Biomedical subjects

D B Miller

Publications and source records attributed to D B Miller.

At least 73 records · Page 4Linked to original sources

PubMed1991

Diethyldithiocarbamate potentiates the neurotoxicity of in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and of in vitro 1-methyl-4-phenylpyridinium.

Diethyldithiocarbamic acid (DDC) potentiates in vivo neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and in vitro neurotoxicity of 1-methyl-4-phenylpyridinium (MPP+). Male C57B1/6 mice were given two or five injections of MPTP (30 mg/kg i.p.) preceded 0.5 h by DDC (400 mg/kg i.p.). The mice were tested for catalepsy, akinesia, or motor activity during and after the period of dosing. Striatal and hippocampal tissues were obtained at 2 and 7 days following the last injection and evaluated for dopamine and norepinephrine levels, respectively. These same tissues were also analyzed for the levels of glial fibrillary acidic protein (GFAP), an astrocyte-localized protein known to increase in response to neural injury. Pretreatment with DDC potentiated the effect of MPTP in striatum and resulted in substantially greater dopamine depletion, as well as a more pronounced elevation in GFAP. In hippocampus, the levels of norepinephrine and GFAP were not different from controls in mice receiving only MPTP, but pretreatment with DDC resulted in a sustained depletion of norepinephrine and an elevation of GFAP, suggesting that damage was extended to this brain area by the combined treatment. Mice receiving MPTP preceded by DDC also demonstrated a more profound, but reversible, catalepsy and akinesia compared to those receiving MPTP alone. Systemically administered MPP+ decreased heart norepinephrine, but did not alter the striatal levels of dopamine or GFAP, and pretreatment with DDC did not alter these effects, but did increase lethality. DDC is known to increase brain levels of MPP+ after MPTP, but our data indicate that this is not due to a movement of peripherally generated MPP+ into CNS.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenylpyridinium↗

PubMed1990

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage of striatal dopaminergic fibers attenuates subsequent astrocyte response to MPTP.

Acute administration of the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the C57BL/6 mouse caused a rapid decrease in the amount of striatal tyrosine hydroxylase (TH), a marker of the nigrostriatal dopaminergic pathway, followed by a large increase in the astrocyte protein, glial fibrillary acidic protein (GFAP). The astrocyte (GFAP) response declined to baseline three weeks after administration of MPTP. Administration of a second dosage of MPTP at this time evoked a second GFAP response. The magnitude of the second response, however, was decreased in comparison to the response seen after only a single exposure to MPTP. Increasing the initial dosage of MPTP resulted in greater reductions of the second GFAP response. These data indicate that MPTP-induced damage or loss of striatal dopaminergic neurons reduces the signal available for initiating astrogliosis and thereby reduces the astrocyte response to a second exposure to MPTP.

Animals↗

PubMed1990

Characterization of the origins of astrocyte response to injury using the dopaminergic neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

We used the dopaminergic neurotoxicant, 1-methyl-1,2,3,6-tetrahydropyridine (MPTP), as a tool to characterize the origins of astroglial response to injury. Radioimmunoassay of the astrocyte protein, glial fibrillary acidic protein (GFAP), was used to quantify the astrocyte reaction to MPTP. Assays of neuron-localized proteins and of dopamine were used to assess neuronal damage caused by MPTP. A single administration of MPTP (12.5 mg/kg, s.c.) to the C57BL/6J mouse resulted in more than a 3-fold increase in striatal GFAP within 48 h, followed by a decline to baseline at 3 weeks. A decrease in the amount of striatal tyrosine hydroxylase (TH), a marker of dopaminergic neurons, preceded the rise in GFAP. The concentration of striatal DARPP-32, a phosphoprotein enriched in neurons receiving dopaminergic input, was not affected by MPTP. Protecting the dopaminergic neurons from the neurotoxic metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP+), either by blocking its formation or by preventing its uptake into dopaminergic neurons, completely blocked the increase in GFAP. MPTP did not appear to disrupt the blood-brain barrier, therefore, blood-borne elements probably did not mediate the increase in GFAP. In addition, immunoblot data indicated that brain-derived interleukin 1, an astrocyte growth factor, also did not play a role in MPTP-induced gliosis. Together, these findings suggest that diffusible factors derived from damaged dopaminergic neurons initiate the astrocyte response to MPTP and that large increases in GFAP can be induced without the participation of serum-derived growth factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

TGF-beta 1 inhibition of transin/stromelysin gene expression is mediated through a Fos binding sequence.

