Experimental demyelinating optic neuropathy: A model for combined morphological and electrophysiological studies

A model is described for the morphological and electrophysiological study of demyelinative optic neuropathy in the rat. Cortical visual evoked potentials (VEPs) to flash stimuli were recorded before and after the intraneural microinjection of lysophosphatidyl choline (LPC) and galacto-cerebroside (Gal-C) antiserum. Progress was monitored by calculating the interocular latency differences (ILD) for the N40 and P60 components of the rat VEP, thus allowing a longitudinal evaluation of optic nerve function. Histological examination of the visual pathway using light and electron microscopy was performed at intervals through the course of the study. LPC produced a less selective lesion than did Gal-C antiserum. In lesions induced by the latter there was relatively little accompanying anoxal degeneration and subsequent remyelination was prominent. Control serum did not result in demyelination. This model should permit accurate electrophysiological and morphological correlations to be made during the developing and the reparative phases of demyelinative optic neuropathy and the assessment of potential therapeutic manoeuvres

Spinal cord lesions induced by antigalactocerebroside serum

The spinal cord lesions induced by micro-injection of high titre anti-galactocerebroside serum (anti-GC) into the dorsal columns of the rat were studied by light and electron microscopy. The lesions typically comprised a central zone of Wallerian-type degeneration surrounded by pockets of primary demyelination. Both oligodendrocytes and astrocytes were reduced in the lesions. Demyelination also occurred in the dorsal roots. Evidence of remyelination by oligodendrocytes and by Schwann cells was found in the 10 to 12 day cord lesions. The dorsal column lesions differ from the optic nerve lesions induced by anti-GC which are almost exclusively demyelinative, and in which astrocytes are largely spared and remyelination is more prominent

Reactive glial cells in CNS demyelination contain both GC and GFAP

The glial cell response to anti-galactocerebroside (GC) induced demyelination of the cat optic nerve was studied using electron microscopy and immunocytochemistry. Oligodendrocytes, which are a primary target for anti-GC, were depleted in the early lesions but astrocytes survived and showed reactive changes. Astrocytic processes exhibited dual staining for both GC and glialfibrillary acidic protein, a feature not seen in astrocytes outside the lesion or in normal optic nerve. These reactive astrocytes did not stain for anti-myelin basic protein, nor did they contain myelin debris, making it unlikely that the GC immunoreactivity was due to phagocytosis of myelin. Rather, it is postulated that the presence of GC in these cells represents a process of dedifferentiation to a more primitive state in which both astrocytic and oligodendrocytic determinants are synthesized, and that these reactive glial cells may be precursors of a new population of remyelinating oligodendrocytes

The origin of remyelinating oligodendrocytes in antiserum-mediated demtelinative optic neuropathy

The origin of the remyelinating oligodendrocyte in a focal antigalactocerebroside-induced demyelinating lesion of the cat optic nerve was studied with detailed correlative electron microscopy and immunocytochemistry using a panel of antigenic makers. Within 10 days of the destruction of all endogenous oligodendrocytes and demyelination of all axons in the lesion, a new population of small glial cells appeared coincident with division of the residual astrocytes and developed a process-bearing axon-embracing morphology. The processes of these small glial cells (SGCs) contained intermediate filaments composed not of glial fibrillary acidic protein but of vimentin and over the ensuing 14 days these cells confirmed their oligodendrocyte destiny by differentiating to lose the intermediate filaments, form myelin and acquire the typical oligodendrocyte antigenic phenotype. It is suggested that the extensive remyelination of this lesion is sponsored by the new population of SGCs which in turn are generated either by differentiated reactive astrocytes or by as yet unidentified precursor cells

Galactocerebroside antiserum causes demyelination of cat optic nerve

A model of immune-mediated optic nerve demyelination is described. Micro-injection of small volumes (< 5 μl) of high titer polyclonal anti-Gal-C serum into the cat optic nerve resulted in a focal, highly selective demyelinative lesion followed by remyelination. Demyelination appears to be due to a dual effect of myelin and on oligadendrocytes. The numbers of these cels within the lesion were initially reduced but subsequently increased as remyelination occured

Experimental demyelinating optic neuropathy induced by intra-neural injection of galactocerebroside antiserum

The morphological changes induced by microinjection of galactocerebroside (Gal-C) antiserum into the rat optic nerve are described. Light and electron microscopic observations were made 2 – 20 days post-injection. The severity and extent of the lesion varied according to the volume of antiserum injected and the depth of penetration into the nerve. With small volumes of antiserum (1–3 μl), primary demyelination was the principal change found from 2 days onwards and by 10 days there was evidence of remyelination by oligodendroglia. Some fibres undergoing Wallerian-type degeneration were also found. The injection of larger volumes of antiserum (5–10 μl) produced a more extensive lesion with marked axonal degeneration in addition to demyelination at the periphery of the lesion. These findings show that Gal-C antiserum can cause demyelination of central nerve fibres when the blood-brain barrier is bypassed