Over the last few years we have reproduced all of the key morphological and biochemical features of human
subacute combined degeneration in the central nervous system and peripheral nervous system of rats made
cobalamin-deficient by means of total
gastrectomy or a chronic
cobalamin-deficient diet. We have also recently clarified the pathogenesis of experimental
subacute combined degeneration induced in the rat by
cobalamin deprivation. The results of our studies strongly support the notion that
cobalamin plays a pivotal role in regulating the balance of the network of
cytokines and
growth factors in the central nervous system of the rat. We have demonstrated that
cobalamin tightly regulates the central nervous system synthesis and/or the cerebrospinal fluid level of two
cytokines,
tumor necrosis factor-alpha and
interleukin-6, and a
growth factor, epidermal growth factor. Of these neuroactive agents, one,
tumor necrosis factor-alpha, is neurotoxic, whereas the others are neurotrophic. Therefore, it becomes clear that
cobalamin-deficient central neuropathy is caused not by the withdrawal of the
vitamin, but reflects a locally increased production of neurotoxic agents, combined with the locally decreased production of neurotrophic agents.