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W Slikker

Publications and source records attributed to W Slikker.

At least 55 records · Page 3Linked to original sources
PubMed1998

Quantitative analysis of free sphingoid bases in the brain and spinal cord tissues by high-performance liquid chromatography with a fluorescence detection.

The o-phthaldialdehyde precolumn derivatives of psychosine, sphinganine and sphingosine extracted from brain and spinal cord tissues were determined by high-performance liquid chromatography-fluorescence detection. This method was developed with the purpose of detecting an endogenous amount of psychosine, sphingosine and sphinganine using small aliquots of brain tissues and spinal cord in rats. These sphingolipid bases were extracted in various ratios of chloroform-methanol and several pH values. Recovery of the method is about 81% in 12 ng/tube (final volume, 320 microl), 90-95% in 45 ng/tube of sphingosine and sphinganine within 2-12% relative standard deviation. Detection limits of these sphingoid bases were about 0.05 pmol/mg brain tissue. In the forebrain, brainstem and spinal cord of rats at three different ages of postnatal days (PND) 1, PND 13 and 6 months old, the endogenous concentrations of psychosine, sphingosine and sphinganine were determined. From these results, this method is suitable for the determination of sphingoid bases in small aliquot of brain and spinal cord tissues.

Aging↗
PubMed1998

Effect of acute exposure to 3-nitropropionic acid on activities of endogenous antioxidants in the rat brain.

The response of endogenous antioxidants to acute exposure of the mitochondrial inhibitor, 3-nitropropionic acid (3-NPA), was investigated in selected rat brain regions. Rats treated with 3-NPA (30 mg/kg, s.c.) were sacrificed at 30, 60, 90 and 120 min after injection to examine the alterations in reduced glutathione levels (GSH), and activities of antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) in the hippocampus (HIP), frontal cortex (FC), and caudate nucleus (CN). CAT activity increased in the HIP 90 min after 3-NPA treatment. While cytosolic copper/zinc SOD (CuZn-SOD) and mitochondrial manganese SOD (Mn-SOD) levels increased in the FC at 120 min, only the Mn-SOD increased in the CN 90 min after treatment. The activity of GPx decreased in the HIP 120 min after 3-NPA injection. When compared with the control, administration of 3-NPA led to GSH depletion in HIP within 120 min. The depletion of GSH and induction of antioxidant enzyme activities after the 3-NPA exposure suggest conditions favorable for oxidative stress.

Animals↗
PubMed1998

Acute effects of dexfenfluramine (d-FEN) and methylenedioxymethamphetamine (MDMA) before and after short-course, high-dose treatment.

The acute behavioral effects of methylenedioxymethamphetamine (MDMA) and dexfenfluramine (d-FEN) were assessed in six rhesus monkeys using performance in the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB); three additional animals served as controls for neurochemical endpoints. The OTB consists of five food-reinforced tasks designed to model aspects of learning, short-term memory and attention, time estimation, motivation, and color and position discrimination. Shortly after the acute effects of each drug were determined, three of the monkeys received a short-course, high-dose exposure (2x /day x 4 days, intramuscular (i.m.) injections) of MDMA (10 mg/kg), while three monkeys were exposed to an identical regimen of d-FEN (5 mg/kg). Approximately one month later, the acute effects of each drug were again determined. In monkeys exposed to high-dose d-FEN, the sensitivities of the OTB tasks to acute disruption by either MDMA or d-FEN were essentially unchanged. Conversely, monkeys treated with high-dose MDMA were less sensitive to the acute behavioral effects of both drugs, although such an effect was seen more frequently for d-FEN and was OTB task specific. Thus a residual behavioral tolerance to the acute behavioral effects of MDMA and d-FEN was noted after high-dose MDMA exposure, but not after high-dose d-FEN exposure. These findings are surprising, as similar neurochemical effects (i.e., significant decreases of ca. 50% in serotonin in frontal cortex and hippocampus) were observed in all monkeys approximately six months after short-course, high-dose MDMA or d-FEN treatment.

Animals↗
PubMed1998

Alteration of electroencephalogram and monoamine concentrations in rat brain following ibogaine treatment.

