thiourea and Neuromuscular-Diseases

Daily administration of dithiobiuret (DTB, 1 mg/kg X 6 days, ip) produced delayed onset muscle weakness in rats as indicated by failure in a treadmill test. In nerve-muscle preparations from DTB-intoxicated rats neuromuscular toxicity was manifested as contractile fatigue during tetanic nerve stimulation. As muscle weakness developed, feed intake decreased and the animals lost body weight. Water intake was not altered during this time, but urine output was increased concomitant with the development of muscle weakness and resulted in a state of negative water balance. Daily administration of d-penicillamine (d-PEN) antagonized DTB-induced treadmill failure in a dose-dependent fashion. A daily dose of d-PEN (1 mMol/kg, ip) that completely antagonized treadmill failure also antagonized the contractile fatigue, reduced feed intake, weight loss and negative water balance caused by DTB administration. In rats already intoxicated with DTB, initiating daily d-PEN treatment or discontinuing further DTB administration, caused the animals to recover normal treadmill performance after a latent period of five days. A single dose of d-PEN (1 mMol/kg, iv) was not effective in reversing treadmill failure or contractile fatigue in rats already intoxicated with DTB. Thus, continuous daily administration of d-PEN was necessary for it to be effective. A single dose of d-PEN (1 m Mol/kg, ip) administered one hr after [14C]-DTB (1 mg/kg, ip) did not affect the plasma and tissue concentrations of DTB-derived radioactivity or their corresponding elimination kinetics. Cumulative urinary and fecal excretion of DTB-derived radioactivity were also unaffected by d-PEN administration as were the relative proportions of DTB and two of its metabolites, monothiobiuret and thiuret, in urine. Other agents that produced dose-dependent antagonism of DTB toxicity were diethyldithiocarbamate, disulfiram, cysteamine and 2,2'-dipyridyl. Considering the chemical and biological properties of DTB and its antagonists, a mechanism of antagonism involving an alteration of the thiol-disulfide and/or divalent metal cation status of motor axon terminals is postulated.

Topics: 2,2'-Dipyridyl; Animals; Cysteamine; Disulfiram; Ditiocarb; Edetic Acid; Male; Neuromuscular Diseases; Penicillamine; Pyridines; Rats; Thiourea; Tissue Distribution

Urinary excretion of porphyrin precursors delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) and total porphyrins was measured during intoxication of rats with 2,4-dithiobiuret (DTB), a chemical which produces delayed-onset neuromuscular weakness, in an attempt to ascertain whether or not DTB poisoning in the rat would serve as an animal model of the neurologic symptoms of acute intermittent porphyria. Daily administration of DTB (1 mg/kg/day, i.p.) produced flaccid skeletal muscle weakness first detected after 4 to 5 days of treatment. Onset of skeletal muscle weakness was associated with a significant increase in urinary excretion of ALA. The excretion of PBG and total porphyrin was also increased; however, the increase was not significant. The increase in porphyrins and porphyrin precursors was due to increased urine output which coincided with the onset of neuromuscular weakness; urinary concentrations of ALA, PBG, and porphyrins were not increased by DTB. Measurements of free-erythrocyte protoporphyrin, taken after 7 days of DTB treatment, indicated a significant elevation of free erythrocyte protoporphyrin concentration. The pattern of alterations in the heme precursors associated with DTB-induced paralysis in rats is quite different from that observed in humans afflicted with acute intermittent porphyria. Therefore, we conclude that DTB-induced paralysis in the rat does not represent an accurate animal model of acute intermittent porphyria.

Topics: Aminolevulinic Acid; Animals; Disease Models, Animal; Levulinic Acids; Male; Muscle Hypotonia; Neuromuscular Diseases; Paralysis; Porphobilinogen; Porphyrias; Porphyrins; Rats; Thiourea; Time Factors

Chronic treatment of rats with dithiobiuret (DTB) produces a delayed onset muscle weakness and, as suggested by a preliminary study, a distal axonopathy. An inhibition of glycolysis resulting in an energy deficit has been suggested as a possible mechanism of neurotoxin-induced distal axonopathies. To determine whether chronic DTB administration (1 mg/kg/day X 7 days; sacrificed on Day 7) might be associated with a perturbation of glucose metabolism in neuronal tissues, lactate production was measured in brain and spinal cord homogenates prepared from rats which exhibited hindlimb skeletal muscle weakness. Kinetic and statistical analysis showed that glucose-dependent lactate production in these homogenates was not different from that of controls. Lactate production was also determined in brain homogenates prepared from rats intoxicated with acrylamide (50 mg/kg/day X 9 days; sacrificed on Day 9), p-bromophenylacetylurea (200 mg/kg/day X 2 days; sacrificed on Day 14) or 2,5-hexanedione (400 mg/kg/day X 21 days; sacrificed on Day 21). The results indicated that whereas 2,5-hexanedione produced a slight decrease in Vmax, acrylamide and p-bromophenylacetylurea did not cause changes in glucose-dependent lactate production. These findings do not support the suggestion that an inhibition of glycolysis represents a common biochemical lesion associated with neurotoxins which cause delayed onset muscle weakness and distal axonopathy.

Topics: Acrylamide; Acrylamides; Animals; Central Nervous System; Glucose; Glycolysis; Hexanones; In Vitro Techniques; Kinetics; Lactates; Lactic Acid; Male; Neuromuscular Diseases; Rats; Rats, Inbred Strains; Thiourea; Urea

Daily dosing with 1-3 mg/kg dithiobiuret for 4-5 days causes progressive, generalised muscle weakness which is fatal in about 50% of cases on day 4 or 5. Survivors recover mobility by day 7 and appear normal, although still weak. Striking changes in the motor nerves and motor end plates can be observed before and during the development of this weakness, using the zinc iodide-osmium staining technique. The terminal internodes of intramuscular axons become densely stained: later this may extend back into the main intramuscular (i.m.) nerves, and is often followed by axonal degeneration. Many motor end plates lose their branching form and become globular, and profuse terminal sprouting develops before any nerve degeneration appears. Following axonal degeneration, collateral sprouting becomes prominent, and, within four weeks of beginning the dose regime, restores the normal appearance of the innervation. This pattern of response was observed clearly in the whole mounts of the sternocostalis muscle: similar but less marked changes occurred in the lumbrical muscles, while in the soleus and tibialis anterior muscles, loss of end plates seemed to be a more common response. Despite marked differences in the severity of the functional disability, the i.m. changes were similar in juvenile and adult rats. These changes are related to previous electrophysiological findings on the possible mechanism of action of dithiobiuret.

Topics: Animals; Female; Hindlimb; Neuromuscular Diseases; Neuromuscular Junction; Rats; Rats, Inbred Strains; Thiourea

Topics: Age Factors; Animals; Cholinesterases; Female; Lethal Dose 50; Male; Neuromuscular Diseases; Neuromuscular Junction; Rats; Sex Factors; Thiourea