Remyelination of the CNS in multiple sclerosis is thought to be important to restore conduction and protect axons against degeneration. Yet the role that remyelination plays in clinical recovery of function remains unproven. Here, we show that cats fed an irradiated diet during gestation developed a severe neurologic disease resulting from extensive myelin vacuolation and subsequent demyelination. Despite the severe myelin degeneration, axons remained essentially intact. There was a prompt endogenous response by cells of the oligodendrocyte lineage to the demyelination, with remyelination occurring simultaneously. Cats that were returned to a normal diet recovered slowly so that by 3–4 months they were neurologically normal. Histological examination of the CNS at this point showed extensive remyelination that was especially notable in the optic nerve where almost the entire nerve was remyelinated. Biochemical analysis of the diet and tissues from affected cats showed no dietary deficiencies or toxic accumulations. Thus, although the etiology of this remarkable disease remains unknown, it shows unequivocally that where axons are preserved remyelination is the default pathway in the CNS in nonimmune-mediated demyelinating disease. Most importantly, it confirms the clinical relevance of remyelination and its ability to restore function.

Brief focal ischemia leading to temporary neurological deficits induces delayed hyperintensity on T1-weighted magnetic resonance imaging (MRI) in the striatum of humans and rats. The T1 hyperintensity may stem from biochemical alterations including manganese (Mn) accumulation after ischemia. To clarify the significance of this MRI modification, we investigated the changes in the dorsolateral striatum of rats from 4 hours through 16 weeks after a 15-minute period of middle cerebral artery occlusion (MCAO), for MRI changes, Mn concentration, neuronal number, reactivities of astrocytes and microglia/macrophages, mitochondrial Mn-superoxide dismutase (Mn-SOD), glutamine synthetase (GS), and amyloid precursor protein. The cognitive and behavioral studies were performed in patients and rats and compared with striatal T1 hyperintensity to show whether alteration in brain function correlated with MRI and histological changes. The T1-weighted MRI signal intensity of the dorsolateral striatum increased from 5 days to 4 weeks after 15-minute MCAO, and subsequently decreased until 16 weeks. The Mn concentration of the dorsolateral striatum increased after ischemia in concert with induction of Mn-SOD and GS in reactive astrocytes. The neuronal survival ratio in the dorsolateral striatum decreased significantly from 4 hours through 16 weeks, accompanied by extracellular amyloid precursor protein accumulation and chronic glial/inflammatory responses. The patients and rats with neuroradiological striatal degeneration had late-onset cognitive and/or behavioral declines after brief focal ischemia. This study suggests that (1) the hyperintensity on T1-weighted MRI after mild ischemia may involve tissue Mn accumulation accompanied by Mn-SOD and GS induction in reactive astrocytes, (2) the MRI changes correspond to striatal neurodegeneration with a chronic inflammatory response and signs of oxidative stress, and (3) the subjects with these MRI changes are at risk for showing a late impairment of brain function even though the transient ischemia is followed by total neurological recovery.

Abstract:We examined the effects of oxidative stress on rat cultured mesencephalic neurons and glial cells. Glial cells were more resistant to 6-hydroxydopamine (6-OHDA) and H 2 O 2 toxicity than neurons. In glial cells, incubation with 6-OHDA and H 2 O 2 induced a significant increase in the expression of ␥-glutamylcysteine synthetase (the rate-limiting enzyme in glutathione synthesis) mRNA, which correlated well with increased TPA-response element (TRE)-binding activity. Furthermore, a subsequent elevation in cellular total glutathione content was also observed. In neurons, both agents decreased TRE-binding activity, and these cells failed to up-regulate the glutathione synthesis. We also examined the mechanisms of the neuroprotective effects of glial cells using a glia conditioned medium. Neurons maintained in glia conditioned medium up-regulated the level of TRE-binding activity, ␥-glutamylcysteine synthetase mRNA expression, and total glutathione content in response to 6-OHDA or H 2 O 2 , and became more resistant to both agents than cells maintained in a normal medium. Neurons maintained in normal medium failed to up-regulate the glutathione synthesis. Our results suggest that transcriptional up-regulation of glutathione synthesis in glial cell appears to mediate brain glial cell resistance against oxidative stress, and that glial cells protect neurons via transcriptional up-regulation of the antioxidant system.

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Recent studies in rodents have demonstrated that diffusion imaging is highly sensitive to differences in myelination. These studies suggest that demyelination/dysmyelination cause increases in the radial diffusivity from diffusion tensor imaging (DTI) measurements and decreases in the restricted diffusion component from high b-value diffusion-weighted imaging experiments. In this study, the shaking pup (sh pup), a canine model of dysmyelination, was studied on a clinical MRI scanner using a combination of conventional diffusion tensor imaging and high b-value diffusion-weighted imaging methods. Diffusion measurements were compared between control dogs and sh pups in the age range 3 months to 16 months, which is similar to the period of early childhood through adolescence in humans. The study revealed significant group differences in nearly all diffusion measures with the largest differences in the zero-displacement probability (Po) from high b-value DWI and the radial diffusivity from DTI, which are consistent with the observations from the published rodent studies. Age-related changes in Po, FA, mean diffusivity, radial diffusivity and axial diffusivity were observed in whole brain white matter for the control dogs, but not the sh pups. Regionally, age-related changes in the sh pup white matter were observed for Po, mean diffusivity and radial diffusivity in the internal capsule, which may be indicative of mild myelination. These studies demonstrate that DWI may be used to study myelin abnormalities and brain development in large animal models on clinical MRI scanners, which are more amenable to translation to human studies.