Transforming growth factor beta 1 (TGF-beta 1) inhibits the growth factor and oncogene induction of transin/stromelysin, a secreted matrix-degrading metalloprotease. We demonstrate that a 10 bp element in the transin promoter is required for the TGF-beta 1 inhibitory effects and that this sequence is conserved in the promoter regions of several other TGF-beta 1-inhibited genes. The TGF-beta 1 inhibitory element (TIE) specifically binds a nuclear protein complex from TGF-beta 1-stimulated rat fibroblasts. Interestingly, this complex contained the c-fos proto-oncogene product, Fos, and induction of Fos expression was required for the inhibitory effect of TGF-beta 1 on transin gene expression. These results suggest that TGF-beta 1 inhibition of gene expression is mediated by the binding of a Fos-containing protein complex to the TIE promoter sequences.

Animals↗

PubMed1990

Effects of chemically induced maternal toxicity on prenatal development in the rat.

The hypothesis that chemically induced overt maternal toxicity induces a characteristic syndrome of adverse developmental effects in the rat was investigated. Pregnant animals (Sprague-Dawley strain) were dosed by oral gavage with one of a series of compounds on days 6-15 of gestation. These chemicals were diquat (DIQ), ethylene-bis-isothiocyanate (EBIS), toxaphene (TOX), styrene (STY), 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenol (2,4,5-Tr), triphenyl tin hydroxide (TPTH), and cacodylic acid (CAC). The compounds were chosen because they exhibited little or no developmental toxicity in previous studies. Dosage levels producing maternal weight loss and/or lethality were determined from preliminary toxicity studies. Significant maternal weight reductions were noted during the course of treatment with all compounds except CAC and 2,4,5-Tr. Maternal lethality was produced by EBIS, TOX, 2,4,-D, and 2,4,5-Tr. The main treatment-related developmental toxicity noted in litters at term consisted of increased lethality (EBIS, TPTH) and decreased fetal weight (EBIS and CAC). Treatment-related anomalies were seen in litters treated with 2,4-D and TOX (supernumerary ribs) and with EBIS and STY (enlarged renal pelvis). No significant developmental effects were produced with DIQ, or 2,4,5-Tr. This study indicates that overt maternal toxicity as defined by weight loss or mortality is not always associated with the same defined syndrome of adverse developmental effects in the rat.

2,4,5-Trichlorophenoxyacetic Acid↗

PubMed1989

Alarm call responsivity of mallard ducklings: VIII. Interaction between developmental history and behavioral context.

Mallard ducklings (Anas platyrhynchos) inhibit their vocal behavior upon hearing the maternal alarm call of their species. The present study assesses the interaction of the ducklings' experiential history with the environment in which they are tested. If ducklings are reared and tested to the alarm call in small social groups, they respond by dramatically inhibiting their vocalizations. If, however, socially reared ducklings are tested to the alarm call individually in an open field, responsiveness drops precipitously. In addition, individually reared ducklings respond at a far greater level to the alarm call when tested individually, not in groups. Thus, there is an interaction between the rearing history and the testing environment such that the same rearing history leads to different behavioral outcomes depending on the context in which the ducklings are observed. This demonstrates the importance of behavioral context, in addition to developmental history, as one of the determinants of behavior.

Animals↗

PubMed1989

Perceptions of caregivers about special respite services for the elderly.

Questionnaires were circulated to 48 family members who had arranged for respite care for ill elderly relatives. Caregiver families used their respite for vacations, personal business, freedom from caregiving, and surgery. Eighteen (78%) wished to participate in respite again because they thought it the best available arrangement to maintain their mental health during caregiving.

Aged↗

PubMed1989

Assessment of chemically-induced alterations in brain development using assays of neuron- and glia-localized proteins.

Chemical-induced injury of the developing central nervous system (CNS) is often manifested by alterations in the cellular ontogeny of specific neuroanatomical regions. Within the affected area, critical developmental processes encompassing a variety of neuronal and glial cell types may be transiently or permanently altered. Because the cellular heterogeneity of the developing CNS is expressed by unique neuronal and glial proteins, we proposed that radioimmunoassays of these proteins can be used to define normal and chemically- altered patterns of CNS development. We are testing this hypothesis by administering prototype neurotoxicants to the developing rat and then assessing the effects of these agents on previously characterized neuronal and glial proteins. Using this approach, we have characterized several features associated with perinatal chemical exposure: (1) region-dependent patterns of altered brain development are revealed by changes in the amounts of specific neuronal and glial proteins; (2) chemical-induced changes in neuronal and glial proteins depend on the time of exposure and nature of the insult; and (3) significant changes in neuron- and glial-localized proteins can be observed in the absence of cytopathology or decreases in brain weight. Data obtained from studies of toxicant-induced injury of the CNS will be presented as models for the use of neuron- and glial-localized proteins as biochemical indicators of altered brain development.

