epidermal-growth-factor and Vitamin-B-12-Deficiency

The pathogenesis of cobalamin (Cbl)-deficient (Cbl-D) neuropathy and the role of normal prions (PrPcs) in myelin maintenance are both subjects of debate. We have demonstrated that Cbl deficiency damages myelin by increasing tumor necrosis factor (TNF)-α, and decreasing epidermal growth factor (EGF) levels in the rat central nervous system (CNS). It is known that TNF-α and EGF regulate PrPc expression in vitro, and that myelin vacuolation, reactive astrocytosis and microglial activation are common to rat Cbl-D neuropathy and some prion diseases. We have shown that Cbl deficiency leads to high levels of PrPcs [particularly the octapeptide repeat (OR) domains] in the rat CNS thereby damaging the spinal cord (SC) myelin, and that chronic intra-cerebroventricular treatment with anti-OR antibodies normalizes SC myelin morphology. We have also found that PrPc levels are increased in the SC of Cbl-D rats by the time the myelin lesions appear, and that this increase is mediated by excess myelinotoxic TNF-α and prevented by EGF treatment, which has proved to be as effective as Cbl in preventing Cbl deficiency-induced lesions. Cbl stimulates PrPc mRNA-related synthesis in Cbl-D SC and duodenum, two rat tissues that are severely affected by Cbl deficiency. New PrPc synthesis is a common effect of various myelinotrophic agents, two of which (EGF and anti-TNF-α antibodies) also stimulate PrPc mRNA-related synthesis in the SC of Cbl-D rats.

Topics: Animals; Central Nervous System; Copper; Epidermal Growth Factor; Prions; Rats; Spinal Cord; Tumor Necrosis Factor-alpha; Vitamin B 12; Vitamin B 12 Deficiency

Subacute combined degeneration (SCD) is a neuropathy due to cobalamin (Cbl) (vitamin B(12)) deficiency acquired in adult age. Hitherto, the theories advanced to explain the pathogenesis of SCD have postulated a causal relationship between SCD lesions and the impairment of either or both of two Cbl-dependent reactions. We have identified a new experimental model, the totally gastrectomized rat, to reproduce the key morphological features of the disease [spongy vacuolation, intramyelinic and interstitial edema of the white matter of the central nervous system (CNS), and astrogliosis], and found new mechanisms responsible for the pathogenesis of SCD: the neuropathological lesions in TGX rats are not only due to mere vitamin withdrawal but also to the overproduction of the myelinolytic tumor necrosis factor (TNF)-alpha and the reduced synthesis of the two neurotrophic agents, epidermal growth factor (EGF) and interleukin-6. This deregulation of the balance between TNF-alpha and EGF synthesis induced by Cbl deficiency has been verified in the sera of patients with pernicious anemia (but not in those with iron-deficient anemia), and in the cerebrospinal fluid (CSF) of SCD patients. These new functions are not linked to the coenzyme functions of the vitamin, but it is still unknown whether they involve genetic or epigenetic mechanisms. Low Cbl levels have also been repeatedly observed in the sera and/or CSF of patients with Alzheimer's disease or multiple sclerosis, but whether Cbl deficit plays a role in the pathogenesis of these diseases is still unclear.

Topics: Animals; Disease Models, Animal; Epidermal Growth Factor; Gastrectomy; Humans; Interleukin-6; Models, Biological; Nerve Degeneration; Rats; Tumor Necrosis Factor-alpha; Vitamin B 12; Vitamin B 12 Deficiency

Vitamin B12 deficiency was recently shown to be associated with elevated levels of tumor necrosis factor-alpha and decreased levels of epidermal growth factor in both rats and humans. These findings suggest a novel pathogenetic mechanism underlying the neuropathology of vitamin B12 deficiency. They may also explain putative relationships between vitamin B12 deficiency and certain disorders, including Alzheimer's disease, rheumatoid arthritis, and AIDS.

