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Abstract
Glial cells, myelin and the interstitium are the structures of the mammalian central
nervous system (CNS) mainly affected by vitamin B(12) (cobalamin, Cbl) deficiency.
Most of the response to the damage caused by Cbl deficiency seems to come from astrocytes
and microglia, and is manifested as an increase in the number of cells positive for
glial fibrillary acidic protein, the presence of ultrastructural signs of activation,
and changes in cytokine and growth factor production and secretion. Myelin damage
particularly affects the lamellae, which are disorganized by edema, as is the interstitium.
Surprisingly, rat Schwann cells (myelin-forming cells of the peripheral nervous system)
are fully activated but the few oligodendrocytes (myelin-forming cells of the CNS)
are scarcely activated. The presence of intramyelin and interstitial edema raises
questions about the integrity of the blood-brain barrier and blood-cerebrospinal fluid
(CSF) barrier. The results obtained in the CNS of Cbl-deficient rats indicate that
cytokine and growth factor imbalance is a key point in the pathogenesis of Cbl-deficient
neuropathy. In the rat, Cbl deficiency increases the spinal cord (SC) synthesis and
CSF levels of myelinotoxic cytokines (tumor necrosis factor (TNF)-alpha and soluble
(s) CD40:sCD40 ligand dyad) and a myelinotoxic growth factor (nerve growth factor),
but decreases SC synthesis and CSF levels of a myelinotrophic cytokine (interleukin-6)
and a myelinotrophic growth factor (epidermal growth factor, EGF). The in vivo administration
of IL-6 or EGF, or agents antagonizing the excess myelinotoxic agent, is as effective
as Cbl in repairing or preventing Cbl-deficiency-induced CNS lesions. An imbalance
in TNF-alpha and EGF levels has also been found in the CSF and serum of patients with
severe Cbl deficiency.