕ Search

Biomedical subjects

A Seregi

Publications and source records attributed to A Seregi.

At least 19 recordsLinked to original sources
PubMed1994

The phorbol ester TPA potentiates cholera toxin- and isoproterenol-stimulated cyclic AMP-synthesis in primary astrocyte cultures.

Cellular responses to changes in the extracellular environment are mediated by intracellular signaling systems. One of the most extensively studied systems is adenylate cyclase which generates the second messenger molecule cAMP. Another one is the phosphatidylinositol (PI) second messenger system giving rise to IP3 and diacylglycerol, the latter stimulating protein kinase C. Recently, a third potential signaling system has attracted increased scientific attention: the phospholipase A2 system which generates arachidonic acid. This substance may be used for eicosanoid synthesis or serve as a second messenger molecule. The present report gives more evidence about mechanisms how these signaling pathways interact in cultured astrocytes. Substances commonly used for stimulation of arachidonic acid release and prostaglandin synthesis in these cultures (A23187, TPA) had no influence on intracellular cAMP levels. Pertussis toxin that had previously been shown to inhibit prostaglandin synthesis, had no influence on cAMP levels either. Cholera toxin, however, raised intracellular cAMP significantly, although much less than the beta-adrenoceptor agonist isoproterenol. Cholera toxin also caused a marked change in astroglial morphology even at reduced concentrations (1-10 ng/ml). A23187 used in combination with Ctx had a moderate stimulatory effect on cAMP synthesis. In contrast, in the presence of Ctx, the PKC-activating phorbol ester TPA synergistically stimulated cAMP production, raising cAMP levels as high as isoproterenol-stimulated levels. The TPA effect was concentration-dependent. It was also dependent on an intact PKC since preincubation of cells with the phorbol ester completely abolished the synergistic effect. The synergistic effect of the phorbol ester was also observed at subthreshold concentrations of isoproterenol. The data reveal that the sole activation of most Gs molecules is a necessary but not sufficient prerequisite to achieve maximal adenylate cyclase activity. The fine-tuning of this activity apparently occurs at the catalytic subunit which is under the (partial) control of phosphorylation by PKC.

Adrenergic beta-Agonists↗
PubMed1993

Meningocortical lesion increases expression of the cholecystokinin gene in rat cerebral cortex: evidence for the involvement of platelet-activating factor (PAF).

In rat neocortex, interneurons express the gene encoding cholecystokinin. After an injury to the meninges and the underlying cortex the levels of cholecystokinin mRNA are transiently enhanced in the ipsilateral hemisphere. In the present study, we have investigated, whether platelet-activating factor plays a role in this phenomenon. Two antagonists of platelet-activating receptors, i.e. WEB 2086 (1.5 mg/kg) and brotizolam (10 mg/kg), were used. When injected 30 min prior to the injury of the parietal cortex, both agents reduced the rise in the concentration of cholecystokinin mRNA in frontal cortex by approximately 60%. They had no significant effect when given 30 min after the injury. Our finding that antagonists of platelet-activating factor receptors diminish the injury-induced change in the activity of cholecystokinin-interneurons opens the possibility that these agents may also affect other pathophysiological aspects of brain trauma.

Animals↗
PubMed1992

Functionally diverse purinergic P2Y-receptors mediate prostanoid synthesis in cultured rat astrocytes: the role of ATP-induced phosphatidyl-inositol breakdown.

Cultured rat astrocytes possess purinergic P2Y-receptors. Stimulation of these receptors with ATP (10(-3) M) results in increased phosphatidylinositol biphosphate (PIP2)-breakdown and prostanoid formation. We have investigated the relevance of the PIP2-pathway in prostanoid synthesis. The intracellular Ca(2+)-mobilizing agent thapsigargin (TG) (10(-6) M) and the diacylglycerol (DAG)-mimetic tetradecaoylphorbol acetate (TPA) (10(-8)-10(-6) M) both stimulate prostaglandin D2 production. ATP-induced prostanoid formation can be mimicked by combined addition of TG and TPA, suggesting the importance of the second messengers IP3 and DAG, generated during P2Y-receptor mediated PIP2-breakdown. Inhibition of ATP-induced PIP2-hydrolysis by TPA (IC50 about 5 x 10(-8) M) or by 10(-4) M neomycine, however, does not affect astroglial prostanoid synthesis, showing that P2Y-receptor mediated prostanoid formation may occur also in the absence of PIP2-hydrolysis. These findings suggest that additional postreceptor mechanisms exist in the signal transduction chain of ATP-induced astroglial prostanoid synthesis. A possible involvement of phospholipase A2 and/or of Ca(2+)-channels, directly coupled to P2Y-receptors is proposed.

