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D M Soderlund

Publications and source records attributed to D M Soderlund.

33 records · Page 2Linked to original sources
PubMed1989

Activation of sodium channels and inhibition of [3H]batrachotoxinin A-20-alpha-benzoate binding by an N-alkylamide neurotoxin.

BTG 502 [(2E,4E)-N-(1,2-dimethyl)-propyl-6-(5-bromonaphth-2-yl)-hexa -2,4- dienamide], a synthetic analog of insecticidal amides isolated from Piper species, stimulated 22Na+ uptake into mouse brain synaptoneurosomes in the presence of saturating concentrations of Leiurus quinquestriatus venom but had no effect on sodium uptake in the absence of venom. In the presence of Leiurus venom, half-maximal stimulation was achieved at a BTG 502 concentration of 1.7 microM, whereas maximal stimulation (2.3-fold greater than nonspecific uptake) was observed at 50 microM. In the absence of other modifiers, BTG 502 inhibited batrachotoxin (BTX)-dependent sodium uptake, producing 50% inhibition at 2 microM. In the presence of Leiurus venom, BTG 502 was a partial inhibitor of BTX-dependent 22Na+ uptake, producing half-maximal inhibition at 1.5 microM. The levels of residual BTX-dependent sodium uptake and maximal BTG 502-dependent sodium uptake measured in the presence of Leiurus venom were identical. BTG 502 inhibited the specific binding of [3H]batrachotoxinin A-20-alpha-benzoate (BTX-B) to the activator recognition site (site 2) of sodium channels in these preparations, producing half-maximal inhibition at 2 microM and maximal inhibition at 30 microM. Equilibrium analysis showed that BTG 502 was an apparent competitive inhibitor of [3H]BTX-B binding, producing a concentration-dependent decrease in the affinity of sodium channels for this ligand without affecting binding capacity. Kinetic analysis demonstrated that BTG 502 slowed the rate of formation of the ligand-receptor complex but did not alter the rate of dissociation of this complex. The effects of BTG 502 on 22Na+ uptake and [3H]BTX-B binding are consistent with the action of this compound as an antagonist at the activator recognition site of the voltage-sensitive sodium channel in the absence of Leiurus venom and as a partial agonist at this site in the presence of Leiurus venom. These results suggest that the N-alkylamides represent a novel chemical class of neurotoxins that act at site 2 of the sodium channel.

Animals↗
PubMed1988

Pyrethroid insecticides and DDT modify alkaloid-dependent sodium channel activation and its enhancement by sea anemone toxin.

The effects of saturating concentrations of DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] and the pyrethroid insecticides cismethrin and deltamethrin on alkaloid-dependent activation of the voltage-sensitive sodium channel were studied using measurements of 22Na+ uptake into mouse brain synaptosomes. In survey experiments, these compounds enhanced sodium uptake stimulated by veratridine and batrachotoxin, but inhibited uptake stimulated by aconitine. Concentration response curves for aconitine run in the absence and presence of 10 microM cismethrin demonstrated that the inhibition was noncompetitive. This unanticipated inhibitory effect of insecticides on aconitine-dependent sodium uptake suggests a possible overlap or negative allosteric coupling between the binding sites for insecticides and aconitine and reveals unique characteristics of the action of aconitine that are not shared by veratridine and batrachotoxin. More detailed studies of the effects of insecticides on veratridine- or batrachotoxin-stimulated uptake found small insecticide-dependent increases in the potency of these activators. In addition to this effect, DDT and deltamethrin also enhanced maximal uptake stimulated by veratridine. Possible mechanisms underlying these effects of insecticides on alkaloid-dependent uptake are discussed in light of a qualitative model formulated from these results and previous biochemical and electrophysiological studies. Additional experiments were designed to assess the interactions of insecticides and toxin II of the sea anemone Anemonia sulcata (ATX II) as modifiers of alkaloid-dependent uptake. DDT and ATX II acted synergistically to increase uptake stimulated by veratridine. Moreover, DDT shifted the potency of ATX II for enhancing veratridine-dependent uptake to 5-fold lower concentrations. In contrast, DDT and subsaturating concentrations of ATX II acted independently in their enhancement of sodium channel activation by batrachotoxin. Mutually exclusive effects on veratridine-dependent uptake were observed when cismethrin was co-applied with ATX II. However, independent effects of cismethrin and ATX II were found with aconitine-modified channels, in that cismethrin was able to inhibit ATX II-enhanced aconitine-dependent sodium flux. Thus, the interactions between insecticides and ATX II as modifiers of alkaloid-dependent uptake are complex and depend on the insecticide-activator combination under study.

