Epidermal growth factor as a local mediator of the neurotrophic action of vitamin B ₁₂ (cobalamin) in the rat central nervous system

Abstract

We have recently demonstrated that the myelinolytic lesions in the spinal cord (SC) of rats made deficient in vitamin B(12) (cobalamin) (Cbl) through total gastrectomy (TG) are tumor necrosis factor-alpha (TNF-alpha)-mediated. We investigate whether or not permanent Cbl deficiency, induced in the rat either through TG or by chronic feeding of a Cbl-deficient diet, might modify the levels of three physiological neurotrophic factors-epidermal growth factor (EGF), vasoactive intestinal peptide (VIP), and somatostatin (SS)-in the cerebrospinal fluid (CSF) of these rats. We also investigated the ability of the central nervous system (CNS) in these Cbl-deficient rats to synthesize EGF mRNA and of the SC to take up labeled Cbl in vivo. Cbl-deficient rats, however the vitamin deficiency is induced, show a selective decrease in EGF CSF levels and an absence of EGF mRNA in neurons and glia in various CNS areas. In contrast, radiolabeled Cbl is almost exclusively taken up by the SC white matter, but to a much higher degree in totally gastrectomized (TGX) rats. Chronic administration of Cbl to TGX rats restores to normal both the EGF CSF level and EGF mRNA expression in the various CNS areas examined. This in vivo study presents the first evidence that the neurotrophic action of Cbl in the CNS of TGX rats is mediated by stimulation of the EGF synthesis in the CNS itself. It thus appears that Cbl inversely regulates the expression of EGF and TNF-alpha genes in the CNS of TGX rats.

Plasma levels of vitamin B12, epidermal growth factor and tumor necrosis factor alpha in patients with alzheimer dementia

“…35,36 We found similar results in AD patients with lower plasma Vit B 12 and EGF levels and higher plasma TNF- levels than the controls. Vit B 12 was reported to down regulate the expression of TNF- and EGF genes in addition to its hormone-like and coenzyme functions in the central nervous system.…”

“…Vit B 12 was reported to down regulate the expression of TNF- and EGF genes in addition to its hormone-like and coenzyme functions in the central nervous system. 36 Studies suggested that Vit B 12 was an essential factor for the signaling pathway of the central nervous system of rats and that VitB 12 deficiency with the absence of EGF which is a neurotropic factor, was associated with central neuropathy. 37 Vit B 12 replacement normalized the EGF levels in the CSF and EGF m-RNA expression in various areas of the central nervous system in rats that underwent total gastrectomy.…”

“…The findings of this in vivo study showed that the neurotropic function of Vit B 12 mediated the stimulation of EGF synthesis in the cerebrospinal fluid (CSF) of gastrectomized rats. 36 Unbalanced production and expression of central nervous system cytokines including TNF- results with neurodegeneration. 38 TNF- and EGF levels are reciprocal in humans with Vit B 12 deficiency similar to that in rats; high production of TNF- causes decreased production of EGF.…”

High tumor necrosis factor‐α in levels in cerebrospinal fluid of cobalamin‐deficient patients

“…3 We recently have identified a potential mechanism by which chronic Cbl deficiency causes SCD in rats: the locally increased production of a myelinolytic agent (tumor necrosis factor [TNF]-␣) 5 combined with the locally decreased production of the neurotrophic agent epidermal growth factor (EGF). 6 Even more importantly, we also have found that the same imbalance in TNF-␣ and EGF levels occurs in the serum of humans with clinically confirmed severe Cbl deficiency (but not in patients with pure irondeficiency anemia) and can be corrected when the severe Cbl deficiency is corrected by Cbl therapy. 7 These results prompted us to verify whether the imbalance in TNF-␣ and EGF levels in favor of the former also occurs in the cerebrospinal fluid (CSF) of patients with SCD.…”

Abnormal expression of epidermal growth factor and its receptor in the forebrain and serum of schizophrenic patients

“…8 In contrast, there are relatively low levels of EGF mRNA expression in the brain. 9 EGF receptors (EGFR) are widely present in both the developing and mature central nervous system (CNS). [10][11][12] EGF and structurally related peptides have been studied extensively with respect to the growth and survival of midbrain dopaminergic neurons.…”