Adenosine Triphosphate↗
PubMed1990

Differential prostaglandin formation induced by convulsions in the brain of mice susceptible (DBA/2J) and resistant (CFLP) to acoustic stimulation.

Endogenous cerebral prostanoids possess anticonvulsant properties. This study investigates possible age-dependent anomalies of prostanoid synthesis in the brain of seizure-prone DBA/2J (DBA2) mice as compared to sound stimulus-resistant CFLP mice. Irrespective of the age of the animals, a large increase of prostaglandin (PG) D2 and E2 in the brain of CFLP mice was observed in response to pentylenetetrazol (PTZ)-, or electroshock (ES)-induced seizures. Significantly less PGD2 and PGE2 was formed in the brain of DBA2 mice at day 21 after birth when subjected to PTZ or ES convulsions. At 42 days of age, however, this deficit of cerebral PGD2 synthesis in DBA2 mice disappeared concomitantly with the age-related decrease in audiogenic seizure (AS) susceptibility, whereas the deficit of PGE2 formation persisted. These results suggest that a deficiency of cerebral PGD2 synthesis may be one of the factors responsible for the AS susceptibility of the DBA2 mice. In contrast to PTZ or ES convulsions, acoustically induced seizures of the DBA2 mice were not accompanied by cerebral prostanoid synthesis. This supports the view that the pathways involved in AS are different from those involved in PTZ or ES models of epilepsy.

Acoustic Stimulation↗
PubMed1990

Characterization of cysteinyl-leukotriene formation in primary astroglial cell cultures.

The formation and composition of cysteinyl-leukotrienes (LT) in primary astroglial cell cultures prepared from newborn rat brain has been studied. Small amounts of cysteinyl-LT determined in terms of LTC4-like material in the supernatants of the cultures, became detectable after stimulation of the cells with 10(-5) M ionophore A23187. Cysteinyl-LT formation increased with time, reaching about 600 pg (mg protein)-1 after 60 min incubation. In contrast, considerable thromboxane (TX) B2 synthesis was found at 5 min following A23187-stimulation (about 30 ng TXB2 (mg protein)-1). The synthesis of cysteinyl-LT was abolished by 5 x 10(-5) M nordihydroguaiaretic acid (NDGA). Irrespective of the duration of incubation, blockage of prostanoid synthesis by 10(-6) M indomethacin did not result in increased cysteinyl-LT production. Reversed phase HPLC combined with radioimmunological detection showed that, after 60 min incubation in the presence of A23187, LTC4 and LTD4 accounted for practically all the LTC4-like immunoreactive material in the supernatants of cell cultures. No significant amounts of LTE4 could be detected. The results show that astrocytes may contribute to brain LTC4 and LTD4 synthesis. However, the cellular site of cerebral LTE4 formation seems to be other than the astroglia.

Animals↗
PubMed1989

Formation and function of eicosanoids in the central nervous system.

Neuronal firing during experimental convulsions triggered a large increase in brain eicosanoid synthesis. Mature astrocytes are an important source of cerebral prostanoids. Endogenously formed prostaglandins possess anticonvulsive properties of biological relevance. These conclusions suggest new ideas that might explain the formation and functions of prostanoids in the brain. First, as augmented neuronal discharge is a prerequisite for enhanced prostanoid synthesis during seizures, a functional coupling between firing neurons and prostanoid-forming astrocytes may be expected. Second, the anticonvulsive effects of endogenous prostanoids suggest that astroglia-derived substances might regulate neuronal activity. The phenomenon of convulsion-induced prostanoid synthesis may, therefore, represent a new example of neuron-glia interaction. Neither K+-induced membrane depolarization nor receptor activation by drugs with affinity to alpha or beta adrenoceptors, dopamine, serotonin, muscarine, histamine, GABA, glutamate, aspartate, adenosine, and opioid receptors evoked eicosanoid synthesis in astrocytes. The only physiologically relevant ligand that induced prostanoid synthesis concentration dependently in astrocytes was ATP and related nucleotide triphosphates, as well as nucleotide disphosphates. In peripheral nerves ATP serves as a cotransmitter. The effect of the P2 agonists was reduced by pertussis toxin. The mechanism by which eicosanoids regulate neuronal activity remains to be elucidated.