Ibogaine (IBO) is a psychoactive indole alkaloid that has antiaddictive properties. However, treatment with IBO may lead to neurotoxicity, since IBO and its metabolites interact persistently with many neurotransmitter systems. Here, we recorded cortical electroencephalogram (EEG) signals from rats anesthetized with isoflurane. The heart rate (HR) was monitored via electrocardiogram (EKG) electrodes. After the baseline EEG was recorded, rats received one intraperitoneal (i.p.) dose of 50 mg/kg IBO. EEG signals were recorded for 2 hr. Rats were then sacrificed and brains dissected into frontal cortex (FC), caudate nucleus (CN), hippocampus (HIP), and brain stem (BS). The level of dopamine (DA), serotonin (5-HT), and their metabolites were determined by high-performance liquid chromatography with electrochemical detection (HPLC-ECD). Compared with baseline, a decrease in HR immediately after IBO injection and a decrease in delta, theta, alpha and beta power spectra frequency bands (1-4, 4-8, 8-13, 13-32 Hz) during the first 30 min after IBO administration was observed. EEG recovered within the next 15 min. In CN, the level of DA decreased and DA turnover rate increased significantly. The levels of 5-HT increased in FC. The pattern of EKG AND EEG response to IBO may be due to multiple receptor interactions of IBO.

Animals↗
PubMed1998

Gestational exposure to cocaine or pharmacologically related compounds: effects on behavior and striatal dopamine receptors.

Gestational cocaine (COC) exposure has been reported to alter behavior and possibly dopamine (DA) receptors. In this paper, we further examined the effects of prenatal COC (40 mg/kg, s.c.) on DA receptor binding and the behavioral response to quinpirole, a DA D2 receptor agonist. In an attempt to elucidate possible mechanisms of such effects, we exposed pregnant dams to specific reuptake blockers; fluoxetine 12.5 mg/kg, a serotonin reuptake blocker; desipramine 10 mg/kg, a norepinephrine reuptake blocker; GBR-12909 10 mg/kg, a DA reuptake blocker; or to a local anesthetic, lidocaine 40 mg/kg. Drugs were administered once daily over gestational days 8-20. Control dams were injected with saline (SAL) or pair-fed to the COC group. Quinpirole challenge was performed in the offspring on post natal day 19. Two pups per litter were injected (s.c.) with 0.03 or 0.09 mg/kg quinpirole-HCl on post-natal day 19. The remaining pups in each litter were sacrificed for analysis of striatal DA receptors. Results showed that only COC exposure altered the behavioral response to the quinpirole challenge by increasing quinpirole-induced stereotypy and motor activity relative to SAL controls. DA receptor analysis showed no alteration in K(D) or B(MAX) for striatal D1 or D2 sites in any group. These results suggest that prenatal COC exposure produces alterations in function of the D2 receptor complex which are not reflected in K(D) or B(MAX) and that these effects are not fully mimicked by exposure to specific monoamine reuptake blockers or a local anesthetic.

Animals↗
PubMed1997

Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration.

Fluoro-Jade is an anionic fluorochrome capable of selectively staining degenerating neurons in brain slices. The histochemical application of Fluoro-Jade results in a simple, sensitive and reliable method for staining degenerating neurons and their processes. The technique will detect neuronal degeneration resulting from exposure to a variety of neurotoxic insults. Fluoro-Jade can be combined with other fluorescent methodologies including immunofluorescence, fluorescent axonal tract tracing, and fluorescent Nissl counterstaining. Compared to conventional methodologies, Fluoro-Jade is a more sensitive and definitive marker of neuronal degeneration than hematoxylin and eosin (H&E) or Nissl type stains, while being comparably sensitive yet considerably simpler and more reliable than suppressed silver techniques.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1997

Transplacental pharmacokinetics and fetal distribution of azidothymidine, its glucuronide, and phosphorylated metabolites in late-term rhesus macaques after maternal infusion.

3'-Azido-3'-deoxythymidine (AZT) is currently prescribed to pregnant women infected with human immunodeficiency virus to reduce the risk of vertical transmission of the virus to the fetus. Consequently, more information is needed concerning the placental transfer and tissue distribution of AZT and its metabolites. In the present study, the placental transfer and fetal accumulation of AZT, its glucuronide metabolite [3'-azido-3'-deoxythymidine-beta-D-glucuronide (AZTG)], and phosphorylated metabolites were examined at steady-state in near-term rhesus macaques. One to 2 weeks before a chronic infusion, an intravenous bolus of 8 mg/kg AZT was administered to pregnant animals to determine the dose of AZT needed to reach steady-state plasma concentrations. On the day of hysterotomy, the mother was administered an intravenous loading dose of AZT, followed by a 3-hr steady-state intravenous infusion that also included a trace of [3H]AZT. After 3 hr of infusion, the mother was anesthetized, and the fetus was delivered. Plasma and amniotic fluid were analyzed for AZT and AZTG by HPLC, and tissue samples were analyzed for AZT, AZTG, and phosphorylated metabolites by strong anion exchange HPLC. Maternal steady-state plasma concentrations were 1.3-2.2 micrograms/ml for AZT and 2.3-8.0 micrograms/ml for AZTG. Fetal AZT and AZTG plasma concentrations were both lower (0.98-2.3 micrograms/ml and 1.3-5.4 micrograms/ml, respectively) than maternal concentrations, with fetal-to-maternal plasma ratios of 0.63-1.0 for AZT. Fetal tissue distribution of tritium was highest in the kidney and lowest in the brain. Although the active triphosphorylated metabolite was not detected in the fetus, the AZT-monophosphate was detected in almost all fetal tissues examined. Our data indicate that AZT is rapidly converted to the glucuronide and monophosphate metabolites in the fetus after maternal infusion.

