UMLS:C0004134 - FACTA Search

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Query: UMLS:C0004134 (ataxia)
15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neurotoxic effects of single subcutaneous injections of 1000 mg triphenyl phosphite (TPP)/kg body weight were investigated in White Leghorn hens. At 7 days postexposure, birds began to show signs of mild to moderate ataxia that progressed to severe ataxia and paralysis at 21 days. Inhibition of whole brain neuropathy target esterase was 85% at 48 hr and 73% by 21 days postexposure. After postexposure periods of 7, 14, and 21 days, hens were killed and their brains and spinal cords were examined for degenerating axons and terminals using the Fink-Heimer silver impregnation method. A small amount of degeneration was noted at 7 days. By 21 days, dense degeneration was noted in the spinal gray matter and funiculi. Degeneration was also present in the granular cell layer of cerebellar folia I-VI and in nuclei and fiber tracts of the medulla. Moderate to dense degeneration was also seen in several forebrain and midbrain areas including the paleostriatum, ansa lenticularis, the dorso-intermediate thalamic nucleus, lateral spiriform, pedunculopontine tegmental, and lateral mesencephalic nuclei and in the deeper layers of the optic tectum. These results indicate that, in addition to affecting the spinal cord and brainstem, exposure to TPP also damages higher order centers responsible for processing and integrating sensorimotor, visual, and auditory information.
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PMID:Neuropathological effects of triphenyl phosphite on the central nervous system of the hen (Gallus domesticus). 160 Dec 12

Triphenyl phosphite (TPP), which is widely used in the chemical industry, is known to produce delayed neurotoxicity in some experimental animals. The effects of aging on the susceptibility to TPP, its disposition and pharmacokinetics, and its in vitro degradation by liver homogenate were studied in chickens. Chickens aged 60 days or less at administration were not affected, but 10 of 15 chickens aged 90 to 180 days developed ataxia 10 to 12 days after the intravenous injection of TPP (50 mg/kg). TPP clearance from the blood and most of the tissues examined was faster in 45-day-old chickens than in 135-day-old chickens. The biological half-life of TPP in the blood was 23.2 min. in the younger group and 30.5 min. in the older group. In the in vitro experiment, the initial TPP concentration of 1.6 x 10(-5) M fell to less than half this level within 60 min. during incubation with liver homogenates from 45-day-old chickens, whereas with homogenates from 135-day-old chickens the level remained high. These results suggested that the age-specific susceptibility to TPP was related to the differences of the tissue load, which derived in part from differing levels of metabolic activity in the liver.
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PMID:Effects of age on susceptibility of chickens to delayed neurotoxicity due to triphenyl phosphite. 237 Dec 46

The organophosphorus compound, triphenyl phosphite (TPP), caused ataxia in chickens 8-14 days after single po or iv administration. The po and iv ED50 values were 1414 and 35.4 mg/kg, respectively. Chickens which developed ataxia lost 14.4 +/- 2.5% (mean +/- SEM, n = 14) of their initial weight at 28 days and the paralyzed birds showed a severe reduction of 29.3 +/- 2.9% (n = 13) of their initial weight at death or at 28 days after dosing. For the first 4-hr interval after iv injection of 50 mg/kg, the elimination of TPP from plasma consisted of at least two exponential phases; the half-lives of the first and second phases were approximately 30 and 60 min, respectively. When the birds received 100 mg/kg (iv) fatty tissue showed the highest TPP concentration, e.g., 215 micrograms/g fresh wt at 6 hr postdosing. The half-life was approximately 24 hr. Among neural tissues, the sciatic nerve had the highest concentration, followed by the spinal cord, the cerebellum, and the cerebrum. The red muscles, such as adductor magnus, contained about 4-30 times as much TPP as did the white muscles, such as biceps brachii, 6 hr after treatment. Time course effects of TPP treatment on mitochondrial enzymes in leg skeletal muscles were examined by treating hens with 50 mg/kg (iv) and euthanizing the birds at 6 hr to 8 days postdosing. The creatine kinase (CK) activities of the adductor and the soleus were significantly decreased at 2 (48 hr), 4, and 8 days, and at 4 and 8 days postdosing, respectively. Adductor magnus and soleus succinate dehydrogenase (SDH) activities were decreased markedly at 24 and 48 hr, and at 2 (48 hr), 4, and 8 days, respectively. Cytochrome oxidase (COD) activity in adductor magnus and soleus did not decrease during the time course. Biceps femoris CK, SDH, and COD activities were not affected by TPP treatment at this dosage. These results suggest that TPP administration affects the mitochondrial metabolism in skeletal muscle, especially red muscle of chickens.
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PMID:Delayed neurotoxicity of triphenyl phosphite in hens: pharmacokinetic and biochemical studies. 278 68