Aconitine↗
PubMed1987

Pharmacological characterization of the voltage-dependent sodium channels of rainbow trout brain synaptosomes.

Batrachotoxin, aconitine, and veratridine, alkaloid activators of voltage-dependent sodium channels, stimulated 22Na+ uptake by rainbow trout brain synaptosomes. The potency and efficacy of activation by these compounds decreased in the following order: batrachotoxin greater than aconitine much greater than veratridine. Aconitine-stimulated sodium uptake was completely inhibited by tetrodotoxin, a specific blocker of voltage-dependent sodium channels. Polypeptide toxins in the venom of the scorpion, Leiurus quinquestriatus, and the insecticide DDT enhanced veratridine-dependent sodium uptake but had no effect on non-specific uptake. These studies identify appropriate conditions for measuring sodium channel-dependent 22Na+ uptake in trout brain synaptosomes and characterize some of the pharmacological properties of trout brain sodium channels. Trout sodium channels differed from those in rat and mouse brain in their responses to batrachotoxin, aconitine, veratridine, and DDT but not to tetrodotoxin and Leiurus venom toxins. These results suggest that the specificity of some of the neurotoxin-binding domains of the trout brain sodium channel may differ from those of sodium channels in mammalian brain.

Animals↗
PubMed1987

Differences in the action of avermectin B1a on the GABAA receptor complex of mouse and rat.

The effects of avermectin B1a (AVM) on the gamma-aminobutyric acid (GABA) receptor-chloride ionophore complex of mouse and rat brain were determined using assays of basal and GABA-stimulated 36Cl-uptake by brain vesicles. In the mouse, AVM acted solely as a potent non-competitive inhibitor of GABA-dependent chloride uptake. In the rat, inhibition of GABA-dependent chloride uptake was potent but incomplete, and AVM applied in the chloride uptake medium stimulated chloride uptake in the absence of GABA. The data provide evidence for qualitative differences between the GABA receptor complexes of mouse and rat brain in their responses to AVM.

Animals↗
PubMed1986

Inhibition of gamma-aminobutyric acid-stimulated chloride flux in mouse brain vesicles by polychlorocycloalkane and pyrethroid insecticides.

Selected polychlorocycloalkane and pyrethroid insecticides were evaluated as inhibitors of gamma-aminobutyric acid (GABA)-dependent chloride flux into mouse brain vesicles. The inhibitory potencies of the polychlorocycloalkane insecticides, measured as concentrations producing 50% inhibition, spanned a 1200-fold concentration range in the following order of decreasing potency: 12-ketoendrin; isobenzan; endrin; dieldrin; heptachlor epoxide; aldrin; heptachlor; and lindane. For the cyclodienes, inhibition of chloride uptake was closely correlated with both mammalian toxicity and the ability to displace the binding of [35S]t-butylbicyclophosphorothionate (TBPS). However, lindane was much less potent as an inhibitor of GABA-dependent chloride uptake than would be expected from its acute toxicity or potency as an inhibitor of [35S]TBPS binding. Mirex and chlordecone were poor inhibitors of GABA-dependent chloride uptake, indicating that other sites are likely to be involved in their toxic action. The pyrethroid insecticide deltamethrin gave 50% inhibition of GABA-dependent chloride uptake at 25 microM, but the extent of inhibition was not increased at higher concentrations. In addition, the nontoxic enantiomer of deltamethrin produced dose-dependent inhibition in the chloride flux assay with a potency about 10-fold less than deltamethrin. These results demonstrate the utility of this functional assay to identify compounds that act at the GABAA receptor-ionophore complex and implicate this complex as the principal site of neurotoxic action for cyclodiene insecticides. Although lindane and deltamethrin also altered GABAA receptor-ionophore function, their low potencies and the incomplete stereospecificity of deltamethrin inhibition suggest that this complex is not involved in the neurotoxic action of lindane and alpha-cyano-substituted pyrethroids.

Animals↗
PubMed1985

Neurotoxic insecticides inhibit GABA-dependent chloride uptake by mouse brain vesicles.