Topics: Acquired Immunodeficiency Syndrome; Alzheimer Disease; Animals; Antineoplastic Agents; Arthritis, Rheumatoid; Epidermal Growth Factor; Humans; Rats; Tumor Necrosis Factor-alpha; Vitamin B 12 Deficiency

We investigated the effect of cobalamin (Cbl) deficiency on epidermal growth factor receptor (EGFR) mRNA levels in the spinal cord (SC) and liver of rats made Cbl-deficient (Cbl-D) by means of total gastrectomy or a Cbl-D diet, and simultaneously measured the levels of the epidermal growth factor (EGF). Both methods of inducing Cbl deficiency decreased EGFR expression in the SC and liver. Cbl replacement treatment normalized or nearly so most of the abnormalities in EGFR expression in the totally gastrectomized (TGX) rats at different times. The EGFR-immunostaining intensity decreased in the SC white matter of the Cbl-D rats and significantly increased in that of the TGX, Cbl-treated rats. EGF levels significantly increased in liver of TGX rats and in SC of 4-month TGX rats, and the increases returned to almost normal levels after a postoperative 2-month administration of Cbl to TGX rats. These findings demonstrate that Cbl deficiency dysregulates the EGFR-EGF dyad in these tissues.

Topics: Animals; Epidermal Growth Factor; ErbB Receptors; Gastrectomy; Immunohistochemistry; Liver; Male; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Spinal Cord; Vitamin B 12; Vitamin B 12 Deficiency

Cobalamin-deficient (Cbl-D) central neuropathy in the rat is associated with a locally increased expression of neurotoxic tumour necrosis factor-alpha (TNF-alpha) and a locally decreased expression of neurotrophic epidermal growth factor (EGF). These recent findings suggest that cobalamin oppositely regulates the expression of TNF-alpha and EGF, and raise the possibility that these effects might be independent of its coenzyme function. Furthermore, adult Cbl-D patients have high levels of TNF-alpha and low levels of EGF in the serum and cerebrospinal fluid. Serum levels of TNF-alpha and EGF of cobalamin-treated patients normalize concomitantly with haematological disease remission. These observations suggest that cobalamin deficiency induces an imbalance in TNF-alpha and EGF levels in biological fluids that might have a role in the pathogenesis of the damage caused by pernicious anaemia.

Topics: Anemia, Pernicious; Animals; Central Nervous System; Disease Models, Animal; Epidermal Growth Factor; Gastrectomy; Humans; Nerve Degeneration; Nerve Growth Factor; Rats; Tumor Necrosis Factor-alpha; Vitamin B 12; Vitamin B 12 Deficiency

We have previously demonstrated that the repeated intracerebroventricular (i.c.v.) microinjection of interleukin-6 (IL-6) prevented the myelinolytic lesions of cobalamin-deficient (Cbl-D) central neuropathy [or subacute combined degeneration (SCD)] in totally gastrectomized (TGX) rats. We therefore hypothesized that cobalamin (Cbl) may actually regulate IL-6 levels in rat cerebrospinal fluid (CSF). We measured IL-6 levels in the CSF of rats made Cbl-D by means of total gastrectomy (TG) or chronic feeding with a Cbl-D diet and killed at different times from the beginning of the experiment, and found that IL-6 levels significantly and progressively decreased over time. Chronic 2-month Cbl administration started 1 week after surgery prevented the decrease in IL-6 levels and, when it was started 2 months after surgery, it significantly increased IL-6 levels, but not to presurgical values. We also investigated whether IL-6 decrease might be ultimately due to the Cbl-deficiency-linked decrease in epidermal growth factor (EGF) synthesis. Repeated i.c.v. administrations of EGF to TGX rats did not modify CSF IL-6 levels. These results, together with those of a previous study showing the preventive effect of IL-6 treatment on SCD lesions, demonstrate that: (i) Cbl selectively regulates CSF IL-6 levels; and (ii) decreased IL-6 availability plays a role in the pathogenesis of the experimental SCD, in which no evidence of inflammatory and/or immunological reaction has been observed.