The signs of neurotoxicity observed in the cat and the rat following single or multiple doses of the phosphorous acid ester triphenyl phosphite (TPP) have been reported to differ from the syndrome known as organophosphorous compound induced delayed neuropathy (OPIDN) caused by some phosphoric acid esters. Since the hen is the test animal traditionally used to test compounds for OPIDN, we chose to study the neurotoxicity of single, subcutaneous doses of TPP using the hen. TPP (1000 mg/kg) produced progressive ataxia and paralysis which developed 5-10 days after dosing. The clinical signs were accompanied by axonal damage in the lateral columns of the spinal cord and peripheral nerve. Similar signs were observed following neurotoxic doses of the OPIDN-causing agents tri-o-cresyl phosphate (TOCP) or diisopropyl phosphorofluoridate (DFP). In addition, TPP caused damage to axons in the brain and gray matter of the spinal cord, and chromatolysis and neuronal necrosis were frequently observed in the spinal cord. These latter areas were not affected by TOCP or DFP. The minimum neurotoxic dose of TPP was found to be 500 mg/kg. Prior administration of phenylmethylsulfonyl fluoride (PMSF) reduced the incidence of damage to the peripheral nerve of animals dosed with TPP, but did not prevent toxic effects on the cell bodies in the spinal cord or the clinical effects. The results of this study indicate that TPP causes neuronal damage in addition to the axonal damage observed with OPIDN. Therefore, we conclude that two distinct mechanisms underlie the neurotoxicity of TPP.
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PMID:Histopathological assessment of triphenyl phosphite neurotoxicity in the hen. 320 32

Chronic thiamine deprivation in the rat leads to ataxia, loss of righting reflex and neuropathological damage to lateral vestibular nucleus. Before onset of neurological symptoms, transketolase (TK) activities were found to be selectively reduced by 25% in lateral vestibular nucleus and surrounding pons. Further progression of thiamine deprivation resulted in a generalized reduction in TK activity. Measurement of enzyme activity in the presence of added TPP cofactor in vitro did not lead to normalisation of enzyme activities suggesting loss of apoenzyme. Administration of thiamine to symptomatic thiamine-deprived rats resulted in reversal of neurological symptoms and to normalisation of defective TK activities in less vulnerable structures such as cerebral cortex, striatum and hippocampus; reduction of TK activity, however, persisted in brainstem and cerebellar regions. Pyrithiamine treatment results, within 3 weeks, in loss of righting reflex, convulsions and more widespread neuropathological damage compared to that observed following thiamine deprivation. TK activity was found to be significantly decreased before the onset of neurological symptoms in all brain regions and appearance of symptoms was accompanied by more severe reductions of TK. In contrast to chronic thiamine deprivation, TK activities following pyrithiamine treatment were: equally reduced in magnitude in vulnerable and non-vulnerable brain structures, unchanged following reversal of neurological abnormalities by thiamine administration.
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PMID:Activities of thiamine-dependent enzymes in two experimental models of thiamine deficiency encephalopathy: 3. Transketolase. 358

The topographies of neuropathic damage produced by triphenyl phosphite (TPP) and tri-ortho-cresyl phosphate (TOCP) are contrasted in the present study. Long-Evans, male rats were exposed (sc) to single (0.1 ml kg-1; 1.0 ml kg-1) or multiple (2 X 1.0 ml kg-1; 3 X 1.0 ml kg-1) doses of TPP, and sampled 1-3 weeks after exposure. Additional animals were dosed acutely with TOCP (1160 mg kg-1, p.o.) alone or in combination with multiple doses of TPP (2 X 1 ml kg-1). Functional changes, seen in multiple-dosed TPP-rats included tail-kinking, circling, and ataxia. Neuropathological damage seen in all but the 0.1 ml kg-1 treated animals consisted of degeneration of the ventrolateral and ventral columns of the spinal cord at all levels, and moderate peripheral nerve fibre damage. Medullary brainstem involvement consisted of axonal swellings and fragmented axons in the medial longitudinal fasciculus, the reticular formation, and the inferior cerebellar peduncles. Tissues examined from TOCP-treated rats displayed severe degeneration of the fasciculus gracilis at the cervical level, mild involvement of the dorsolateral columns at the lumbar levels and a sparing of all other cord and brainstem regions. Rats treated with neuropathic doses of both TPP and TOCP showed a composite pattern of degeneration that included damaged sites characteristic of the individual neurotoxicants. These data indicate that the neuropathic profile of TPP differs markedly from the delayed neuropathy (OPIDN) associated with exposure to model organophosphorus compounds such as TOCP.
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PMID:Triphenyl phosphite neuropathy differs from organophosphorus-induced delayed neuropathy in rats. 361 45

