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Biomedical subjects

D A Fox

Publications and source records attributed to D A Fox.

At least 127 records · Page 7Linked to original sources
PubMed1983

Triethyltin decreases maximal electroshock seizure severity in adult rats.

Acute and subacute treatment of adult rats with triethyltin bromide (TET) caused dose-dependent and time-dependent decreases in maximal electroshock seizure (MES) severity. This decrease in excitability was characterized by both a decrease in the percentage of animals exhibiting a maximal seizure and a corresponding decrease in the extension durations and an increase in the flexion durations. Acutely treated rats received (ip) 0, 1, or 5 mg/kg TET while subacutely exposed (po) received 0, 1, 5, or 10 ppm TET in the drinking water for 10 days. Experiments were designed so that the total consumed dose of TET, on a milligram per kilogram basis, equaled that in the acute experiment. No alterations in body weight were observed in either experiment. Acutely, the onset of action of TET was detectable within 0.5 hr. For the 1 mg/kg group, the effect peaked between 4 and 24 hr and completely recovered by 72 to 96 hr. For the 5 mg/kg group, the marked effect peaked at 4 hr, however, no recovery was observed. Subacute exposure for 1 to 2 days produced marked decreases in MES severity which were still present in the 5- and 10-ppm groups 14 days after cessation of exposure. Comparison of the onset and recovery data in the acute and subacute experiments revealed a close correspondence in similarly dosed rats. Comparison with other MES data from our laboratory revealed that adult rats were more sensitive to TET than adult mice or developing rats. Additionally, the MES test was able to detect subtle functional alterations in the central nervous system at lower doses of TET than previously reported neurobehavioral evaluation procedures.

Animals↗
PubMed1983

Immediate and long-term alterations in maximal electroshock seizure responsiveness in rats neonatally exposed to triethyltin bromide.

Neonatal rats were injected (sc) with 0, 0.25, 0.5, 1.0, 2.5, or 5.0 mg/kg triethyltin bromide (TET) in a 2% ethanol vehicle on Days 0, 5, 10, 15, and 20 postnatally. TET-exposed neonates exhibited a dose-dependent delay in the ontogenetic appearance of both the clonic and tonic maximal electroshock seizure (MES) responses which were apparent up to Day 45, as evaluated by the MES grade distributions and the durations of the individual phases of the MES. In marked contrast, adult rats (exposed to TET only as neonates) exhibited long-term increases in MES severity, as evaluated by the durations of the individual phases of the MES. At 75 days of age, a time when the 1.0 mg/kg developmentally TET-treated group exhibited an increased seizure severity, a single challenge dose of 1.0 mg/kg TET (ip) produced a proportional decrease in MES severity in both developmentally treated and control rats. No changes in preweaning or postweaning body weight were observed in the animals in the 0.25, 0.5, 1.0, or 2.5 mg/kg groups. A 30% decrease in weaning weight and an approximate 15% decrease in postweaning weight were observed in the 5.0 mg/kg group. These seizure results demonstrate that developmental exposure to TET produces immediate and long-term alterations in central nervous system functioning, which are of an opposite character. Interesting, we have previously shown that developmental lead exposure produces a similar developmental/adult dichotomy of effects with regard to the MES severity; however, the two patterns are reversed (D. A. Fox, S. R. Overmann, and D. E. Woolley (1979).

Aging↗
PubMed1983

Surfactants selectively ablate enteric neurons of the rat jejunum.

Surfactants, a group of nonspecific membrane perturbating substances, can cause nerve damage. Various concentrations of the cationic surfactants benzalkonium chloride (BAC) and benzethonium chloride, the anionic surfactants sodium ricinoleate, dioctyl sodium sulfosuccinate and sodium lauryl sulfate and the nonionic surfactant Triton X-100 were applied to the serosal surface of the rat jejunum every 5 min for 0.5 hr and then rinsed off with saline. Thirty days after surfactant application, the treated and an untreated segment of jejunum were removed and examined histologically. All surfactants which were tested significantly reduced the number of ganglion cells in the myenteric plexus. In addition, sodium ricinoleate significantly reduced the number of ganglion cells in the submucosal plexus. Higher concentrations of the cationic agents BAC and benzethonium chloride caused a generalized tissue damage including disruption of the smooth muscle, lymphocytic infiltration, intestinal perforation and death. Using BAC as a prototype surfactant, peptidergic neuron distribution and gut electrical activity were examined. BAC treatment markedly reduced the immunoreactivity of somatostatin, substance P, met-enkephalin and vasoactive intestinal peptide in the myenteric plexus. In addition, the electric properties of the smooth muscle were altered. BAC treatment resulted in an erratic, markedly distorted basic electric rhythm and an alteration in spike potential generation. These studies demonstrate that surfactants in appropriate concentrations selectively ablate the myenteric neurons and alter peptidergic neuron distribution and gut electrical parameters in the rat jejunum.

