myelin-basic-protein and Diabetic-Neuropathies

Diabetic peripheral neuropathy (DPN) is one of the downstream complications of diabetes. This complication is caused by the deficiency of insulin action and subsequent hyperglycemia, but the details of their pathogenesis remain unclear. Hence, it is of critical importance to understand how such hormonal variation affects the expression of myelin proteins such as myelin basic protein (MBP) and myelin associated glycoprotein (MAG) in the peripheral nerve. An earlier report from our lab has demonstrated the expression of insulin receptors (IR) in Schwann cells (SCs) of sciatic nerve. To assess the neurotrophic role of insulin in diabetic neuropathy, we studied the expression of these myelin proteins under control, DPN and insulin treated DPN subjects at developmental stages. Further, the expression of these myelin proteins was correlated with the expression of insulin receptor. Expression of myelin proteins was significantly reduced in the diabetic model compared to normal, and upregulated in insulin treated diabetic rats. Similarly, an in vitro study was also carried out in SCs grown at high glucose and insulin treated conditions. The expression pattern of myelin proteins in SCs was comparable to that of in vivo samples. In addition, quantitative study of myelin genes by real time PCR has also showed the significant expression pattern change in the insulin treated and non-treated DPN subjects. Taken together, these results corroborate the critical importance of insulin as a neurotrophic factor in demyelinized neurons in diabetic neuropathy.

Topics: Animals; Diabetic Neuropathies; Glucose; Insulin; Male; Myelin Basic Protein; Myelin-Associated Glycoprotein; Rats; Rats, Wistar; Receptor, Insulin; RNA, Messenger; Schwann Cells; Sciatic Nerve

Tumor necrosis factor-α (TNF-α) is an important inflammatory factor produced by activated macrophages and monocytes and plays an important role in the pathogenesis of diabetic peripheral neuropathy (DPN). To evaluate the effect of TNF-α signaling suppression and the potential of TNF-α in the treatment of DPN, a recombinant human TNF-α receptor-antibody fusion protein (rhTNFR:Fc) was used. We focused on the pathophysiology of the sciatic nerve and examined the expression of myelin basic protein (MBP) under DPN status with or without TNF-α inhibition.. The DPN rat model was generated by intraperitoneal injection of streptozotocin and by feeding with a high-fat, high-sugar diet. The nerve conduction velocity (NCV) in sciatic nerve of rat was monitored over a period of four weeks. The histopathological changes in nerve tissue were examined through traditional tissue histology and ultrastructure transmission electron microscopy (TEM). The expression of MBP was examined through western blot analysis.. The DPN induced rats showed significant signs of nerve damage including lower NCV, demyelination of nerve fibers, disorganization of lamellar and axonal structures, and decreased expression of MBP in the nerve tissue. The inhibition of TNF-α in the DPN rats resulted in a significant recovery from those symptoms compared to the DPN rats.. Our study demonstrates that TNF-α plays a key role in the pathogenesis of DPN and its inhibition by rhTNFR:Fc can prove to be a useful therapeutic strategy for the treatment of and/or prevention from DPN symptoms.

Topics: Animals; Axons; Blotting, Western; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Humans; Immunohistochemistry; Male; Microscopy, Electron, Transmission; Motor Neurons; Myelin Basic Protein; Nerve Fibers; Neural Conduction; Peripheral Nervous System Diseases; Rats; Rats, Wistar; Receptors, Tumor Necrosis Factor, Type I; Recombinant Fusion Proteins; Sciatic Nerve; Sensory Receptor Cells; Tumor Necrosis Factor-alpha

Polyneuropathies are diffuse diseases of the peripheral nervous system. Pathological and anatomical investigations of the nerve fibres show that alterations of the peripheral axon and myelin are most significant at the distal end of the nerve fibres. Alcoholic polyneuropathy primarily affects the axon; during the chronic course of the disease, however, the myelin sheath is involved into the pathological process. Polyneuropathies are characterized by a deficiency and metabolic disturbance of the vitamins B1, B6 and B12. The vitamins of the B-group not only play an important role in the intermediate metabolism, but in paticular pathological situations high concentrations of the vitamins are necessary at a cellular and subcellular level. The experimental allergic neuritis (EAN) may be considered as a model of polyneuropathies characterized by disturbances of myelin metabolism. EAN was induced by the injection of human peripheral nerve homogenate the complete Freund's adjuvants. During EAN a marked reduction of phosphatidylinositol, sulfatides and serine-plasmalogen as well as a significant increase of phospholipase A2 activity could be observed.

Topics: Alcoholism; Animals; Avitaminosis; Axons; Diabetic Neuropathies; Humans; Lipid Metabolism; Myelin Basic Protein; Myelin Proteins; Myelin Sheath; Neuritis, Autoimmune, Experimental; Polyneuropathies; Polyradiculoneuropathy; Rabbits

Neuropathological evidence of demyelination was found in the brain and sciatic nerve of diabetic patients at autopsy. The activity of acid proteinase was somewhat increased in the white matter but decreased in the gray matter of diabetic patients. No increase was observed in the activity of neutral proteinase in diabetic white and gray matter. The activities of beta-glucuronidase and 2',3'-cyclic nucleotide-3'-phosphohydrolase (CNP) were of the same level as those of the controls. The activities of all 4 enzymes appeared to be increased in the diabetic nerve, with the possible exception of CNP which was measured from only 1 nerve. Furthermore, the amount of total protein was markedly decreased in diabetic peripheral myelin. The encephalitogenic basic protein of diabetic brain myelin was normal in the disc gel electrophoretic patterns of brain myelin proteins. However, the basic proteins of peripheral myelin were reduced in a number of diabetic patients. The present biochemical findings for diabetic white and gray matter were largely normal. Instead, the increased activities of at least the proteinases and beta-glucuronidase in diabetic peripheral nerve, together with the loss of basic proteins, indicate extensive biochemical damage of the peripheral nervous system in diabetes. They suggest that demyelination and other phenomena observed in diabetic peripheral nerve are not caused only by angiopathy and impaired circulation.

Topics: 2',3'-Cyclic-Nucleotide Phosphodiesterases; Adult; Aged; Brain; Demyelinating Diseases; Diabetic Neuropathies; Female; Glucuronidase; Humans; Male; Middle Aged; Myelin Basic Protein; Myelin Proteins; Nervous System; Peptide Hydrolases; Peripheral Nerves