The neurotoxic insecticides endrin, dieldrin, aldrin, lindane (gamma-1,2,3,4,5,6-hexachlorocyclohexane) and deltamethrin inhibited gamma-aminobutyric acid-dependent 36Cl- uptake by mouse brain vesicles. Of the insecticides examined, the chlorinated cyclodienes endrin and dieldrin were the most potent, producing 50% inhibition at 2.8 and 13.9 microM, respectively. Lindane and deltamethrin were less effective, and with deltamethrin the effect was incompletely stereospecific. These results demonstrate the disruption of gamma-aminobutyric acid receptor-chloride ionophore function in mammalian brain by neurotoxic insecticides and provide evidence that this complex is the principal site of cyclodiene action.

Animals↗
PubMed1984

Hydrolysis of pyrethroid insecticides by soluble mouse brain esterases.

trans-Permethrin, a pyrethroid insecticide, was hydrolyzed by one or more carboxylesterases located in the soluble fraction of mouse brain homogenates. The apparent affinity of this activity for trans-permethrin was greater than that reported for mouse hepatic carboxylesterase activity, but the apparent maximum velocity was considerably lower than that of the hepatic activity. Soluble brain esterases also hydrolyzed several other pyrethroid esters with a substrate specificity different from that of the hepatic esterases. In particular, alpha-cyano-3-phenoxybenzyl esters of noncyclopropane acids (e.g., fenvalerate and fluvalinate) were hydrolyzed by brain esterases at rates equal to or greater than that measured for trans-permethrin. These results suggest that hydrolysis in the brain may contribute to the detoxication of some pyrethroids in mammals.

Animals↗
PubMed1984

Mouse brain synaptosomal sodium channels: activation by aconitine, batrachotoxin, and veratridine, and inhibition by tetrodotoxin.

Batrachotoxin, veratridine and aconitine, activators of the voltage-dependent sodium channel in excitable cell membranes, increase the rate of 22Na+ uptake by mouse brain synaptosomes. Batrachotoxin was both the most potent (K0.5, 0.49 microM) and most effective activator of specific 22Na+ uptake. Veratridine (K0.5, 34.5 microM) and aconitine (K0.5, 19.6 microM) produced maximal stimulations of 22Na+ uptake that were 73% and 46%, respectively, of that produced by batrachotoxin. Activation of 22Na+ uptake by veratridine was completely inhibited by tetrodotoxin (I50, 6 nM ), a specific blocker of nerve membrane sodium channels. These results identify appropriate conditions for measuring sodium channel-dependent 22Na+ flux in mouse brain synaptosomes. The pharmacological properties of mouse brain synaptosomal sodium channels described here are distinct from those previously described for sodium channels in rat brain synaptosomes and mouse neuroblastoma cells.

Aconitine↗
PubMed1983

Receptor-like stereospecific binding of a pyrethroid insecticide to mouse brain membranes.

A heterogeneous particulate fraction of mouse brain homogenates binds NRDC 157 (3-phenoxybenzyl [1R, cis]-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylate), a potent pyrethroid insecticide, stereospecifically and with high affinity. Stereospecific binding is a minor component of total binding (2.8%); the remainder of observed binding is predominantly nonspecific and unsaturable. Stereospecific binding is half-saturated at 4 X 10(-8)M and fully saturated at concentrations in excess of 1 X 10(-7)M. The stereospecific binding capacity of this preparation was 200-250 pmoles of NRDC 157 per gram equivalent of brain tissue (2.3-2.8 pmol/mg protein). This binding site may represent the neural receptor involved in the stereospecific toxic action of pyrethroids.

Animals↗
PubMed1983

Effects of non-neural mechanisms on pyrethroid structure-activity relationships.

Structural requirements for high insecticidal activity in pyrethroid insecticides are very stringent. Observed structure-activity relationships may arise either from specificity at the site of pyrethroid action in the nervous system, from selectivity in the pharmacokinetic processes governing the appearance and persistence of compounds at that site, or from a combination of these mechanisms. Recent studies of the metabolism of trans and cis isomers of pyrethroids in insect tissue preparations in vitro and of their pharmacokinetic behavior in insects in vivo permit an assessment of the impact of non-neural mechanisms on the toxicity differences observed between these isomers.