Animals↗
PubMed1997

Prenatal fumonisin (FB1) treatment in rats results in minimal maternal or offspring toxicity.

To investigate the neurobehavioral and developmental effects of the mycotoxin, FB1, Sprague-Dawley rats were treated with FB1 on gestational days 13-20. In Experiment 1, FB1 was obtained from culture material and pregnant rats were gavaged with 0, 0.8 or 1.6 mg/kg. In Experiment 2, pregnant rats were gavaged with purified FB1 at doses of 0, 1.6 or 9.6 mg/kg. Offspring were evaluated on a battery of behavioral tests as well as measures of whole and regional brain weight. There were no effects on maternal weight gain, reproductive outcomes, or offspring body weight through adulthood in either experiment. Complex maze performance, open field and running wheel activity were not altered by prenatal FB1 treatment. In Experiment 2, acoustic startle response was depressed at two ages during the first or second block of 9 trials in males treated with purified FB1. Females exhibited no such alterations. Play behavior at PND 33, but not PND 26, was increased in males prenatally treated with 9.6 mg/kg relative to those treated with 1.6 mg/kg. There were no substantive treatment effects on regional brain weight. These results suggest that doses of < or = 9.6 mg purified FB1/kg and/or < or = 1.6 mg FB1/kg obtained from culture material cause minimal maternal toxicity and produce few development functional alterations. In addition, potential FB1-related functional alterations were evident only in males providing further support for a mild sex-specific effect for fumonisin.

Animals↗
PubMed1997

Fumonisin B1 in developing rats alters brain sphinganine levels and myelination.

Objectives of this study were to test the hypothesis that fumonisin B1 (FB1) alters sphinganine (Sa) levels and myelin synthesis in the central nervous system of developing rats. FB1 (subcutaneous, 0.4 or 0.8 mg/kg/day) from postnatal days (PND) 3 to PND 12 resulted in a significant reduction of body weight gain and decreased survival rates. Both Sa levels and Sa/sphingosine (So) ratios were significantly increased in the brain of rats given 0.8 mg FB1/kg/day. To confirm the effect of limited nutrition on changes in the Sa levels and myelinogenesis, rats given 0.8 mg FB1/kg/day or treated by limited nutrition (temporary removal from dam during postnatal period) were compared to those in saline controls. Sa levels and Sa/So ratios were increased significantly in the 0.8 FB1-treated, but were not altered in the limited nutrition group. Myelin deposition in the corpus callosum and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) activities were decreased significantly in both nutritionally limited and FB1-exposed rats. These data indicate that sphingolipid metabolism in the central nervous system of developing rats is vulnerable to FB1 exposure. The hypomyelination associated with FB1-treatment may be mediated by limited nutrition.

Animal Nutritional Physiological Phenomena↗
PubMed1997

Elevated environmental temperatures can induce hyperthermia during d-fenfluramine exposure and enhance 5-hydroxytryptamine (5-HT) depletion in the brain.

d-Fenfluramine (d-Fen) has been demonstrated to alter body temperature (BT), decrease 5-hydroxytryptamine (5-HT) and decrease 5-HT plasma membrane transporters (PMT) in rats. Therefore, experiments were designed to test whether a correlation existed between elevated BT and brain 5-HT depletions. It was hypothesized that d-Fen would induce hyperthermia if the environmental temperature was elevated. Experiments were conducted to determine 1) the dose-response of d-Fen on BT in a 28 degrees C environment, 2) the acute effect of d-Fen on long-term depletion of 5-HT and 5-HT PMT in a 4 degrees C, 22 degrees C or 28 degrees C environment and 3) the effect of a 22 degrees C environment vs. a 28 degrees C environment on the plasma levels of d-Fen and d-norfenfluramine. d-Fen produced a dose-dependent elevation of BT in the 28 degrees C environment, decreased BT in the 4 degrees C environment and had no effect on BT in the 22 degrees C environment. Exposure to d-Fen in the 4 degrees C or 22 degrees C environment reduced 5-HT and 5-HT PMT concentrations compared with control. However, greater reductions of 5-HT and 5-HT PMT concentrations occurred in the 28 degrees C environment. Conversely, the plasma levels of d-Fen and d-norfenfluramine were not altered. Thus these experiments demonstrate that increased BT during d-Fen exposure occurs at elevated environmental temperatures without altering the plasma concentrations of the drug and results in an enhanced long-term depletion of brain 5-HT and 5-HT PMT.