Animals↗

PubMed1988

The neurotoxicant MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) increases glial fibrillary acidic protein and decreases dopamine levels of the mouse striatum: evidence for glial response to injury.

The neurotoxicant MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), administered to male or female mice, decreased striatal dopamine content and increased the levels of the astrocyte intermediate filament protein, glial fibrillary acidic protein (GFAP). The rise in GFAP was evident as early as two days following the last dose of MPTP, was maximal 7 days after the toxicant and returned to control levels by two months, post MPTP. Striatal dopamine content was decreased post-MPTP administration, showing a slight recovery between one and two months after the toxicant. No differences were observed among male and female mice in their responses to the toxicant. Hippocampal noradrenaline content was not affected by the toxicant, neither was the GFAP content altered by MPTP in this structure. Additionally, pargyline pretreatment prevented both the rise in GFAP and the decrease in dopamine in striatum. MPTP produced a smaller elevation in GFAP levels within a midbrain section of tissue containing the substantia nigra, without significantly decreasing the dopamine content of this structure, suggesting neurotoxic involvement at the level of dopamine perikarya. The toxicant did not affect the molecular radius of the protein detected by the antibody to GFAP, as determined by immunoblot analysis.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1988

Restraint-induced analgesia in the CD-1 mouse: interactions with morphine and time of day.

The tail-flick response of adult male CD-1 mice was used to assess the analgesic properties of restraint alone and in combination with morphine during the diurnal and nocturnal periods. Mice were restrained in conical metal devices that allowed a change in position from supine to prone but not from front to back. Restraint induced an analgesia equipotent to a 2.5 mg/kg dose of morphine within 0.5 h of its initiation. Although habituation occurred over the restraint period a pronounced analgesia was still evident at the end of the 3 h test period. The habituation to restraint-induced analgesia was more rapid at night. Although the basal tail-flick latency to thermal stimulation was decreased during the nocturnal period the time of day did not alter the degree of analgesia induced by either restraint or morphine. Morphine induced a dose- and time-dependent analgesia during both the diurnal and nocturnal periods and this analgesia was potentiated by restraint stress only during the nocturnal period. Naloxone at high doses (10.0 or 20.0 mg/kg) blocked the analgesia induced by morphine but did not totally block the analgesia induced either by restraint or morphine plus restraint. These data suggest the potentiation of an opiate effect by stress may depend on habituation or tolerance to the stressor.

Analgesia↗

PubMed1988

Alarm call responsivity of mallard ducklings: VII. Auditory experience maintains freezing.

Mallard ducklings (Anas platyrhynchos) freeze upon hearing the maternal alarm call, which the hen issues when there are disturbances (e.g., potential predators) near the nest. Our previous work indicates that ducklings that have been devocalized embryonically and reared in auditory isolation exhibit a significant reduction in the incidence of freezing, as compared to vocal ducklings or to devocal ducklings that have been exposed to duckling sounds throughout the perinatal period up to the time of testing at 12 hr posthatch. The main purpose of this paper is to assess whether there is a prenatal or postnatal sensitive period for such auditory experience. Two groups of 30 devocalized ducklings were either (a) stimulated with duckling sounds prenatally and tested to the alarm call at 12 hr posthatch (Expt. 1), or (b) stimulated from the time of hatching to the time of testing at 12 hr (Expt. 2). These experiments rendered no conclusive evidence of either a prenatal or postnatal sensitive period, but they suggested that auditory experience might be important in maintaining freezing. To test this hypothesis, a third group of 30 ducklings was stimulated from hatching to 12 hr and tested at 24 hr (Expt. 3). Only those ducklings receiving auditory experience contiguous with the time of testing (Expt. 2) showed high levels of freezing. Whenever a gap occurred between the offset of stimulation and the onset of testing (Expts. 1 and 3), the incidence of freezing dropped. Thus, auditory experience is important in maintaining the freezing response. This effect contrasts markedly with traditional conceptions of sensitive periods.

Acoustic Stimulation↗

PubMed1988

Anhydrolevuglandin D2 inhibits the uterotonic activity of prostaglandins F2 alpha and D2.