Animals↗
PubMed1988

Multiple pertussis toxin substrates as candidates for regulatory G proteins of adenylate cyclase coupled to the somatostatin receptor in primary rat astrocytes.

The involvement of G proteins in receptor mediated astroglial cAMP formation was studied. Isoproterenol or prostaglandin E2 stimulated adenylate cyclase of primary astroglial cells was inhibited by somatostatin. Preincubation of cells with increasing concentrations of islet activating protein (IAP) diminished somatostatin inhibition of adenylate cyclase. At an IAP concentration of 50 ng/ml somatostatin inhibition was completely abolished. Studies on IAP catalyzed 32P-ADP-ribosylation of astroglial cell particulate material revealed an incorporation of radiolabel into three polypeptides in the molecular weight range of 41,000-39,000 Dalton. Pretreatment of intact cells with IAP reduced radiolabeling of this molecular species in a concentration dependent manner. No further radiolabeling above background level was detectable after pretreatment of cultures with 10 ng IAP/ml or more. At present, the occurrence of at least three IAP substrates (G proteins) does not permit an identification of the somatostatin receptor coupled G protein. Rather, the finding reveals that astrocytes are endowed with multiple variants of GTP binding proteins likely to be coupled to different receptors.

Adenylate Cyclase Toxin↗
PubMed1988

Effect of adjuvant reserpine treatment on catecholamine metabolism in schizophrenic patients under long-term neuroleptic treatment.

The clinical and biochemical effects of adjuvant reserpine treatment were investigated in 12 chronic schizophrenic patients on long-term neuroleptic medication. The global severity of the symptoms using the Brief Psychiatric Rating Scale did not change significantly in the whole group, however, a moderate decrease in positive symptoms (factors though disturbance, activation and hostile-suspiciousness) was observed for 5 patients. Cerebrospinal fluid (CSF) noradrenaline levels showed a consistent decrease, but other biochemical parameters (CSF dopamine metabolites, platelet MAO and serum dopamine-beta-hydroxylase activities) did not change significantly. The changes of clinical symptoms and biochemical parameters did not show any correlation.

Adjuvants, Pharmaceutic↗
PubMed1988

Characterization of seizure-induced cysteinyl-leukotriene formation in brain tissue of convulsion-prone gerbils.

Tonic-clonic seizures elicited in convulsion-prone gerbils resulted in a large increase in immunoreactive prostaglandin (PG) F2 alpha and in a smaller increase in immunoreactive leukotriene (LT) C4-like material in brain tissue. Brain tissue contents of both eicosanoids were found to reach a maximum at 6 min after the onset of seizures and were still elevated at 54 min after the beginning of convulsions. By reversed phase HPLC the immunoreactive LTC4-like material was identified as LTC4 and LTD4 at 6 min after the onset of convulsions, whereas at 54 min after the onset, transformation of LTD4 to LTE4 could be detected as well. In gerbils showing only weak seizure activity a small increase in PGF2 alpha but no increase in immunoreactive LTC4-like material could be detected at 6 min after the onset of convulsions. Pretreatment with indomethacin abolished the formation of PGF2 alpha but significantly enhanced the biosynthesis of immunoreactive LTC4-like material at 18 min after the beginning of seizures. The results demonstrate formation of cysteinyl-LT following tonic-clonic convulsions in spontaneously convulsing gerbils which could be enhanced by inhibition of the cyclooxygenase pathway of arachidonic acid metabolism. Since cysteinyl-LT have potent biological actions in various organs this finding warrants further investigations on the potential role of cysteinyl-LT in the CNS.

Animals↗
PubMed1988

The stable prostacyclin-analogue, iloprost, unlike prostanoids and leukotrienes, potently stimulates cyclic adenosine monophosphate synthesis of primary astroglial cell cultures.

