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

Repeated intracerebroventricular (i.c.v.) microinjection of tumor necrosis factor-alpha (TNF-alpha) into normal rats causes intramyelin and interstiti al edema in the white matter of the spinal cord (SC). This response is iden tical to that observed in the SC white matter of rats made cobalamin (Cbl) deficient by total gastrectomy (TG). Immunoblot analysis showed that: 1) th e level of the biologically active form of the TNF-alpha protein (17 kDa) i s 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 -alpha protein (17 kDa) in 2-mo-TGX-, Cbl-treated rats are reduced to contr ol. Repeated i.c.v. microinjections of anti-TNF-alpha antibodies, transform ing growth factor-beta(1) (TGF-beta(1)) or interleukin-6 (IL-6) into TGX ra ts, begun shortly after TG, substantially reduced both intramyelin and inte rstitial edema in the SC white matter. This study provides the first eviden ce that the hallmark myelin damage of Cbl-deficient central neuropathy, whi ch is a pure myelinolytic disease, is not caused directly by the withdrawal of the vitamin itself, but reflects enhanced production of the biologicall y active form of TNF-alpha by SC cells. This study thus supports the view t hat TGF-beta(1) and IL-6 may act as neuroprotective agents in Cbl deficienc y central neuropathy.