Showing papers on "Neurotoxicity published in 1984"

Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism.

Abstract: The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces an irreversible neurological syndrome in man and monkey which is similar to idiopathic Parkinson's disease in its clinical, pathological, neurochemical and pharmacological response properties. MPTP is selectively neurotoxic to the dopaminergic regions of the brain, destroying neurones in the substantia nigra (A8 and A9 cells, nigrostriatal system) but not the ventral tegmental area (A10 cells, mesolimbic system). Selective dopamine depletion and nigral cell loss after MPTP treatment has also been reported recently in the mouse. The mechanism by which a peripherally administered, low-molecular weight compound exerts permanent but selective toxic effects on dopamine systems in the brain may be relevant to parkinsonian syndromes induced by other toxins and to the disease process in idiopathic Parkinson's disease. We report here that MPTP is oxidized in the brain to a pyridinium species (a compound with potent herbicidal activity) and, in the monkey, is trapped intraneuronally. Furthermore, we demonstrate that this enzymatic oxidation is blocked in vivo in the mouse by a monoamine oxidase inhibitor, a condition which also blocks the neurotoxicity, indicating that the oxidative metabolism of MPTP is required for its neurotoxic effect.

Catecholamine toxicity : a proposal for the molecular pathogenesis of manganese neurotoxicity and Parkinson's disease

Abstract: An hypothesis is presented which attempts to relate the pathogenesis of both manganese neurotoxicity and Parkinson's disease to cytotoxicity from products of catecholamine oxidation. These include the products resulting from the partial reduction of oxygen (superoxide anion, hydroxyl radical, and hydrogen peroxide) and the semiquinones and ortho quinones produced during autoxidation or oxidation of catecholamines initiated by trivalent manganese.

The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the monkey and man.

Abstract: l-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) selectively destroys dopaminergic neurons in the pars compacta of the substantia nigra (A8 and A9 cells). MPTP or its metabolite enters nerve cells at the level of their terminals in the caudate nucleus and putamen leading to a disturbance in axoplasmic flow and retrograde degeneration. The species-dependent neurotoxicity of MPTP (primate vs. rodent) suggests that a biochemical property of the cell related to neuromelanin may be important in the mechanism of cell injury.

Neurological complications of antineoplastic therapy.

Abstract: Increasingly vigorous chemotherapy of cancer including primary and metastatic central nervous system disease has resulted in prolonged good-quality survival. However, there has been an associated increase in neurotoxicity from both radiation therapy and chemotherapy. All classes of chemotherapeutic agents contain drugs that are potentially neurotoxic, often only at high doses. Mechlorethamine, the first nitrogen mustard, is not neurotoxic at conventional dosage, but at high doses, it may produce both an acute and a delayed encephalopathy. Methotrexate administered intrathecally often induces reversible aseptic meningitis, but chronic administration, either intrathecally or high-dose intravenously, may produce fatal leukoencephalopathy. 5-Fluorouracil at high dosage may cause cerebellar ataxia, but may also do so at low dosage when combined with thymidine infusions. Cytosine arabinoside at high dosage may also produce cerebellar ataxia. Vincristine produces a peripheral neuropathy, and less commonly causes both autonomic and cranial neuropathy. The enzyme L-asparaginase can produce a dose-related reversible encephalopathy. BCNU, now the mainstay of glioma chemotherapy, may combine with radiation to produce long-term cerebral atrophy. Both intracarotid and high-dose intravenous BCNU administration may cause encephalopathy. Several other chemotherapeutic agents have also been reported to cause neurotoxicity under certain circumstances.

Neurotransmitters and neurotransmitter receptors in developing and adult rats during manganese poisoning.

Abstract: Manganese neurotoxicity has been recognized among industrial workers as a consequence of chronic exposure to the metal in the form of fumes or dust. Hazards for the general population, including newborn and developing children, and other living organisms may also originate from prolonged low-level exposure to manganese and its organometallic compounds released into the environment as a result of their variety of applications. Experimental evidence has been presented to show that developing mice and rats are not able to excrete manganese for first 17-18 days of life, with excessive tissue accumulation, and their brain is more susceptible to the neurotoxic effects of manganese. Prolonged exposure to manganese causes depletion of dopamine and other monoamines in adult rats. The short-term exposure produces an increase in the binding of dopaminergic antagonist [3H]-spiroperidol to striatal membranes without affecting the other neurotransmitter receptors at low doses (10 mg/kg X 15). A higher dose (15 mg/kg X 15), causes a decrease in cerebral GABA, frontal cortical serotonin and striatal muscarinic binding and an increase in binding of [3H]-spiroperidol to striatal membranes. No significant changes occur in the levels of dopamine or serotonin at either of these two doses. The neonatal rat in certain respects shows a different effect on dopamine levels and receptor sensitivity. Exposure to manganese causes an increase in levels of dopamine and norepinephrine. Neonatal exposure to manganese (10 mg/kg X 15) produces a decrease in binding of [3H]-spiroperidol to striatal membranes and of serotonin to frontal cortical membranes.