The effect of different eicosanoids on adenosine-3', 5'-cyclic-monophosphate (cAMP) accumulation in primary astroglial cell cultures prepared from newborn rat brain was studied. The stable prostacyclin-analogue, iloprost, effectively stimulated cAMP synthesis in a concentration-dependent, saturable manner, the EC50 being about 3 x 10(-8) M. Prostaglandin (PG) E2 was less potent, without reaching plateau even at 10(-5) M. Prostaglandins D2 and F2 alpha, and the stable thromboxane A2-analogue, U 46619, as well as leukotrienes (LT) B4, C4, D4 and E4 were not effective and did not attenuate basal or isoprenaline (10(-8) M)-stimulated astroglial cAMP formation. This is the first indication for the existence of a prostacyclin receptor coupled positively to the adenylate cyclase in astrocytes. Other eicosanoids are unlikely to be involved in receptor-mediated regulation of astroglial cAMP levels.

Animals↗
PubMed1987

Are cerebral prostanoids of astroglial origin? Studies on the prostanoid forming system in developing rat brain and primary cultures of rat astrocytes.

Prostanoid forming capacity in vitro and convulsion-induced prostanoid formation in vivo were studied in the developing rat brain. For comparison, prostanoid synthesis in homogenates of primary astrocyte cultures of different ages was also examined. There was no significant prostanoid production in homogenates from primary astrocyte cultures prepared one week after cultivation. Two-week-old astrocyte cultures possessed a prostanoid synthesizing system of high specific activity. The relative proportions of the products were similar to those obtained in brain homogenates of adult rats, prostaglandin D2 (PGD2) being the major product. Prostanoid forming capacity of brain homogenates was low at birth, increased during development and nearly reached adult values by day 21. Generalized convulsions could be evoked by pentylenetetrazol (PTZ) irrespective of age, but convulsion-induced prostanoid formation characteristic of adult rodents did not take place before the third week of postnatal life. The close similarities between the characteristic features of prostanoid synthesis in both brain and astroglial homogenates, together with the coincidence during brain development of the expression of cerebral prostanoid synthesis with the appearance of mature astrocytes suggest that astrocytes are an important source of brain prostanoids.

Animals↗
PubMed1987

Formation of sulphidopeptide-leukotrienes in brain tissue of spontaneously convulsing gerbils.

Five minutes after the onset of seizures high amounts of immunoreactive prostaglandin (PG) F2 alpha and smaller amounts of sulphidopeptide (SP)-leukotriene (LT)-like immunoreactivity could be detected in gerbil brain tissue. Bilateral carotid artery ligation followed by 15 min of reperfusion even more enhanced brain tissue contents of PGF2 alpha and SP-LT-like material. Analysis of the immunoreactive SP-LT-like material by reversed phase high pressure liquid chromatography (h.p.l.c.) revealed immunoreactivity co-eluting with authentic LTC4 and LTD4.

Animals↗
PubMed1986

Synthesis and pharmacological evaluation of some new tetrahydroisoquinoline derivatives inhibiting dopamine uptake and/or possessing a dopaminomimetic property.

As shown by structure-activity relationship studies in 8-(substituted-amino)-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines, the most important structural requirement for a marked antidepressant action is the presence of an ureido, (alkoxycarbonyl)amino, or [(alkylamino)acyl]amino group attached to the isoquinoline skeleton in position 8. In one of the biological tests a significant difference was found between 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydroisoquinoline (nomifensine) and the new compounds synthesized. Nearly all compounds substituted in the amino group either decrease the spontaneous motility in mice or exert no effect on it. Two syntheses have been elaborated for the preparation of the compounds represented by the general formulas II-V where R1 = hydrogen, halogen, or methyl; Y = CONHR, OCOR, or CO(CH2)nNHR, in which R = alkyl or aralkyl or NHR = cyclic amine and n = 1-2. The syntheses start either from the corresponding 8-amino-4-aryl-2-methyl-1,2,3,4-tetrahydroisoquinolines or from the corresponding noncyclized amino alcohols. Of the compounds, 4-(p-chlorophenyl)-8-[(ethoxy-carbonyl)amino]-2-methyl-1,2,3,4- tetrahydroisoquinoline was found to possess the highest activity.

Animals↗
PubMed1985

The formation and regional distribution of prostaglandins D2 and F2 alpha in the brain of spontaneously convulsing gerbils.

