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Myelinolytic lesions in spinal cord of cobalamin-deficient rats are TNF--mediated

^a Institutes of General Pathology,

^b Human Anatomy,

^c Biometrics and Medical Statistics,

^d 2nd Department of Neurology, Faculty of Medicine, University of Milan, Milano, Italy; and

^e Gife Laboratory, Lugano, Switzerland

Repeated intracerebroventricular (i.c.v.)microinjection of tumor necrosis factor- (TNF-) into normal rats causes intramyelin and interstitial edema in the white matter of the spinal cord (SC). This response is identical to that observed in the SC white matter of rats made cobalamin (Cbl) deficient by total gastrectomy (TG). Immunoblot analysis showed that: 1) the level of the biologically active form of the TNF- protein (17 kDa) is higher in the SC of totally gastrectomized (TGX) rats 2 months after TG, i.e., at the postoperative time when edema is observed; 2) SC levels of TNF- protein (17 kDa) in 2-mo-TGX-, Cbl-treated rats are reduced to control. Repeated i.c.v. microinjections of anti-TNF- antibodies, transforming growth factor-ß₁ (TGF-ß₁) or interleukin-6 (IL-6) into TGX rats, begun shortly after TG, substantially reduced both intramyelin and interstitial edema in the SC white matter. This study provides the first evidence that the hallmark myelin damage of Cbl-deficient central neuropathy, which is a pure myelinolytic disease, is not caused directly by the withdrawal of the vitamin itself, but reflects enhanced production of the biologically active form of TNF- by SC cells. This study thus supports the view that TGF-ß₁ and IL-6 may act as neuroprotective agents in Cbl deficiency central neuropathy.—Buccellato, F. R., Miloso, M., Braga, M., Nicolini, G., Morabito, A., Pravettoni, G., Tredici, G., Scalabrino, G. Myelinolytic lesions in spinal cord of cobalamin-deficient rats are TNF--mediated.

Key Words: myelinolysis • subacute combined degeneration • tumor necrosis factor

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