Animals↗
PubMed1982

Effects of organotin compounds on maximal electroshock seizure (MES) responsiveness in mice. I. TRI(n-alkyl)tin compounds.

Male mice (25-30 g) were injected (ip) with 0, 3.5 X 10(-6), or 17.5 X 10(-6) mol trimethyltin bromide (TMT), triethyltin bromide (TET), tri-n-propyltin chloride (TPT), or tri-n-butyltin bromide (TBT) per kg. Additional groups of mice were also injected (ip) with either 0 or 17.5 X 10(-6) mol sodium bromide (NaBr) or 17.5 X 10(-6) mol stannic bromide (SnBr4) per kg. The mice were tested with maximal electroshock seizure (MES) at 0.5, 4, 21-24, and 96 h following exposure to the organotin compounds. Mice exposed to TMT, TET, TPT, or TBT exhibited dose-dependent decreases in MES severity as evaluated by seizure-grade distributions and duration of tonic seizure phases. The tri-n-alkyltin compounds exhibited a structure-activity relationship in their ability to decreased maximal responsiveness to the MES test. In order of decreasing ability they were: TMT greater than TET greater than TPT greater than TBT. Administration of NaBr and SnBr4 did not alter MES responsiveness, indicating the essential role of the alkyl moieties of the tri-n-alkyltin compounds in producing alterations in central nervous system function.

Animals↗
PubMed1982

Effects of organotin compounds on maximal electroshock seizure (MES) responsiveness in mice. II. Tricyclohexyltin and triphenyltin.

Male mice (25-30 g) were injected (ip) with either 0, 3.5 X 10(-6), 17.5 X 10(-6), or 26.25 X 10(-6) mol/kg of either tricyclohexyltin bromide (TCT) or triphenyltin acetate (TPhT) in a corn-oil vehicle. The mice were tested for maximal electroshock seizure (MES) at 0.5, 4, 24, and 96 h following exposure to the organotin compounds, and the durations of seizure phases were measured and used to assess seizure severity. No significant changes in seizure-grade distribution, as compared to controls, were observed in any of the TCT- or TPhT-treated groups at any of the time points examined. No significant changes in the duration of seizure phases, as compared to controls, were observed in animals dose with 3.5 X 10(-6) mol/kg of TCT or TPhT at any of the time points evaluated. At 0.5 h following exposure, the mice dosed with the two higher levels of TCT or TPhT exhibited increases in MES severity. At 4 and 24 h following exposures, the mice exposed to the two higher dose levels of TPhT exhibited decreases in MES severity, followed by a recovery of normal seizure severity at 96 h. Conversely, the animals dosed with the higher dose levels of TCT exhibited at increased MES severity at 4, 24, and 96 h following exposure. These results, in combination with those in the preceeding paper (Doctor and Fox, 1982), reveal that at equimolar doses TCT And TPhT possess a different spectrum of action than the tri-n-alkyltins.

Animals↗
PubMed1979

Heavy metals affect rod, but not cone, photoreceptors.

Low concentrations of lead, mercury, or cadmium depress the amplitude of the rod receptor potential in the perfused bullfrog retina. Responses from the cones were not affected. The data implicate the rods as a lesion site in animals exhibiting scotopic vision deficits as a result of heavy metal poisoning.

Animals↗
PubMed1979

Physiological and neurobehavioral alterations during development in lead exposed rats.

