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J A Ferrendelli

Publications and source records attributed to J A Ferrendelli.

At least 55 records · Page 3Linked to original sources
PubMed1986

Adenosine-mediated regulation of cyclic AMP levels in isolated incubated retinas.

The effect of adenosine on the modulation of retinal cAMP levels was assessed in several mammalian species including mouse, rat, guinea pig and rabbit. Adenosine had no effect when added to incubated rat, mouse and guinea pig retinas. However, levels of cAMP were elevated in dose-dependent manner by adenosine in both light- and dark-adapted incubated rabbit retinas. Isobutylmethylxanthine (IBMX) blocked the elevation elicited by adenosine. Norepinephrine and dopamine also elevated cAMP in incubated rabbit retinas and these effects were not blocked by IBMX. The elevations of cyclic AMP levels produced by adenosine were additive with the effects of dopamine or norepinephrine. These results indicate that an adenosine-sensitive cAMP system exists in rabbit retina, and it is probably distinct from the dopamine and norepinephrine regulated cyclic AMP systems.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Alkyl-substituted thiolo-, thiono-, and dithio-gamma-butyrolactones: new classes of convulsant and anticonvulsant agents.

A series of sulfur-containing congeners have been prepared from alpha-ethyl-alpha-methyl-gamma-butyrolactone, beta-ethyl-beta-methyl-gamma-butyrolactone, and alpha,alpha,beta,beta-tetramethyl-gamma-butyrolactone as potential neuropharmacologic agents. The lactones were treated with benzyl mercaptide anion to form 4-(benzylthio)butyric acid, which, on treatment with trifluoroacetic acid, cyclized to yield thiololactones. The thiono- and dithiolactones were prepared by treating the corresponding lactones either with Lawesson's reagent or with phosphorus pentasulfide, respectively. As had been observed previously for the lactones, the beta-substituted and alpha,beta-substituted congeners were potent convulsants that caused generalized clonic and tonic seizures in mice. The alpha-substituted congeners were effective in inhibiting pentylenetetrazole-induced seizures in mice. alpha-Ethyl-alpha-methylthiolo-gamma-butyrolactone showed an increase in potency over the congeneric alpha-ethyl-alpha-methyl-gamma-butyrolactone and, additionally, was effective against maximal electroshock seizures. In no cases was a convulsant converted to an anticonvulsant or vice versa by sulfur-for-oxygen substitution.

4-Butyrolactone↗
PubMed1985

Indoleamine-sensitive adenylate cyclase in rabbit retina: characterization and distribution.

Previous histological, electrophysiological, and biochemical reports have addressed the hypothesis that serotonin functions as a neurotransmitter in mammalian retinas. We have tested the effect on the levels of cyclic AMP of the application of exogenous serotonin, 5-methoxytryptamine, melatonin, and 5-methoxydimethyl-tryptamine to isolated, incubated rabbit retinas. All indoleamines tested significantly elevated intracellular levels of cyclic AMP in both light- and dark-adapted, incubated, intact retinas, provided a phosphodiesterase inhibitor was present. In homogenates of rabbit retina, all indoleamines tested also markedly increased adenylate cyclase activity over basal levels. Maximal activity was observed with 50 microM indoleamine; addition of GTP augmented this increase. The increase in enzyme activity persisted in the presence of known antagonists of dopamine and serotonin 5-HT2-receptors, but was blocked by the mixed 5-HT1, 5-HT2-antagonist lysergic acid diethylamide. The retinal locations of this response have also been identified using layer microdissection techniques on freeze-dried samples obtained from rabbit eyecups suprafused with indoleamine plus phosphodiesterase inhibitor. Cyclic AMP levels were measured in discrete retinal layers of both light- and dark-adapted suprafused eyecups, and increased levels were observed primarily in the inner and outer plexiform layers, which contain the synapses of the retinal neurons.

1-Methyl-3-isobutylxanthine↗
PubMed1984

Interruption of the mammillothalamic tract prevents seizures in guinea pigs.

Interruption of the connection between the mammillary bodies and the anterior nucleus of the thalamus in guinea pigs, by discrete bilateral electrolytic lesions of the mammillothalamic tract, resulted in essentially complete protection from the behavioral and electroencephalographic convulsant action and lethal effect of pentylenetetrazol. This result demonstrates that the mammillary bodies and their rostral efferent connections are important for the propagation and perhaps initiation of generalized seizures.

Animals↗
PubMed1984

Regulatory effects of neurotransmitters on electroshock and pentylenetetrazol seizures.

Evidence that biogenic amines and a neuroactive purine are involved in pathophysiological mechanisms of experimental seizures produced by electroshock or pentylenetetrazol is reviewed. Diminishing the influence of norepinephrine (NE) in the brain by depleting its content or by blockade of beta adrenoreceptors enhances seizure activity, and increasing its influence may suppress seizures. Serotonin appears to have action similar to that of NE, but dopamine has little effect in these seizure models. Adenosine also appears to suppress seizure activity. Thus NE, serotonin, and adenosine may be natural, endogenous substances that inhibit or confine seizure activity in the brain.

