Extensive injury of descending neurons demonstrated by retrograde labeling in a virus-induced murine model of chronic inflammatory demyelination.

Persistent Theiler's virus infection of SJL/J mice was used as a model to quantitatively assess the extent of descending neuron injury by chronic inflammatory demyelination of the spinal cord. By 9 months postinfection, inflammatory demyelinating lesions were present throughout the spinal cord, affecting up to 31% of the cross-sectional area of the ventrolateral columns. Axon dropout was evident in the lesions by electron microscopy and by quantitation of axons in normal-appearing white matter. Axon number in the ventrolateral columns at L1/L2 was reduced by 23% and total axon area was reduced by 37%, compared with uninfected mice. The most informative data on descending neuron injury, however, was a reduction in retrograde. Fluoro-Gold labeling. Labeling from T11/T12 of rubrospinal, reticulospinal/raphespinal, and vestibulospinal neurons was reduced by 60%, 70%, and 93%, respectively. Retrograde responses to axonal injury were observed, consisting of atrophied cell bodies, indented nuclei, and abundant lipofuscin, but cell body dropout was minimal. The number of cell bodies of vestibulospinal neurons was reduced by only 35%, whereas the number of cell bodies of rubrospinal neurons was unchanged. These results demonstrate that chronic inflammatory demyelination can severely injure axons and emphasize the need to design neuroprotective therapies in human multiple sclerosis.