Neonatal rats were exposed to lead (Pb) from parturition to weaning via the milk of dams which consumed 0 (tap water), 0.02% or 0.2% PbAc2 solutions. To determine if this regimen altered physiological and neurobehavioral development, responses to a battery of sensory-motor tests were evaluated during maturation and as adults. The tests were: visual evoked responses (VER), temperature regulation, maximal electroshock seizure patterns, reflex patterns, and neuromuscular performance. Overall results revealed that the Pb-exposed group compared to controls exhibited delayed maturation, altered developmental patterns and long-term CNS disturbances. Additionally, low-level strychnine administration during development caused additive interactions with both Pb groups, uncovering subtle effects of toxicant exposure. These sensitive and quantifiable techniques proved useful for assessing CNS functioning following perinatal insult, and except for the VER, are simple to conduct and cost efficient because they require a minimal amount of personnel training, equipment cost and time invested per animal. These screening tests also suggest further areas of study and may indicate the mechanism(s) responsible for the deficit.

Animals↗
PubMed1977

Hapten-specific IgE antibody responses in mice. VII. Conversion of IgE "non-responder" strains to IgE "responders" by elimination of suppressor T cell activity.

Mice of the inbred strains SJL (H-2s) and AKR (H-2k) are "non-responders" and "low-responders," respectively, in terms of their capacity to develop antibody responses of the IgE class when immunized with conventional proteins and hapten-protein conjugates under conditions optimal for eliciting IgE responses in "high-responder" mice, such as BALB/c (H-2d), to these same antigens. For example, BALB/c mice preimmunized with ASC and then challenged 7 days later with DNP-ASC develop peak augmented primary IgE anti-DNP antibody responses of 320 PCA units, whereas SJL and AKR mice develop responses which are 16-fold and 4-fold lower, respectively. However, pretreatment of the latter two strains with appropriate doses of either x-irradiation (150 R), cyclophosphamide (100 mg/kg) or ALS (150 mul) before carrier-preimmunization strikingly enhances the magnitude of IgE antibody responses in such mice to levels as high as 64-fold above those of untreated control mice of the same strains. Evidence obtained in these experiments indicates that the capacity of such maneuvers to to convert poor IgE responders to high responder status reflects elimination of nonantigen-specific suppressor T lymphocytes which are naturally present and normally function to suppress or "dampen" the IgE antibody response in a relatively selective manner. It appears that these cells modulate IgE responses by acting at least at two distinct points: 1) The most effective activity seems to be at the level of induction of carrier-specific helper T cells; 2) A second locus of inhibitory activity is more distal in the response, either impeding helper T cell-B cell cooperative interactions or suppressing B cell differentiation and/or function directly. Taken collectively, these observations demonstrate that the state of poor responsiveness of the SJL and AKR strains for the IgE antibody class is not a reflection of a genetic inability to develop IgE responses but rather a manifestation of a genetic capability to actively inhibit IgE antibody synthesis.

Animals↗
PubMed1977

Cell density dependence of focus formation in the C3H/10T1/2 transformation assay.

Some of the dynamics of neoplastic transformation in vitro have been studied with the use of benzo(a)pyrene as the carcinogen in the C3H/10T1/2 morphological transformation assay. Experiments that involved the dsipersion of cells into new culture dishes at various times after carcinogen treatment have shown that no change in the fraction of potentially transformed cells occurs while cultures grow to form a confluent monolayer, that little or no change in the fraction of potentially transformed cells occurs for approximately 3 weeks after confluence is attained, and that this fraction increases rapidly some 7 weeks after BP treatment. When confluent benzo(a)pyrene-treated cultures are dispersed in new culture dishes prior to the onset of growth toward focus formation, the formation of transformed foci is suppresssed at high cell densities of seeding. This phenomenon is independent of the total number of divisions undergone by cells after treatment. We suggest that phenotypic expression of morphological transformation is dependent on colony interactions in the C3H/10T1/2 system, which we do not yet understand, but which are independent of time posttreatment either in cell generations or absolute time.

Animals↗
PubMed1976

Hapten specific IgE antibody responses in mice. V. Differential resistance of IgE and IgG B lymphocytes to X-irradiation.