Biochemical, functional and morphological indicators of neurotoxicity: effects of acute administration of trimethyltin to the developing rat.

Abstract: The neurotoxic organometal, trimethyltin (TMT), was administered to rats on postnatal day (PND)5. Neurotoxicity was assessed throughout subsequent development using morphological, biochemical and functional endpoints. These consisted of brain weight measures and histology (morphology), assays of nervous system-specific proteins (biochemistry) and neurobehavioral indices of activity and learning (function). All three indices were affected. TMT caused dose-related decreases in brain weights at all ages examined, PND13, 22 and 66, with the hippocampus being the most severely reduced. Histological examination of the hippocampus revealed loss of pyramidal neurons in CA3 to CA4. Exposure to TMT was followed by dose- and age-dependent reductions in synapsin I, a neuron-specific phosphoprotein associated with synaptic vesicles; these effects of TMT were greater in hippocampus than in forebrain. TMT did not alter the concentration or protein composition of isolated myelin. The ontogeny of locomotion was altered in a dose- and time-dependent manner; TMT induced hypoactivity early in development (PND13) and hyperactivity by weaning (PND21); hyperactivity was also observed in the adult. Finally, TMT also affected learning ability throughout development. Deficits were observed in: acquisition and retention of an instrumental alleyway response; acquisition of a step-through passive avoidance response; and radial-arm maze performance. These results demonstrate the use of a multi-endpoint, multi-timepoint strategy for the detection and characterization of neurotoxicity.

Neurophysiological studies on the relation between the structural properties and neurotoxicity of aliphatic hydrocarbon compounds in rats

Abstract: In order to determine the specific structural properties responsible for neurotoxic activity, the comparative neurotoxicity of n-hexane, methyl n-butyl ketone, 2,5-hexanedione, and their relatives was investigated in the peripheral nerves of rats. The maximum conduction velocity of motor and sensory fibres and the motor distal latency of the tail nerves of rats were periodically examined in animals receiving repeated subcutaneous injections of 11 aliphatic monoketone or diketone compounds and their relatives for prolonged periods. A study of the comparative neurotoxicity of n-hexane, methyl n-butyl ketone, and their metabolites showed that 2,5-hexanedione was the most actively neurotoxic. Furthermore, a study of other symmetrical diketones with different carbon numbers showed that 2,4-pentanedione, which is structurally similar to 2,5-hexanedione, possessed a different type of neurotoxic activity than 2,5-hexanedione. Regarding aliphatic monoketone compounds, acetone, 2-pentanone, 2-heptanone, and 2-octanone were confirmed non-neurotoxic for the peripheral nervous system. Evidence from some previous reports, however, suggested that 3-heptanone, 4-octanone, and 5-nonanone might produce neuropathies by being converted to 2,5-diketones under specific conditions.

Changes of n-hexane neurotoxicity and its urinary metabolites by long-term co-exposure with MEK or toluene.

Abstract: It is well known that the neurotoxicity of n-hexane may be modified upon co-exposure with other organic solvents. In order to elucidate this mechanism further, rats were exposed to 500ppm n-hexane, 500ppm n-hexane plus 500ppm methyl ethyl ketone (MEK), 500ppm n-hexane plus 500ppm toluene, or air only for 8h per day for 33 weeks. The body weight, motor nerve conduction velocity (MCV) and distal latency (DL) were determined before exposure and after 4, 8, 12, 16, 20, 24, 29, and 33 weeks of exposure. From each group one rat was histologically examined after 33 weeks of exposure. To establish a relationship between the n-hexane neurotoxicity and changes in biotransformation, urinary metabolites (2-hexanol, methyl n-butyl ketone (MBK), 2,5-hexanedione, 2,5-dimethylfuran, and γ-valerolactone) were measured by gas chromatography on the first exposure day, and after 1, 2, 4, 8, 12, 16, 20, 24, 29, and 33 weeks of exposure. The total amounts of metabolites of n-hexane in the urine significantly decreased upon co-exposure of n-hexane, with MEK as well as with toluene, in comparison with those of animals exposed to n-hexane alone. 2,5-Hexanedione, which is considered the ultimate neurotoxic metabolite of n-hexane, also decreased. Electrophysiological and histological studies did not reveal statistically significant differences between any two groups among the four groups. It is considered that the present results might explain the combined effects of n-hexane and toluene which decrease n-hexane neurotoxicity, but do not explain those of n-hexane and MEK. Therefore, other mechanisms of the combined effects of n-hexane and MEK should be studied.