Adenosine↗
PubMed1983

Measurement of prostaglandin biosynthetic capacity in discrete areas of the rabbit hippocampal formation.

Assay conditions sensitive enough to measure prostaglandin (PG) biosynthetic capacity in discrete brain areas have been developed. Serial sections of the rabbit hippocampal formation were dissected from the brain, frozen, and 16 micron sections were cut and freeze dried. The assay was performed with 40-200 micrograms dry weight of tissue in a 30 microliter incubation volume containing high specific activity arachidonic acid. The whole hippocampal formation slice or its subdivisions (subiculum, dentate gyrus, and hippocampus) when assayed individually demonstrated the ability to produce approximately 30-50 pmol/mg dry weight PGF2 alpha, PGE2, and lesser amounts of PGD2 (in a ratio of 1:0.8:0.3). A modest yet significant increase in PGE2 production was measured in the dentate gyrus when compared to PGE2 formation in the subiculum or hippocampus. An intact PGE2 isomerase was confirmed in the hippocampal formation slice by incubations with PGH2 endoperoxide. These results demonstrate that quantitative histochemical techniques can be used to measure PG metabolism in microscopic regions of brain.

Animals↗
PubMed1983

Localization of an endogenous substrate for cyclic AMP-stimulated protein phosphorylation in retina.

Incubation of mouse or rabbit whole retina homogenates in the presence of [gamma 32P]-ATP and Mg2+ leads to the phosphorylation of various proteins, as demonstrated using SDS-polyacrylamide gel electrophoresis and autoradiography. The phosphorylation of one protein (ca. approximately equal to 31000 mol. wt) was increased by cyclic AMP in both species, with half-maximal stimulation at 5 x 10(-7)M. Cyclic GMP was also active, but much less potent. Protein phosphorylation patterns were compared in retina homogenates from normal mice (C57BL/6J), from adult C57BL/6J mice homozygous for the retinal degeneration gene (rd/rd) in which rod photoreceptor cells are absent, and from 21-day-old 020/Cpb mice homozygous for the retinal degeneration slow gene (rds/rds) in which only the outer segments of the rod photoreceptors are missing. The 31 K protein was only present in normal and in 21-day-old rds/rds mice. When rabbit retina was microdissected into outer segment, inner segment plus outer nuclear, and inner retina layers, cyclic AMP-stimulated phosphorylation of the 31 K protein was evident only in the inner segment plus outer nuclear layer. These data indicated the presence of a specific, endogenous substrate for a cAMP-dependent protein kinase which is found in the inner portions of rod photoreceptor cells.

Animals↗
PubMed1983

Effects of alkyl-substituted gamma-butyrolactones and succinimides on the evoked and spontaneous activity of hippocampal slices in vitro.

Alkyl-substituted and unsubstituted derivatives of gamma-butyrolactone (GBL), gamma-hydroxybutyrate (GHB), and succinimide were tested for their effects on the evoked potential (EP) and spontaneous activity of hippocampal slices incubated in vitro. When tested alone, only beta-ethyl-beta-methyl-GBL (beta-EMGBL) and tetramethylsuccinimide (TMSM) had any effect, producing greatly augmented EPs and spontaneous epileptiform discharges. The nonexcitatory drugs were also tested for the ability to block the excitation produced by beta-EMGBL, TMSM, and penicillin. The unsubstituted compounds had no effect on the augmented EP induced by any of the convulsants. The alpha-ethyl-alpha-methyl-substituted GBL (alpha-EMGBL) and ethosuximide (ESM), blocked the augmented EP induced by beta-EMGBL and TMSM but not that induced by penicillin. The spontaneous activity induced by all three excitatory agents was blocked by GHB. Unsubstituted succinimide had no effect on spontaneous activity. The spontaneous activity produced by beta-EMGBL and TMSM was blocked by alpha-EMGBL, but ESM blocked only that induced by TMSM. Neither alpha-EMGBL nor ESM blocked the spontaneous activity produced by penicillin. We conclude that the ability to block the EP more closely parallels in vivo anticonvulsant activity whereas effects on the spontaneous activity may be more related to neuronal depressant effects. The alkyl-substituted GBLs and succinimides had very similar, albeit not identical, effects on incubated hippocampal slices. That may indicate that they have a similar but not a common mechanism of action.

4-Butyrolactone↗
PubMed1983

Potentiation of the antiepileptic activity of phenobarbital by nicotinamide.