Animals↗
PubMed1977

Separation and analysis of the pyrethrins by combined gas-liquid chromatography-chemical ionization mass spectrometry.

Pyrethrins, the 6 naturally occurring insecticidal esters of pyrethrum extract, were analyzed by combined gas-liquid chromatography-chemical ionization mass spectrometry. Separation was best on an OV-25 column with temperature programming; The chemical ionization mass spectra for the 6 esters as well as for the thermally isomerized pyrethrins I and II are reported and discussed. Using selective ion monitoring, a lower limit of detectability of all 6 esters was 114 ng of total extract injected on the column.

Chromatography, Gas↗
PubMedDate not supplied

Structure-biodegradability relationships in pyrethroid insecticides.

The metabolism of 20 pyrethroids has been examined to evaluate the contribution of detoxification in their selective action between insects and mammals. The studies utilized living houseflies, mice, or rats, or esterase and oxidase systems derived from these organisms. Pyrethroid-hydrolyzing esterases cleave the primary alcohol trans-substituted-cyclopropanecarboxylates much faster than the corresponding cis-isomers but are ineffective in hydrolyzing secondary alcohol esters. Microsomal enzymes oxidize the (+)-trans-chrysanthemate moiety at the trans-methyl group of the isobutenyl substituent and at one of the gem-dimethyl groups whereas the (+)-cis-isomer is attacked at either of the isobutenyl methyl groups. Products isomerized at C3 of the cyclopropane are also detected but only after ester cleavage and oxidation of an isobutenyl methyl group. Each alcohol moiety has its own unique sites for oxidation involving pentadienyl, allyl, benzylic methylene, and aromatic substituents. An enhancement of insecticidal activity is expected on replacement of the biodegradable groupings with substituents relatively resistant to metabolism but this may also increase the mammalian toxicity.

Animals↗
PubMedDate not supplied

Metabolic considerations in pyrethroid design.

1. Synthetic pyrethroids, based on the naturally-occurring insecticidal components of pyrethrum extract, emerged in the 1970s as the fourth major chemical class of synthetic insecticides. They are widely used today in the control of agriculture and household pests and disease vectors. 2. Early efforts in the design of synthetic analogues focused on the need to identify novel structural moieties that preserved or enhanced intrinsic insecticidal activity while eliminating known sites of metabolic and photolytic attack in the natural compounds. Subsequent efforts focused on achieving high levels of insecticidal activity while minimizing costs of synthesis and retaining desirable levels of selective toxicity. 3. The synthetic compounds obtained in these efforts constitute a group of insecticides having unprecedented biological activity against target species with low acute toxicity to mammals. 4. The evolutionary development of the pyrethroids illustrates how knowledge of metabolic fate can contribute to the design of novel insecticides with improved insecticidal activity and selective toxicity.

Animals↗
PubMedDate not supplied

Differential sensitivity of sodium channel isoforms and sequence variants to pyrethroid insecticides.

Pyrethroids are commonly regarded as safe insecticides. However, some widely used pyrethroids, particularly single neurotoxic isomers of potent Type II compounds, have acute oral toxicities comparable to many organophosphorus insecticides. The majority of studies of the action of pyrethroids on voltage-sensitive sodium channels, the principal target sites for these compounds, have not considered differences in sodium channel structure as determinants of sensitivity. In mammals, voltage-sensitive sodium channels are encoded by a multi-gene family and exhibit both anatomical and developmental regulation of expression. Studies in this laboratory using cloned rat sodium channel isoforms expressed in Xenopus oocytes have documented profound differences in pyrethroid sensitivity between isoforms. Although the role of sodium channel gene mutations in altering pyethroid sensitivity has not been addressed in the case of the mammalian sodium channel gene family, the potential significance of allelic variation is illustrated in studies of point mutations in a sodium channel gene of the house fly that confer resistance to the lethal actions of pyrethroids and modify the sensitivity of house fly sodium channels expressed in Xenopus oocytes to these compounds. It is of particular interest that some of these resistance-associated mutations in the fly sodium channel occur at amino acid residues that are also the sites of mutations in human skeletal muscle sodium channels that are associated with inherited paralytic disorders. These findings document the pharmacological significance of structural differences between sodium channel isoforms and between genetic variants of an individual isoform as determinants of pyrethroid sensitivity.

Animals↗