Animals↗
PubMed1996

Distribution of 2,4-dichlorophenoxyacetic acid (2,4-D) in maternal and fetal rabbits.

The distribution of 2,4-dichlorophenoxyacetic acid (2,4-D) was examined in maternal and fetal rabbits. Pregnant New Zealand rabbits (28-30 d gestational age) were anesthetized with ketamine/xylazine and the femoral vein and artery were catheterized for compound administration and sampling. Dams received iv [14C]2,4-D (12.5 microCi/kg) with unlabeled sodium 2,4-D (1, 10, or 40 mg/kg) in saline. Blood and tissue were collected up to 2 h after dosing. Fetal to maternal plasma AUC ratios were 0.09, 0.07, and 0.16 after the 1, 10, or 40 mg/kg dose, respectively. Extraplasma AUCs were greatest in maternal kidney and uterus and lowest in maternal and fetal brain. A greater than fourfold elevation in fetal AUC was found when the dose was increased from 10 to 40 mg/kg, suggesting saturation of maternal plasma binding of 2,4-D. Although the in vitro fetal brain tissue to incubation media ratio was unity (1.03 +/- 0.1, mean +/- SD), fetal brain AUCs were 10% or less of the fetal plasma AUCs, indicating the brain barrier system to 2,4-D is functioning in the late-gestation fetal rabbit. However, its development may not be complete due to the higher brain tissue to plasma ratios in the fetus compared to the dam.

2,4-Dichlorophenoxyacetic Acid↗
PubMed1996

Methamphetamine-induced dopaminergic toxicity in mice. Role of environmental temperature and pharmacological agents.

1. Multiple injections of METH (4 x 10 mg/kg, i.p.) at room temperature (23 degrees C) produced a significant depletion of dopamine (DA) and its metabolites DOPAC and HVA in striatum at 24 and 72 hr, and 1 and 2 wk. 2. Three days post 4 x 10 mg/kg METH at 23 degrees C, an 80% decrease in striatal dopamine (DA) occurred, while the same dose at 4 degrees C produced only a 20% DA decrease, and 4 x 20 mg/kg METH at 4 degrees C produced a 54% DA decrease. A similar pattern in the decreases of the DA metabolites DOPAC and HVA was observed after METH administration. 3. At 23 degrees C (+)MK-801 completely blocked while phenobarbital (40% decrease) and diazepam (65% decrease) partially blocked decreases in striatal DA produced by 4 x 10 mg/kg METH. Decreases in DOPAC and HVA were similar to the decreases in DA after METH and antagonists. 4. Multiple injections of METH (4 x 10 mg/kg, i.p.) at room temperature also produced a significant depletion of serotonin (5-HT) in striatum at 24 and 72 hr, and 1 and 2 wk. The depletion of 5-HT metabolite 5-HIAA was found only at 72 hr post-dosing. 5. This depletion of 5-HT and its metabolite 5-HIAA at room temperature was blocked either by changing the environmental temperature to 4 degrees C, or by pretreatment with MK-801, diazepam and phenobarbital after METH treatment. 6. Therefore, these data suggest that drugs that block METH toxicity, such as haloperidol (D2 receptors), pentobarbital and phenobarbital (chloride channels) and MK-801 (NMDA/glutamate receptors), do not necessarily have the same mechanism of action but may either induce hypothermia or block induction of hyperthermia. 7. In summary, these studies show that in the mouse, environmental temperature greatly influences METH neurotoxicity, and that the protective effects of compounds such as diazepam, phenobarbital and MK-801 may be mediated by blockade of METH-induced hyperthermia.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Neuroendocrine and neurochemical effects of acute ibogaine administration: a time course evaluation.