Nicotinamide is a ligand of the benzodiazepine receptor and has been reported to have anticonvulsant activity. In addition, our previous clinical experience has raised the possibility that it may also potentiate the action of barbiturates. Therefore, we have examined the anticonvulsant activity and neurotoxicity of nicotinamide alone and in combination with phenobarbital in mice. Nicotinamide had its maximal anticonvulsant effect 15 min and its maximal sedative effect 45 min after intraperitoneal injection. At 15 min, the median effective dose was 586.5 mg/kg against bicuculline and 2,019 mg/kg against pentylenetetrazol. Nicotinamide was ineffective against maximal electroshock. It had a sedative effect, with a median toxic dose of 874.8 mg/kg by the Rotorod Toxicity Test at 45 min. At doses that were ineffective by themselves (0.01 effective dose) nicotinamide potentiated the anticonvulsant activity of phenobarbital against bicuculline and pentylenetetrazol, but the toxicity was not potentiated and therefore the therapeutic index of phenobarbital was improved by nicotinamide. These results suggest that nicotinamide may be useful as a therapeutic adjunct for the treatment of epilepsy with phenobarbital or primidone.

Animals↗
PubMed1983

Primidone, phenobarbital, and PEMA: I. Seizure protection, neurotoxicity, and therapeutic index of individual compounds in mice.

Neurotoxicity and protection against maximal electroshock and Metrazol seizures from primidone (PRM), phenobarbital (PB), and phenylethylmalonamide (PEMA) were determined in mice for each drug separately and expressed in terms of brain concentrations. Compared with PB, PEMA was 16 times less potent against electroshock and Metrazol seizures but only 8 times less toxic. Primidone was markedly less neurotoxic than PB and equally potent against electroshock, but PRM had no effect against Metrazol or bicuculline. PRM is a relatively nontoxic anticonvulsant with a different action than PB, and PEMA is both a weak and a relatively toxic anticonvulsant.

Animals↗
PubMed1983

Primidone, phenobarbital, and PEMA: II. Seizure protection, neurotoxicity, and therapeutic index of varying combinations in mice.

Neurotoxicity and protection against maximal electroshock (MES) and pentylenetrazol (Metrazol) seizures were determined in mice for various combinations of primidone (PRM), phenobarbital (PB), and phenylethylmalonamide (PEMA). The results suggest that PRM and PB together are superior to either one alone in terms of spectrum of activity and relative toxicity. The protection against Metrazol and the toxicity of PB are both potentiated by PEMA at low concentrations. PEMA also potentiates the toxicity of combined PRM plus PB, without altering their protection against MES, thus lowering their therapeutic index. We conclude that PRM and PB together have an advantage over PB alone, especially when their brain concentration ratio is at or above 1 and PEMA concentrations are low. These conditions are usually not present at steady state in patients treated with PRM.

Animals↗
PubMed1983

Cyclic GMP systems in the retina.

Evidence for the presence of multiple cyclic GMP (cGMP) systems in the vertebrate retina is examined. Levels of this cyclic nucleotide are characteristically high in the photoreceptor cell, whereas in the inner retina they are similar to those found in other areas of the central nervous system. Guanylate cyclase and cGMP phosphodiesterase show a similar uneven distribution, with very high levels of activity in outer segments. At least three forms of guanylate cyclase, one of which may be unique to the photoreceptor cell, have been described. Similarly, differences in the regulation of cGMP phosphodiesterase within localized areas of retina indicate the existence of multiple forms of this enzyme. Factors that influence cGMP levels also have regionally variable effects. Light adaptation leads to reduced cGMP levels in the distal retina, whereas inner retina layers do not show parallel changes. Calcium suppresses the formation of cGMP in photoreceptors, but has no effect or stimulates cGMP formation in the inner retina. Cellular depolarization appears to reduce levels of cGMP in photoreceptors and increases it in the inner retina. Furthermore, endogenous proteins whose phosphorylation is apparently controlled by cGMP seem to be localized to specific retinal cells or subcellular organelles. These data lead to the conclusion that multiple cGMP systems exist in the retina, each with a distinct location and function.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1983

Computer-assisted modeling of the picrotoxinin and gamma-butyrolactone receptor site.

Three-dimensional models of the picrotoxinin and alkyl-substituted gamma-butyrolactone (GBL) receptor sites were constructed with the aid of a molecular graphics computer system (MMS-X). These two independently derived models proved to be very compatible, which suggested that both types of compounds share a common site of action. Since picrotoxinin is known to act at gamma-aminobutyric acid-regulated chloride channels, a hypothesis was made and tested that the convulsant GBL and picrotoxinin analogues physically impede the passage of chloride ions through the channel. It was also shown that it was theoretically possible for the anticonvulsant GBLs to act at this same site without blocking chloride flux. Finally, the model was applied to several convulsant and anticonvulsant compounds of different chemical classes and was found to be of somewhat general applicability.

4-Butyrolactone↗