Neuron-specific phosphoproteins as biochemical indicators of neurotoxicity: effects of acute administration of trimethyltin to the adult rat.

Abstract: The cytoarchitecture of the adult central nervous system is expressed by proteins specific to individual cell types. In this investigation, a subclass of these proteins, the neuron-specific phosphoproteins, was examined after the administration of trimethyltin (TMT), a neurotoxicant which preferentially damages neurons in limbic structures. After acute administration of TMT (0.0-9.0 mg/kg i.v.), effects on neuronal phosphoproteins were examined by three separate techniques: endogenous phosphorylation of total synaptic membrane proteins; radiometric assay of synapsin I, a neuron-specific phosphoprotein associated with synaptic vesicles; and radioimmunoassay of synapsin I and protein III, another synapse specific, synaptic vesicle-localized phosphoprotein. All three procedures gave similar results. TMT caused dose- and time-dependent decreases in hippocampal phosphoproteins. These effects were large in magnitude and were still evident 14 weeks after exposure to TMT. Microdissection of slices of dorsal hippocampus did not reveal significant regional differences in the extent to which TMT affected synapsin I. Phosphoproteins in frontal cortex, unlike those in hippocampus, were not affected by TMT. Our findings are consistent with the neuropathological effects of this compound and suggest that neuron-specific phosphoproteins may be useful biochemical indicators of neurotoxicity.

Neuronal effects of water-soluble contrast agents.

Abstract: The in vitro rat hippocampus slice preparation has been utilized to examine the direct neurotoxicity of water-soluble contrast agents. Intraneuronal recordings were obtained from pyramidal cells in the CA1 field of rat hippocampus slices. Synaptic activity was evoked by Schaffer's collateral stimulation. The effects of Na-diatrizoate and metrizamide were studied. Test solutions were 300 to 345 mOsm and had iodine concentrations of 22.5 to 30 mg I/ml which are probably near clinical concentrations. The two effects of the contrast agents are apparent within 10 minutes and reversible within 30 to 45 minutes. The first is an epileptogenic property reflected by repetitive action potentials arising from an early prolonged depolarization. The second effect is a depression of electrical activity characterized by hyperpolarization of the resting membrane potential. Na-diatrizoate predominantly produced the first effect. Metrizamide principally produced the second effect. These results indicate that contrast agent seizure activity is not due to hyperosmolarity but a more direct chemical effect. The depression, however, may be related to a hyperosmolar effect. The differences between the dominant effects of the ionic vs. nonionic agents observed in these experiments seem to correlate with clinical experience and may indicate the etiology of central nervous system neurotoxicity of these drugs.

Molecular Mechanism of Hexane Neuropathy: Significant Differences in Pharmacokinetics between 2.3-, 2.4-, and 2.5-Hexanedione

Abstract: Hexane neuropathy is thought to be produced through the direct action of its metabolite, 2, 5-hexanedione (2, 5-HD), on nervous tissues. 7-Diketones in-cluding 2, 5-HD are reported to be neurotoxic, whereas α, β, and δ-diketones are reported to be not. Experiments were designed to investigate the specificity of the y-diketones in terms of pharmacokinetics. 2, 3-HD (a-diketone), 2, 4-HD (α-diketone), and 2, 5-HD (7-diketone) were tested in this study. Aqueous solutions containing 0.5% of each HD were administered to rats by gavage. HDs in blood, brain, and sciatic nerve were determined at specific intervals after gavage by the extraction method with chloroform or the direct injection method using gas chromatography-mass spectrometry.Examination of tissue distribution revealed that 2, 5-HD was not selectively re-tained by nervous tissues. However, 2, 5-HD had higher concentrations and much longer elimination times in both blood and nervous tissues than 2, 3-HD and 2, 4-HD. Therefore, for an identical dose, 2, 5-HD has a much larger effective dose (con-centration in tissue x time retained by tissue) than 2, 3-HD and 2, 4-HD. These results suggest that the specific neurotoxicity of the 7-diketones is due to their pharmackinetic specificity.

