In vivo damage of CNS myelin and axons induced by peroxynitrite.

In multiple sclerosis (MS) the mechanisms of injury caused by peroxynitrite remain uncertain. To study histological, ultra structural and molecular alterations caused by peroxynitrite in brain, the peroxynitrite donor 3-morpholinosydnonimine was injected in rat corpus callosum. Peroxynitrite induces strong primary axonal damage with characteristics of primary acute axonopathy, together with severe myelin alteration, myelin vacuolation and demyelination, and nitrotyrosine formation as confirmed by detection of nitrosated target proteins. Administration of the peroxynitrite scavenger uric acid inhibited these effects. In vivo, peroxynitrite leads to a disorganisation of myelin and to axonal damage presenting some similarities to the formation of MS lesions. Understanding the action of peroxynitrite in this process will open new therapeutic strategies by specific inhibition of peroxynitrite formation and action.

In vivo evaluation of remyelination in rat brain by magnetization transfer imaging.

The aim of this work was to assess quantitatively and qualitatively the ability of magnetization transfer imaging to follow in vivo remyelination. Demyelination lesions were induced in rats by the injection of L-alpha-lysophosphatidylcholine stearoyl into the corpus callosum and imaging was performed in vivo on a 4.7-Tesla system at different time points. The percentage of magnetization transfer ratio (MTR) decrease was calculated for each animal. To evaluate the MTR findings for remyelination, myelin was quantitated by histological analysis of the lesion size and counting the number of remyelinating axons. An MTR decrease was observed when demyelination was present at 7 days after injection. During the remyelinating phase between day 30 and 40 after injection, contralateral values almost complete returned to normal, thus indicating remyelination. Histologically, at days 30 and 40 after injection, the lesion area was reduced in size and the axons were surrounded by a thin myelin sheath, indicating the remyelination process. Statistical analysis showed that the profile of MTR values was significantly correlated with the course of remyelination. All the MTR changes show a correlation with both myelin damage and repair. In conclusion, the study of the MTR profile in this myelin lesion model demonstrates in vivo the loss of myelin and the presence of spontaneous remyelination. This methodological approach which can also be applied to multiple sclerosis patients to show demyelination, should prove helpful to determine the degree of spontaneous and therapeutically induced remyelination in multiple sclerosis lesions, and thus to validate therapeutic treatments for myelin repair.