The studies presented in this paper were undertaken to determine whether IgE- and IgG-producing murine B lymphocytes could be distinguished by differential resistance to x-irradiation in vivo. Sensitivity or resistance of B lymphocytes to various doses of x-irradiation was monitored by measuring the production by irradiated cells of hapten-specific IgG and IgE antibody. The results indicate that both primed and unprimed IgG B lymphocytes are less radioresistant than corresponding IgE B lymphocytes. Primed IgG B lymphocytes are more radioresistant than unprimed IgG B cells whereas unprimed IgE B lymphocytes are at least as radioresistant as primed IgE B lymphocytes. The relative radioresistance of primed IgE vs IgG B cells was best demonstrated in an adoptive transfer system. Thus, exposure of ASC-primed mice to 300 R 24 hr after transfer into these mice of syngeneic, DNP-KLH-primed spleen cells led to a sustained failure to produce IgG anti-DNP antibody after challenge with DNP-ASC; under these conditions IgE anti-DNP production was not impaired. This was shown to reflect differential radioresistance of the corresponding B cell populations. In addition, exposure to x-irradiation tended to augment IgE anti-DNP antibody responses when compared to unirradiated controls. This phenomenon is thought to reflect the effects of x-irradiation on regulatory mechanisms controlling the mouse IgE response and is explored in detail in an accompanying manuscript. The results described in this paper are discussed in the light of our evidence suggesting that, in both mouse and man, IgE B lymphocytes have certain unique characteristics by which they may be distinguished from other classes of B lymphocytes.

Animals↗
PubMed1976

Hapten-specific IgE antibody responses in mice. VI. Selective enhancement of IgE antibody production by low doses of X-irradiation and by cyclophosphamide.

Exposure of BALB/c, A/J, and (BALB/c X A/J)F1 mice, which are IgE high responder animals, to total body x-irradiation ranging from 50 to 200 R resulted in a dose-dependent enhancement of the hapten-specific IgE antibody level as compared to unirradiated control mice. In contrast, anti-hapten antibody responses of the IgG class in these same animals were rarely enhanced, and when so, were of a lesser degree. This relatively selective augmentation of the IgE vs IgG antibody responses was observed in both unprimed and primed mice. By utilizing adoptive transfer systems, it was demonstrated that the enhancing effects of x-irradiation resulted from its action on the carrier-primed cell population and not upon the responding B cells or upon macrophages. The data presented herein suggest that this enhancement phenomenon is the result of the elimination of T cells (or their products) with suppressive functions and that these cells are neither dependent upon nor specific for the carrier antigen employed in the immunization. This hypothesis is given indirect support by the observations that treatment of the same strains of mice with cyclophosphamide, in doses known to abrogate suppressive T cell functions, resulted in a similar enhancing effect to that observed after low doses of x-irradiation. In addition an interesting difference between IgE and IgG precursor B lymphocytes was observed by the ability of IgE B cells to differentiate to the secretory state at a strikingly more rapid rate than IgG B lymphocytes when exposed to comparable T cell helper influences. These observations may provide important clues to the cellular mechanisms of the immune regulation of the IgE response and its relationship to allergic diseases.

Animals↗
PubMedDate not supplied

Kentsin: tetrapeptide from hamster embryos produces naloxone-sensitive effects without binding to opioid receptors.

The opioid nature of kentsin (Thr-Pro-Arg-Lys) and its ability to alter pain perception and intestinal transit were examined. Kentsin (30,000 nM) did not inhibit electrically stimulated contractions of the guinea pig ileum (GPI) or mouse vas deferens (MVD), nor did it cause a rightward displacement of the inhibitory concentration-response curves of the mu-selective opioid agonist PL017 in the GPI or the delta-selective agonist DPDPE in the MVD. Kentsin (10,000 nM) did not displace [3H] naloxone from rat brain homogenates. These results indicate that kentsin lacks opioid agonist and mu and delta opioid antagonist properties and does not bind to opioid receptors. In vivo, kentsin produced dose-dependent analgesia in both the hotplate and abdominal stretch tests when administered intracerebroventricularly (ICV) and intrathecally but not intravenously. The central analgesic effect of kentsin was partially antagonized by the opioid antagonist naloxone. Kentsin inhibited intestinal transit in a dose-dependent manner after ICV administration only. The intestinal antitransit effect of kentsin was not blocked by pretreatment with naloxone. These results suggest that kentsin acts centrally to produce both opioid and non-opioid effects. Further, the opioid-mediated analgesic effects of kentsin involve mechanisms other than direct interaction with opioid receptors.

Animals↗