Organophosphorus compounds which, after acute administration, inhibit neurotoxic esterase (NTE) by greater than or equal to 65% and undergo a subsequent "aging" reaction, produce a delayed neuropathy characterized by degeneration of large and long nerve fibers (OPIDN). The present studies examine in detail the NTE-inhibiting properties of triphenyl phosphite (TPP), a plasticizer which produces ataxia and degeneration of the spinal cord in animals. A neurotoxic dosing regimen (1184 mg/kg/week, sc, for 2 weeks) inhibited both brain and spinal cord NTE (less than or equal to 40%) only marginally 4 and 48 hr postdosing. By contrast, TPP was shown in vitro to be a potent (150 = 0.98 microM) inhibitor of rat brain NTE relative to Mipafox or diisopropyl phosphorofluoridate. Compounds structurally related to TPP (i.e., triphenyl phosphate, triphenyl phosphine, trimethyl phosphite, and phenol) failed to inhibit NTE in vitro at less than 10 microM concentrations. Close examination of the TPP inhibition of NTE showed a nonlinear relationship between the duration of incubation time and loss of log(NTE activity). Preincubation of 10 microM TPP in buffer (37 degrees C) resulted in a time-dependent loss of TPP's ability to inhibit NTE. In summary, TPP is a powerful NTE inhibitor in vitro, but only a marginal NTE inhibitor after in vivo administration. These results raise questions as to the causal events mediating TPP-induced neuropathy in the rat.
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PMID:Triphenyl phosphite: in vivo and in vitro inhibition of rat neurotoxic esterase. 382 83

The presentation and treatment of a central hypoventilation syndrome in a boy with pyruvate dehydrogenase complex (PDHC) deficiency are reported. Dephosphorylated PDHC was assayed in disrupted fibroblasts after pretreatment with dichloroacetate, a pyruvate dehydrogenase kinase inhibitor. Maximal specific activity of activated patient PDHC was 10% to 30% of control values. Patient PDHC activity was not increased by alterations in concentrations of pyruvate or cofactors (thiamine pyrophosphate [TPP], coenzyme A [CoA], oxidized form of nicotinamide adenine dinucleotide [NAD+]). Clinically, normalization of plasma lactate by a high-lipid diet did not prevent slowly progressive neurologic decline. The patient manifested intermittent ataxia, episodic profound weakness, moderate psychomotor retardation, ophthalmoplegia, and retinal pigment epithelial changes. A true central hypoventilation syndrome was documented on the basis of rigorous radiologic, electrophysiologic, and pulmonary function criteria. Theophylline, progesterone, and ritalin neither altered ventilatory response to CO2 nor permitted weaning from the ventilator. In contrast, peripheral chemoreceptor stimulants (intravenous doxapram; oral almitrine) effected an acute doubling of minute ventilation with appropriate decreases in PaCO2. However, a positive response to long-term therapy with almitrine could not be unequivocally shown. It was concluded that measurement of disrupted fibroblast PDHC following dichloroacetate activation constitutes an accurate assay for PDHC deficiency. PDHC deficiency must be considered in the differential diagnosis of the central hypoventilation syndrome; this appears to be the first report of such an association. Finally, a therapeutic trial of a peripheral chemoreceptor agonist is warranted in the management of central hypoventilation syndrome.
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PMID:Central hypoventilation syndrome in pyruvate dehydrogenase complex deficiency. 643 1

