Cervical MRI of subacute myelo-optico-neuropathy.

STUDY DESIGN: Case study. OBJECTIVES: Subacute myelo-optico-neuropathy (SMON) is a severe neuro-degenerative disorder caused by poisoning due to over-dose and prolonged oral administration of clioquinol; this disorder was more frequent during 1957-1970. It is characterized by axonal degeneration and gliosis in the cervical gracile fasciculus. Recently, copper-deficient myelo-neuropathies presenting similar symptoms (that is, painful dysesthesia/paresthesia in the lower limbs, ataxia, spastic paraplegia, autonomic disorders and visual impairment) were reported. Magnetic resonance imaging (MRI) of these patients detected T2-weighted hyperintensities in the cervical spinal cord. An unbalanced zinc-copper metabolism was suggested as one of the candidate pathogenesis of clioquinol toxicity because of its metal-chelating ability. The aim of this study was to present MRI findings of old SMON patients and to compare them with those of current copper-deficient myelo-neuropathies. SETTING: Japan. METHODS: We conducted and analyzed cervical and brain MRIs of seven old SMON patients who contracted the disorder during the 1960s. Serum iron, magnesium, copper, zinc and ceruloplasmin levels were also measured. RESULTS: Cervical T2-weighted MRIs showed mild volume loss and faint hyperintensities in the dorsal columns, which might reflect residual gliosis. Brain fast fluid-attenuated inversion-recovery images and tractography were normal. Current levels of serum copper and zinc were within almost normal ranges. CONCLUSION: Although fainter, the abnormal T2 MRI signals we observed were similar to and occurred in the same locations as those reported in copper-deficient myelo-neuropathy patients. We suggest that these findings are useful to study the mechanism of clioquinol toxicity before using it to treat neurodegenerative diseases such as Alzheimer's disease.

The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced hepatotoxicity in mice.

The liver-selective nitric oxide (NO) donor, O(2)-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO), is metabolized by P-450 enzymes to release NO in the liver, and is shown to protect the liver from tumor necrosis factor alpha (TNF-alpha)-induced apoptosis and D-glactosamine/endotoxin-induced hepatotoxicity. This study was undertaken to examine the effects of V-PYRRO/NO on acetaminophen-induced hepatotoxicity in mice. Mice were given V-PYRRO/NO via osmotic pumps (1.8-5.4 mg/mL, 8 microL/h) 4 to 16 hours before a hepatotoxic dose of acetaminophen (600 mg/kg, intraperitoneally [ip]). V-PYRRO/NO administration dramatically reduced acetaminophen-induced hepatotoxicity in a dose- and time-dependent manner, as evidenced by reduced serum alanine aminotransferase (ALT) activity, reduced hepatic congestion, apoptosis, and improved hepatocellular pathology. The protection afforded by V-PYRRO/NO does not appear to be caused by a decrease in the formation of toxic acetaminophen metabolites, which consumes glutathione (GSH), because V-PYRRO/NO did not alter acetaminophen-induced hepatic GSH depletion. Acetaminophen-induced lipid peroxidation, as determined by the concentrations of 4-hydroxyalkenals (4-HNE) and malondialdehyde (MDA), was reduced significantly by V-PYRRO/NO treatment. Although pretreatment was most effective, administration of V-PYRRO/NO simultaneously with acetaminophen also was able to reduce acetaminophen hepatotoxicity. Genomic analysis of the liver samples 10 hours after acetaminophen intoxication showed the enhanced expression of genes associated with stress/oxidative stress, apoptosis/cell death, and DNA damage/repair. Acetaminophen-induced alterations in gene expression were attenuated significantly by V-PYRRO/NO. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and Western-blot analysis confirmed microarray results. In conclusion, V-PYRRO/NO is effective in blocking acetaminophen-induced hepatotoxicity in mice. This protection may involve the reduction of oxidative stress, the inhibition of apoptosis, and possibly the maintenance of hepatic vasculature to prevent congestion.

Insulin-like growth factor-1 inhibits mature oligodendrocyte apoptosis during primary demyelination.

Metabolic insult results in apoptosis and depletion of mature oligodendrocytes during demyelination. To examine the role of insulin-like growth factor-1 (IGF-1) during acute demyelination and remyelination in the adult CNS, we exposed transgenic mice that continuously express IGF-1 (IGF-1 tg) to cuprizone intoxication. Demyelination was observed within the corpus callosum in both wild-type and IGF-1 tg mice 3 weeks after exposure to cuprizone. Wild-type mice showed significant apoptotic mature oligodendrocytes and a dramatic loss of these cells within the lesion that resulted in near complete depletion and demyelination by week 5. In contrast, the demyelinated corpus callosum of the IGF-1 tg mice was near full recovery by week 5. This rapid recovery was apparently caused by survival of the mature oligodendrocyte population because apoptosis was negligible, and by week 4, the mature oligodendrocyte population was completely restored. Furthermore, despite demyelination in both wild-type and IGF-1 tg mice, oligodendrocyte progenitors accumulated only in the absence of mature oligodendrocytes and failed to accumulate if the mature oligodendrocytes remained as demonstrated in the IGF-1 tg mice. These results suggest that IGF-1 may be important in preventing the depletion of mature oligodendrocytes in vivo and thus facilitates an early recovery from demyelination.

Death in sheep following dosing with copper diethylamine oxyquinoline sulphonate as a commercial injectable copper preparation.

Death occurred in sheep following diethylamine oxyquinoline sulphonate (DOS) copper injections given at recommended dose rates. The copper content in unused portions of DOS copper packs was normal and free of bacterial contamination. Liver and blood copper levels in dead and sick sheep were not high. Sick sheep showed signs of hepatic encephalopathy and dead sheep were generally piled against fences and scrub. Deaths were associated with acute, severe, generalised, centrilobular, hepatocellular necrosis and live sheep had elevated circulating levels of liver enzymes consistent with liver damage. In recovered sheep there were no residual complications. It would appear that even at 0.5 mg/kg of DOS copper the safety threshold may sometimes be exceeded in some sheep.