Ibogaine (IBO) is an indole alkaloid that is reported to facilitate drug abstinence in substance abusers. Despite considerable investigation, the mechanism of IBO action in vivo and its suitability as a treatment for drug addiction remains unclear. The present study was designed to evaluate the time-course effects of acute IBO on neuroendocrine and neurochemical indices. Adult male rats were treated with i.p. saline or 50 mg/kg IBO and sacrificed 15, 30, 60, 120 min and 24 h later. Trunk blood was collected for hormone measures and brains were dissected for neurochemical analyses. IBO produced a rapid elevation in plasma prolactin that declined to control levels by 60 min. Corticosterone levels increased 15 min after drug administration, continued to increase for 120 min, but returned to control levels 24 h after dosing. IBO decreased dopamine (DA) concentrations in the striatum and frontal cortex at 30, 60 and 120 min after injection while DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were elevated over the same time period. 24 h after IBO, DOPAC concentrations in striatum and HVA levels in the frontal cortex were below control values. Serotonin (5-HT) and its metabolite 5-hydroxyindole acetic acid (5-HIAA) were decreased at 60 min after IBO administration only in the striatum. These data indicate that a single injection of IBO produces a spectrum of effects that includes: (1) elevation of plasma prolactin and corticosterone, (2) short- and long-term effects on DA neurotransmission, and (3) modest, transient effects of 5-HT neurotransmission. The effects of IBO reported herein may have relevance to the anti-addictive properties of this drug, and this proposal warrants further investigation.

Animals↗
PubMed1996

Parenterally administered 3-nitropropionic acid and amphetamine can combine to produce damage to terminals and cell bodies in the striatum.

The combined effects of amphetamine (AMPH) and 3-nitropropionic acid (3-NPA) were investigated to determine how the energy depletion proposed to be produced by AMPH interacts with an inhibitor of mitochondrial respiration to produce striatal neurotoxicity. Neither two doses (2 h apart) of 3.75 mg/kg AMPH alone nor a single dose of 30 mg/kg 3-NPA i.p. produced neurotoxicity in the striatum or lowered striatal dopamine content in rat. Administration of 40 mg/kg of 3-NPA alone almost invariably produced either lethality or did not produce neurotoxicity in the striatum of surviving animals. However, 30 mg/kg of 3-NPA administered along with 2 doses of 3.75 mg/kg AMPH to 47 animals produced striatal damage in the 31 survivors with 15 of the surviving rats showing muscle rigidity/catatonia for several days after dosing, along with decreased food consumption. Thirteen of these 15 rats showed degeneration of axons and cell bodies in the medial caudate-putamen with minimal damage to the globus pallidus. However, two rats exhibited hindlimb paralysis and signs of axonal and neuronal soma degeneration in the thalamus and cerebellar nuclei as well as striatum. Sixteen of the rats given both AMPH and 3-NPA exhibited only torpidity and loss of muscle tone 1-3 h after dosing. Such rats showed no signs of neuronal cell degeneration in the striatum, but did show significant dopamine depletions (60% of control) and reductions in tyrosine hydroxylase immunoreactivity at 14 days postexposure. The mitochondrial dysfunction produced by 3-NPA combined with activation of neuronal pathways by AMPH may have predisposed terminals, axons and cell bodies in striatum to degeneration.

Amphetamine↗
PubMed1996

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Journal Article↗
PubMed1996

Role of metallothionein and other antioxidants in scavenging superoxide radicals and their possible role in neuroprotection.

Based on the inhibition of nitrite formation by generating superoxide from xanthine/xanthine oxidase (X/XO) reaction system, metallothionein (MT) and other sulfhydryl containing amino acids have been selected to test their abilities to scavenge superoxide radicals. Different concentrations of metallothionein and other sulfhydryl containing molecules e.g. cysteine, N-acetyl-cysteine and glutathione, were used to assess superoxide scavenging properties. Metallothionein scavenges superoxide radical in a dose-dependent manner with increasing concentrations as evidenced by the inhibition of nitrite formation. Similar abilities to scavenge superoxide radicals were shown by cysteine, N-acetyl-cysteine. Glutathione also scavenges superoxide radical in a dose-dependent manner. In vitro experiments demonstrated that metallothionein is superior in scavenging superoxide radicals compared to other sulfhydryl molecules such as cysteine, N-acetyl-cysteine and even glutathione. The data, further, suggest that metallothionein-II has a 6-fold higher capacity to scavenge superoxide radical than metallothionein-I. In addition, metallothionein-like protein was isolated from different regions of mouse brain treated with zinc. Brain metallothionein-like protein inhibits nitrite formation as demonstrated by other scavengers; however, the extent of inhibition is different by this protein isolated from different brain regions. The present study suggests that metallothioneins and metallothionein-like proteins isolated from mouse brain act as neuroprotective agents by scavenging superoxide radicals.

Acetylcysteine↗