The neurotoxic effects of single oral doses of tri-ortho-tolyl phosphate (TOTP) (500 mg/kg body weight) or single subcutaneous injections of triphenyl phosphite (TPP) (62.5-500 mg/kg body weight) were investigated in the Japanese quail (Coturnix coturnix japonica). Oral doses of TOTP resulted in no detectable clinical signs while injections of TPP resulted in mild ataxia to severe paralysis depending upon the dosage level. At 24 hr postdosing, whole-brain activity of neuropathy target esterase (NTE) was inhibited by 90% in birds exposed to TOTP and by 11-87% in birds injected with TPP. Oral doses of TOTP resulted in only sparse Fink-Heimer silver-impregnated degeneration in the white matter of the cerebellum with no degeneration noted in any other region of the brain. Injections of TPP resulted in widespread degeneration in large numbers of brainstem nuclei and tracts and in all cerebellar foliae and deep nuclei. These results indicate that the Japanese quail responds differentially to exposure to TOTP and TPP. Oral doses of TOTP do not result in clinical signs or in significant amounts of degeneration in the brain even though NTE activity is inhibited by 90%. In contrast, injections of TPP at higher dosage levels yield severe clinical signs, widespread axonal and terminal degeneration in the CNS, and significant inhibition of NTE activity. This sharp dichotomy in relative sensitivity to TOTP and TPP in the Japanese quail suggests that each compound may have its own unique effect on CNS structure and function. In addition, the relationship between levels of NTE inhibition and the onset of clinical signs or neuropathology remains unclear.
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PMID:Organophosphorus-induced delayed neurotoxicity: a comparative study of the effects of tri-ortho-tolyl phosphate and triphenyl phosphite on the central nervous system of the Japanese quail. 760 44

Single doses of triphenyl phosphite (TPP), a triester of trivalent phosphorus, cause ataxia and paralysis in hens. Characteristics of neurotoxicity were described as somewhat different from organophosphate induced delayed polyneuropathy (OPIDP), which is caused by triesters of pentavalent phosphorus. The onset of TPP neuropathy was reported to occur earlier than that of OPIDP (5-10 versus 7-14 days after dosing, respectively), and chromatolysis, neuronal necrosis and lesions in certain areas of the brain were found in TPP neuropathy only. Pretreatment with phenylmethanesulfonyl fluoride (PMSF) protects from OPIDP, but it either partially protected from effects of low doses or exacerbated those of higher doses of TPP. In order to account for these differences with OPIDP, it was suggested that TPP neuropathy results from the combination of two independent mechanisms of toxicity: typical OPIDP due to inhibition of neuropathy target esterase (NTE) plus a second neurotoxicity related with other target(s). We explored TPP neuropathy in the hen with attention to the phenomena of promotion and protection which are both caused by PMSF when given in combination with typical neuropathic OPs. When PMSF is given before neuropathic OPs it protects from OPIDP; when given afterwards it exaggerates OPIDP. The former effect is due to interactions with NTE, the latter to interactions with an unknown site. The time course of NTE reappearance after TPP (60 or 90 mg/kg i.v.) inhibition showed a longer half-life when compared to that after PMSF (30 mg/kg s.c.) (10-15 versus 4-6 days, respectively). The clinical signs of TPP neuropathy (60 or 90 mg/kg i.v.) were similar to those observed in OPIDP, appeared 7-12 days after treatment, correlated with more than 70% NTE inhibition/aging and were preceded by a reduction of retrograde axonal transport in sciatic nerve of hens. TPP (60 mg/kg i.v.) neuropathy was promoted by PMSF (120 mg/kg s.c.) given up to 12 days afterwards and was partially protected by PMSF (10-120 mg/kg s.c.) when given 24 h before TPP (60 or 90 mg/kg i.v.). The previously reported early onset of TPP neuropathy might be related to the higher dose used in those experiments and to the resulting more severe neuropathy. The lack of full protection might be explained by the slow kinetics of TPP, which would cause substantial NTE inhibition when PMSF effects on NTE had subsided. Since PMSF also affects the promotion site when given before initiation of neuropathy, the resulting neuropathy would then be due to both protection from and promotion of TPP effects by PMSF. No promotion by PMSF (120 mg/kg s.c.) was observed in TPP neuropathy (90 mg/kg i.v.) partially protected by PMSF (10-30 mg/kg s.c.). This might also be explained by the concurrent effects on NTE and on the promotion site obtained with PMSF pretreatment. We conclude that TPP neuropathy in the hen is likely to be the same as typical OPIDP. The unusual effects of combined treatment to hens with TPP and PMSF are explained by the prolonged pharmacokinetics of TPP and by the dual effect of PMSF i.e. protection from and promotion of OPIDP.
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PMID:Triphenylphosphite neuropathy in hens. 857 29

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