An acute and subacute neurotoxicity assessment of trichlorfon

Abstract: The toxicity of trichlorfon (O, O-dimethyl-2,2,2,-trichloro-1-hydroxyethylphosphonate, Dipterex®, Dylox®), reported to elicit delayed neurotoxicity in man and chickens, was studied by administering...

Hemolysis as a possible indicator of neurotoxicity induced by organic solvents.

Abstract: The expense, length of time and number of animals required for routine toxicity testing have provided the incentive for finding alternative techniques which are faster, less expensive and equally valid. The purpose of this work was to examine the value of a simple in vitro test (hemolysis) as a correlate of the neurotoxicity produced by commonly used industrial organic solvents. Incubation of rat erythrocytes with organic alcohols produced hemolysis which correlates with the potency of the same alcohols to suppress membrane excitability, measured as reduction in the evoked action potential of the rat sciatic nerve. The hemolytic activity also reflects changes in water solubility among the compounds and thus can be used as an index of in vivo neurotoxicity, the extent of which partly depends on absorption of the agent and delivery to nerve tissue. Hemolysis therefore may be of value as a preliminary test for assessing the neurotoxicity of organic solvents.

Misonidazole neurotoxicity in rats: Part I. Evaluation of misonidazole neurotoxicity in rats by analysis of brain stem auditory and cortical evoked potentials.

Abstract: The effects of misonidazole (MISO) on brain stem evoked potentials (BAEPs) and cortical evoked potentials (CEPs) were evaluated in 16 Sprague-Dawley rats treated with the agent. As found in previous studies, serial BAEP values were diagnostic of the onset of MISO toxicity before clinical signs and symptoms appeared. However, MISO had no effects on CEPs, which remained essentially unchanged through the course of the experiment. At histologic examination, significant changes were found in the area of the brain stem, but there was no histologic evidence of damage to cortical or subcortical structures caused by MISO administration. The results of this study suggest that the neurotoxic effects of MISO are species-specific, and that while the rat model may be useful for comparison of the relative toxic effects of nitroimidazole radiosensitizers, it is not a model suited for measurement of neurotoxicity caused by MISO in humans and nonhuman primates.

Ethanol neurotoxicity in vitro

Abstract: Prenatal exposure to ethanol produces a characteristic phenotype and a constellation of nervous system abnormalities. Effects of ethanol on the developing nervous system occur during early neurogenesis when neuron-matrix interactions and process formation are proceeding.

The influence of systemic factors on acrylamide‐induced changes in brain, nerve, and other tissues

Abstract: In order to define the locus of acrylamide neurotoxicity, the effects of chronic intoxication (total dose 500 mg/kg) on cholinergic synthesis and transport, the Schwann cell-myelin complex, lysosomal activity, and several metabolic pathways were determined in rat sciatic nerve, spinal cord, and brain. No changes were found in hematological measures or in the levels of clinically important blood enzymes, indicating no major damage to other organs. The activities of choline acetyltransferase (ChAT), 2',3'-cyclic nucleotide phosphohydrolase, beta-glucuronidase, and lactate dehydrogenase were unaffected in acrylamide paralyzed animals, but creatine kinase (CK) decreased in sciatic nerve, muscle, and brain, particularly in animals dying of the intoxication. CK blood and the CK isoenzyme patterns in blood were unchanged. The synthesis of protein in brain and spinal cord (measured in vivo) were decreased in rats exposed to high-dose acrylamide. However, in brain and cord, CK decreased only after animals became systemically ill and suffered weight loss, with the lowest activities in those animals sick enough to die. The degree of stress to which the animals had been subjected was indicated by enlargement of the adrenal glands and decreased sulfolipid synthesis in the adrenals. Rats exposed to 25 mg/kg/day acrylamide to a total dose of 250 mg/kg developed leg weakness but not paralysis or weight loss and had a 25% decrease in CK only in the distal sciatic nerve. Because of the apparently stress-related or agonal loss of CK, no specific effect of acrylamide on the enzyme could be definitely demonstrated. Neither could the changes in protein synthesis be attributed solely to a direct effect of the toxin. These results illustrate the difficulties encountered in interpreting intoxication studies that produce systemic illness and support the suggestion that CK activity may be a useful marker of the severity and duration of the agonal state in studies of postmortem human brain.