Topics: Animals; Epidermal Growth Factor; Gastrectomy; Injections, Intraventricular; Injections, Subcutaneous; Interleukin-6; Leptin; Male; Rats; Rats, Sprague-Dawley; Vitamin B 12; Vitamin B 12 Deficiency

We have previously demonstrated that vitamin B12 (cobalamin)-deficient central neuropathy in the rat is associated with local overexpression of neurotoxic tumour necrosis factor (TNF)-alpha combined with locally decreased synthesis of neurotrophic epidermal growth factor (EGF). The aims of this study were to investigate whether a similar imbalance also occurs in the serum of adult patients with clinically confirmed cobalamin deficiency and whether it can be corrected by vitamin B12 replacement therapy.. We studied 34 adult patients with severe cobalamin deficiency, 12 patients with pure iron deficiency anaemia and 34 control subjects. Haematological markers of cobalamin deficiency and serum TNF-alpha and EGF levels were measured using commercial kits. Thirteen cobalamin-deficient patients were re-evaluated after 3 and 6 months of parenteral vitamin B12 treatment.. TNF-alpha was significantly higher (p < 0.01) and EGF significantly lower (p < 0.01) in the patients with cobalamin deficiency, but both were unchanged in patients with pure iron deficiency anaemia. In cobalamin-deficient patients the serum TNF-alpha levels correlated significantly with plasma total homocysteine levels (r = 0.425; p < 0.02). In the treated patients TNF-alpha and EGF levels normalised concomitantly with clinical and haematological disease remission.. In humans, as in rats, cobalamin concentration appears to be correlated with the synthesis and release of TNF-alpha and EGF in a reciprocal manner, because cobalamin deficiency is accompanied by overproduction of TNF-alpha and underproduction of EGF.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Hypochromic; Anemia, Megaloblastic; Animals; Bone Marrow; Epidermal Growth Factor; Female; Folic Acid; Follow-Up Studies; Gastritis, Atrophic; Homocysteine; Humans; Iron; Iron Deficiencies; Male; Middle Aged; Peripheral Nervous System Diseases; Rats; Species Specificity; Tumor Necrosis Factor-alpha; Vitamin B 12; Vitamin B 12 Deficiency

In order to get further evidence for a mandatory involvement of epidermal growth factor (EGF) in the neutrophic action of vitamin B12 (cobalamin (Cbl)) in the central nervous system (CNS) of the rat, we observed the effects of repeated intracerebroventricular (ICV) microinjections of EGF in rats made Cbl-deficient through total gastrectomy. Morphometric analysis demonstrated a significant reduction in both intramyelinic and interstitial edema in the white matter of the spinal cord (SC) of totally gastrectomized (TGX) rats after treatment. Intramyelinic and interstitial edema are characteristic of Cbl-deficient central neuropathy in the rat. Similar lesions were also present in SC white matter of rats treated with repeated ICV microinjections of specific anti-EGF antibodies without any modification in their Cbl status. These results, together with those of a previous study showing the cessation of EGF synthesis in the CNS of TGX rats, demonstrate that: a) EGF is necessarily involved in the signaling pathway of Cbl in the rat CNS; and b) the lack of a neurotrophic growth factor EGF, and not the mere withdrawal of Cbl, causes or at least contributes to neurodegenerative Cbl-deficient central neuropathy.

Topics: Animals; Antibodies, Monoclonal; Cerebral Ventricles; Edema; Epidermal Growth Factor; Gastrectomy; Humans; Injections, Intraventricular; Male; Nerve Fibers, Myelinated; Rats; Rats, Sprague-Dawley; Signal Transduction; Spinal Cord; Vitamin B 12; Vitamin B 12 Deficiency

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.

Topics: Animals; Autoradiography; Brain; Epidermal Growth Factor; Gastrectomy; Gene Expression Regulation; Male; Nerve Growth Factors; Rats; Rats, Sprague-Dawley; RNA, Messenger; Spinal Cord; Tumor Necrosis Factor-alpha; Vitamin B 12; Vitamin B 12 Deficiency