The distribution of the two major cyclooxygenase products prostaglandin D2 (PGD2) and prostaglandin F2 alpha (PGF2 alpha) in 7 different regions of the brain (medulla, cerebellum, hypothalamus, striatum, midbrain, hippocampus and cerebral cortex) was studied. Basal levels were highest in hypothalamus and cortex. Following convulsions elicited by environmental stress prostaglandin concentrations increased in all areas, with largest increases (10-20-fold) in hippocampus and cortex, reaching 70 ng/g PGD2 in hippocampus and 115 ng/g PGD2 in cortex. These results demonstrate that, during spontaneous seizures, there is a greater increase in prostanoid production in those areas involved in the convulsive process.

Animals↗
PubMed1985

Formation and functions of prostaglandins in the central nervous system in rodents.

Electrically- and chemically-induced convulsions, as well as spontaneous convulsions, triggered off a large increase in brain PG synthesis occurring mainly in cerebral cortex and hippocampus. Prevention of PG synthesis by cyclooxygenase inhibitors had no influence on the onset of the first clonic seizure, but markedly reduced the latency time of the final tonic seizure. Accordingly, also the acute toxicity of the convulsant PTZ was enhanced after cyclooxygenase inhibition by various NSAIDs (decrease in LD50). On the other hand, if brain concentrations of prostanoids were increased by a preceding ECS treatment, the onset of PTZ-induced clonic seizures was markedly delayed, and the acute toxicity of the convulsant was reduced. Both effects were abolished after inhibition of PG synthesis. The major cerebral PG formed during convulsions (PGD2) proved to have anticonvulsive properties when injected i.c.v. Also, in convulsion-prone gerbils, anticonvulsive effects of cerebral PGs were observed. These results suggest that endogenously formed brain PGs possess anticonvulsive properties of biological relevance.

Animals↗
PubMed1984

Decreased levels of brain cyclo-oxygenase products as a possible cause of increased seizure susceptibility in convulsion-prone gerbils.

Basal levels of 5 cerebral prostanoids (PGD2, PGF2 alpha, PGE2, 6-keto-PGF1 alpha and thromboxane/TX/B2) were measured radioimmunologically in normal and convulsion-prone gerbils. Significantly less PGD2,PGE2 and 6-keto-PGF1 alpha was found in the brain of seizure-sensitive animals. After treatment with indomethacin, which reduced the amount of brain cyclo-oxygenase products, also normal gerbils exhibited convulsions following environmental stress. The results are in accordance with the hypothesis that endogenous prostanoids play a role in the regulation of seizure susceptibility.

Alprostadil↗
PubMed1984

Changes in cyclooxygenase activity and prostaglandin profiles during monoamine metabolism in rat brain homogenates.

The effect of different monoamine oxidase (MAO) substrates on the endogenous prostaglandin(PG) and thromboxane (TX) biosynthesis in rat brain homogenates was studied. In the absence of MAO substrates the following pattern of arachidonic acid metabolites was found: PGD2 greater than PGF2 alpha greater than TXB2 greater than PGE2 greater than or equal to 6ketoPGF1 alpha. Phenylethylamine(PEA) stimulated the cyclooxygenase activity 1.5-fold (expressed as the sum of the products formed), without altering the product profile. Tyrosine(Tyr) caused a twofold increase in cyclooxygenase activity and slightly modified the product composition (PGD2=PGF2 alpha greater than PGE2 greater than TXB2 greater than 6ketoPGF1 alpha). In the presence of noradrenaline(NA) there was a threefold stimulation of cyclooxygenase activity. The increase of PGF2 alpha was more pronounced than that of the other metabolites (PGF2 alpha greater than PGD2 greater than TXB2 greater than PGE2 greater than 6ketoPGF1 alpha). alpha-Methylnoradrenaline(alpha metNA ) (not a substrate for MAO but bearing the catechol group) altered the PG pattern in the same way as NA, but without enhancing the cyclooxygenase activity. PEA or Tyr when administered together with alpha metNA produced a NA-like effect both on the cyclooxygenase activity and on the product profile. The increase in cyclooxygenase activity was abolished by pargyline or by catalase, independently of the activator system used. The results support the hypothesis that NA-stimulation of brain PG (and TX) formation is mediated by H2O2 formed during the degradation of the amine via MAO. The role of the catechol group in protection of the cyclooxygenase against inactivation and in the changes of product composition, as well as the possible significance of the coupling between arachidonate and monoamine metabolism is discussed.

Amines↗