Anhydrolevuglandin D2 (AnLGD2), which is produced from PGH2 by a water-induced rearrangement and subsequent dehydration, is uterotonic. However, increasing concentrations caused decreased responses of the uterine horns. AnLGD2 inhibited responses of uteri to stimulation by specific prostaglandins. PGF2 alpha was inhibited at an AnLGD2:PGF2 alpha ratio of 0.05:1 with 5 to 25 pg/ml concentrations of PGF2 alpha. The response to PGD2 was inhibited at an AnLGD2:PGD2 ratio of 0.05:1 with PGD2 concentrations of 5 to 75 pg/ml. In contrast, the uterotonic effects of PGE2 were not inhibited by AnLGD2. When AnLGD2 was added to baths with contracting uteri it inhibited contractions less if the exposure period was 5 min than if it was 10 min. The longer exposure times produced prolonged inhibition of contractile activity with bath concentrations of AnLGD2 as little as 2.5 pg/ml.

Animals↗

PubMed1988

Developmental effects of maternal stress in the CD-1 mouse induced by restraint on single days during the period of major organogenesis.

Maternal stress during gestation can produce significant fetal and/or postnatal effects, and can enhance the teratogenicity of other agents. We have previously shown that restraint stress on gestational day 8 in CD-1 mice produces significant increases in encephaloceles and supernumerary and fused ribs. In the present study we have examined the effects of stress induced by restraint on individual days during the period of major organogenesis (days 6-14). Weight loss and stress-induced analgesia as assessed by the tail-flick method were used to determine the degree of stress induced by a 12-h restraint period. Restrained animals lost significantly more weight and had longer tail-flick latencies than the concurrent food and water deprived controls on all gestational days. Significant increases in embryo/fetal mortality were also observed in the offspring of restrained animals. An increased incidence of supernumerary ribs was found in mice restrained on days 7 and 8. Since maternal toxicity induced by chemical teratogens may be accompanied by a general increase in maternal stress, our data suggest that such stress may be an etiological factor in teratology bioassays in which dose levels are sufficiently high to induce overt maternal toxicity.

Analgesia↗

PubMed1988

Acute exposure of the neonatal rat to triethyltin results in persistent changes in neurotypic and gliotypic proteins.

Measurements of neuron-specific (neurotypic) and glia-specific (gliotypic) proteins were used to characterize the toxic effects of triethyltin (TET) on the developing central nervous system. Six proteins, each of which is associated with specific aspects of neuronal and glial development, were evaluated as follows: 1) neurofilament-200, an intermediate filament protein of the neuronal cytoskeleton; 2) synapsin I, a synapse specific, synaptic vesicle localized protein; 3) p38, another synaptic-vesicle localized protein; 4) myelin basic protein, a protein unique to myelin-forming oligodendroglia; 5) glial fibrillary acidic protein, the intermediate filament protein of astrocytes; and 6) beta-tubulin, a constituent primarily of neuronal microtubules. The amount of each protein in homogenates of hippocampus, forebrain and cerebellum, brain regions with different developmental profiles, was determined by radioimmunoassay. After a single administration on postnatal day 5, TET (3 or 6 mg/kg i.p.) caused permanent dose- and region-dependent decrements in brain weight, with the hippocampus being the most affected. These effects were not associated with light microscopic evidence of cytopathology but were accompanied by large dose-, time- and region-dependent alterations in all neurotypic and gliotypic proteins evaluated. On a per structure (total) basis, TET caused permanent decreases in most neurotypic and gliotypic proteins in all areas. On a per milligram of tissue protein (concentration) basis, changes in specific proteins also were observed in all regions but were most prevalent in hippocampus and cerebellum. In hippocampus and cerebellum, decrements in the concentration of neurotypic and gliotypic proteins were observed in the absence of TET-induced decreases in the weights of these structures. The data indicate that 1) neonatal exposure to TET causes permanent deficits in neuronal as well as glial development, 2) the effects of TET are region-dependent but do not appear to be related to region-dependent stages in development and 3) assays of neurotypic and gliotypic proteins may be used to characterize the temporal and regional patterns of neuronal and glial responses to toxic exposures of the developing central nervous system.

Animals↗

PubMed1988

Acute exposure of the neonatal rat to tributyltin results in decreases in biochemical indicators of synaptogenesis and myelinogenesis.

