epidermal-growth-factor and Peripheral-Nervous-System-Diseases

The neuroprotective effect of epidermal growth factor (EGF) has been documented in different contexts, but its potential benefits in peripheral neuropathies have been little studied. We investigated the neuroprotective action of EGF in experimental neuropathy induced by acrylamide (ACR). Mice and rats were treated chronically with acrylamide for 6 and 8 weeks, respectively. Concurrently they received EGF in daily doses of 1 and 5 mg/kg in mice and 3 mg/kg in rats, or saline (PBS). ACR severely affected the neurological score, the muscle strength, and the muscle potential M, in mice, as well as F-waves (F-Wii), sensory potentials (SPii), and apomorphine-induced penile erection, in rats. EGF reduced the ACR effects in both species. A dose-dependent effect of EGF was manifested in the proportion of diseased animals at the end of treatments, as well as in the reduction of M amplitude throughout the treatment. F-Wii parameters were less protected by EGF than SP. The results show a protective effect of EGF in acrylamide-induced neuropathy and support previous studies concerning the neuroprotective action of this peptide.

Topics: Acrylamide; Action Potentials; Animals; Apomorphine; Disease Models, Animal; Dopamine Agonists; Electric Stimulation; Epidermal Growth Factor; Hand Strength; Male; Mice; Mice, Inbred C57BL; Neurologic Examination; Neuroprotective Agents; Penile Erection; Peripheral Nervous System Diseases; Rats; Rats, Wistar; Time Factors

In the mammalian nervous system, axons are commonly surrounded by myelin, a lipid-rich sheath that is essential for precise and rapid conduction of nerve impulses. In the peripheral nervous system (PNS), myelin sheaths are formed by Schwann cells which wrap around individual axons. While the tyrosine kinase receptors ERBB2 and ERBB3 are established mediators of peripheral myelination, less is known about the functions of the related epidermal growth factor receptor (EGFR) in the regulation of PNS myelination. Here, we report a peripheral neurodegenerative disease caused by increased EGFR activation. Specifically, we characterize a symmetric and distally pronounced, late-onset muscular atrophy in transgenic mice overexpressing the EGFR ligand epigen. Histological examination revealed a demyelinating neuropathy and axon degeneration, and molecular analysis of signaling pathways showed reduced protein kinase B (PKB, AKT) activation in the nerves of Epigen-tg mice, indicating that the muscular phenotype is secondary to PNS demyelination and axon degeneration. Crossing of Epigen-tg mice into an EGFR-deficient background revealed the pathology to be completely EGFR-dependent. This mouse line provides a new model for studying molecular events associated with early stages of peripheral neuropathies, an essential prerequisite for the development of successful therapeutic interventions.

Topics: Animals; Blotting, Western; Demyelinating Diseases; Epidermal Growth Factor; Epigen; ErbB Receptors; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscular Atrophy; Myelin Sheath; Peripheral Nervous System Diseases; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction

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