Respiratory chain inhibition: one more feature to propose MPTP intoxication as a Leigh syndrome model.

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice have been widely used to model the loss of dopaminergic neurons. As this treatment leads to basal ganglia degeneration, it was proposed that MPTP mice could be used as a model of Leigh syndrome. However, this mitochondrial pathology is biochemically characterized by a respiratory chain dysfunction. To determine if MPTP can affect in vivo mitochondria function, we measured the activities of mitochondrial respiratory chain complexes in several tissues. Our results show that MPTP affects mainly mitochondrial respiratory chain complex IV, as found in Leigh Syndrome, confirming that acute MPTP intoxicated mice are a good model of Leigh Syndrome.

MPTP intoxication in mice: a useful model of Leigh syndrome to study mitochondrial diseases in childhood.

The basal ganglia, which are interconnected in the striato-nigral dopaminergic network, are affected in several childhood diseases including Leigh syndrome (LS). LS is the most common mitochondrial disorder affecting children and usually arise from inhibition of the respiratory chain. This vulnerability is attributed to a particular susceptibility to energetic stress, with mitochondrial inhibition as a common pathogenic pathway. In this study we developed a LS model for neuroprotection trials in mice by using the complex I inhibitor MPTP. We first verified that MPTP significantly inhibits the mitochondrial complex I in the brain (p = 0.018). This model also reproduced the biochemical and pathological features of LS: MPTP increased plasmatic lactate levels (p = 0.023) and triggered basal ganglia degeneration, as evaluated through dopamine transporter (DAT) autoradiography, tyrosine hydroxylase (TH) immunohistochemistry, and dopamine dosage. Striatal DAT levels were markedly decreased after MPTP treatment (p = 0.003). TH immunoreactivity was reduced in the striatum and substantia nigra (p = 0.005), and striatal dopamine was significantly reduced (p < 0.01). Taken together, these results confirm that acute MPTP intoxication in young mice provides a reproducible pharmacological paradigm of LS, thus opening new avenues for neuroprotection research.

[Transient subacute encephalopathy induced by high-dose methotrexate treatment in children with acute lymphoblastic leukemia and malignant lymphoma].

Transient subacute encephalopathy was detected in 4 of 83 patients undergoing treatment with high-dose methotrexate (HD-MTX) and citrovorum factor rescue for childhood acute lymphoblastic leukemia and malignant lymphoma from 1984 to 1991. Subacute encephalopathy occurred in relatively older patients and early in the course of treatment with HD-MTX. The average interval between the HD-MTX course and the onset of the neurologic disturbance was 6.5 days. All 4 patients treated had no neurological sequelae. Laboratory evaluations disclosed nontoxic plasma MTX levels at onset of symptom and not detected in liquor. CT in 4 patients disclosed no abnormality, but MR images revealed abnormal signal intensity patterns of cerebral white matter in 2 cases. In one case the abnormal MR finding resolved after 3 months. The pathogenesis of this neurologic symptom remains unknown, but further HD-MTX treatment may be acceptable in follow-up of MR image, because the prognosis of subacute encephalopathy seems favorable.