Assays of neuron-localized (neurotypic) and glia-localized (gliotypic) proteins were used to detect and characterize the toxic effects of tributyltin (TBT) on the developing rat central nervous system. Four proteins associated with specific aspects of neuronal and glial development were evaluated: 1) p38, a synaptic vesicle-associated protein; 2) neurofilament 200, an intermediate filament protein of the neuronal cytoskeleton; 3) myelin basic protein, an oligodendroglia and myelin-sheath associated protein; and 4) glial fibrillary acidic protein, an intermediate filament protein of astrocytes. On postnatal days 13, 22 and 60, the amount of each protein in homogenates of cerebellum, forebrain and hippocampus was determined by radioimmunoassay. A single administration of TBT (2, 3 or 4 mg/kg i.p.) on postnatal day 5 caused dose- and region-dependent decreases in brain weight with the cerebellum being most affected. These decrements were not associated with light microscopic evidence of altered brain development (on postnatal day 61) but were accompanied by large dose- and region-dependent decreases in p38 and myelin basic protein. Decrements in both the per tissue (total) and per milligram of tissue protein (concentration) values for these proteins were observed in cerebellum and forebrain; hippocampus was largely unaffected. TBT-induced reductions in p38 and myelin basic protein were seen at dosages that did not affect brain, thymus or body weight. At dosages of TBT that did not affect body weight, reductions in brain weight, p 38 and myelin basic protein did not persist into adulthood. The data indicate that exposure to TBT on postnatal day 5 is toxic to the developing nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

An increase in glial fibrillary acidic protein follows brain hyperthermia in rats.

Previously, we have demonstrated that an increase in the astrocyte-associated protein, glial fibrillary acidic protein (GFAP), accompanies brain injury induced by a variety of chemical insults. In the present study we examined the effects of microwave-induced hyperthermia of the CNS on the concentration of GFAP in several brain regions of the Long-Evans rat. Irradiation resulted in a time-related increase in GFAP in olfactory bulbs and cortex, areas of maximum heating. The increase in GFAP following a brain temperature increase suggests that heating of brain tissue may be sufficient to provoke an injury response comparable to that induced by chemical and physical insult.

Animals↗

PubMed1987

Alarm call responsivity of mallard ducklings: V. Age-related changes in repetition rate specificity and behavioral inhibition.

Twenty-four-hour-old mallard ducklings (Anas platyrhynchos) exhibit a high degree of behavioral freezing (i.e., vocal and locomotor inhibition) upon hearing the maternal alarm call, which the hen utters when potential predators are near the nest. In this study, we assessed age-related changes in alarm call responsivity between 12 and 72 hr after hatching. Experiment 1 revealed that, although a significant reduction in vocal activity occurred upon exposure to the alarm call at all ages tested (12, 24, 36, 48, 60, 72 hr), birds older than 48 hr exhibited lower levels of freezing than younger birds. Furthermore, 12-hr-old ducklings exhibited the greatest level of freezing among the younger-aged groups. In Experiment 2, 12-, and 72-hr-old ducklings were tested to variations of the alarm call that differed in repetition rate (0.2 to 2.6 notes/sec, in increments of 2/10 of a second) to ascertain whether there are age-related changes in perceptual specificity and whether ducklings exhibit perceptual sharpening. Although older ducklings exhibited a slight shift in perceptual specificity toward faster repetition rates, they froze significantly less than younger ducklings at all repetition rates. Therefore, there was no evidence of perceptual sharpening. These data suggest that alarm call responsivity may represent an adaptation that appears to be associated with the timing of the nest exodus.

Adaptation, Biological↗

PubMed1987

Dexamethasone and indomethacin attenuate cryopexy. Induced breakdown of the blood-retinal barrier.

Pigmented rabbits were pretreated for 3 days with dexamethasone (0.4 mg/kg) or indomethacin (6 mg/kg tid) and then, along with control rabbits, treated with cryopexy administered to the peripheral retina. Drug treatment was continued for the duration of the study. Vitreous fluorophotometry (VFP) was performed prior to cryopexy and on postcryopexy days 3 and 7. Breakdown of the blood-retinal barrier occurred in all three groups but was significantly greater in the control group. Differences were most marked on postcryopexy day 7 when intravitreous fluorescein leakage was decreased to 36% of control in dexamethasone-treated rabbits and 42% of the control group in indomethacin-treated rabbits. Some rabbits, after dexamethasone or indomethacin treatment for 3 days, were given a single posterior cryoapplication just inferior to the optic nerve. On postcryopexy days 1, 3, 7, and 10, VFP was performed by scanning over the treated area. In control rabbits, fluorescein leakage increased over 3 days, while in dexamethasone- and indomethacin-treated rabbits, this increase was significantly blunted. These data demonstrate the beneficial effects of dexamethasone and indomethacin on cryopexy-induced breakdown of the blood-retinal barrier and also suggest a possible mechanism for how such a breakdown occurs.

Animals↗