Extracellular Vesicles as Pro- and Anti-inflammatory Mediators, Biomarkers and Potential Therapeutic Agents in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of the central nervous system (CNS) characterized by multiple demyelinating lesions in the spinal cord and brain. Neuronal disruption caused by myelin loss or demyelination, which may accompany axonal changes, leads to multiple neurological symptoms. They may transiently appear for weeks during periods of disease worsening (relapse) in relapsing-remitting form of MS (RRMS). Although a number of genetic, metabolic and environmental factors influencing the development of MS have been identified, the precise mechanisms involved in the CNS tissue damage in MS are still poorly understood. Recent studies have revealed a significant role of circulating extracellular vesicles (EVs) in many diseases. EVs are known to serve as a cellular communication tool between two cell types either in close proximity or in different parts of the body. During the recent development in understanding of the pathogenesis of MS, studies have revealed the possible role of EVs in MS. Furthermore, circulating EVs can be used as a biomarker for monitoring disease progression and activity of MS, and they can also be therapeutic reagents or targets of therapy. In this review we overview and discuss in detail about generation of EVs and their diversified roles in MS.

The correlation between insulin and OCT-6 transcription factor in Schwann cells and sciatic nerve of diabetic rats.

Insulin signal is one of the vital signaling cascade required for Schwann cells to myelinate the axons of peripheral nervous system (PNS). Myelin formation of peripheral nerve is a complex molecular event controlled by different neurotrophic and transcription factors. The altered or failure in this signaling progression is one of the reasons behind the demyelination of peripheral neurons in diabetic peripheral neuropathy (DPN). The Schwann cell in PNS includes POU domain transcription factor OCT-6 expression. This factor is considered as crucial for the initiation and enhancement of myelination during nerve regeneration. To know the importance of OCT-6 gene, here we studied the long term expression of OCT-6 nuclear protein in sciatic nerve of normal and diabetic neuropathic rats. Also for the first time we elucidated the role of insulin in controlling the expression of OCT-6 in hyperglycemic Schwann cells and sciatic nerve of diabetic neuropathic rats. The results shows that, there will be long term OCT-6 expression in sciatic nerve of adult rats and also their significant decrease is observed in the diabetic condition. But, addition of Insulin for primary Schwann cells and diabetic rats shows the increased OCT-6 expression in both in vivo and in vitro. Together these results indicate the failure of OCT-6 support in neuropathy and also the importance of insulin signaling cascade in the expression of OCT-6 transcription factor.

Insulin-induced upregulation of lipoprotein lipase in Schwann cells during diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is one of the major complications associated with diabetes. It is characterized by the degeneration of the myelin sheath around axons, referred to as demyelination. Such demyelinations are often caused by reduced lipid component of the myelin sheath. Since, lipoprotein lipase (LPL) provides the lipid for myelin sheath by hydrolysing the triglyceride rich lipoproteins, and also helps in the uptake of lipids by the Schwann cells (SCs) for its utilization, LPL is considered as the important factor in the regeneration of myelin sheath during diabetic neuropathy. Earlier reports from our laboratory have provided the insights of insulin and its receptor in SCs during diabetic neuropathy. In order to evaluate the long term effect of insulin on lipid metabolism during diabetic neuropathy, in this study, we analyzed the expression of LPL in SCs under normal, high glucose and insulin treated conditions. A decrease in the expression of LPL was observed in SCs of high glucose condition and it was reversed upon insulin treatment. Histochemical observations of sciatic nerve of insulin treated neuropathy subjects showed the improved nerve morphology, signifying the importance of insulin in restoring the pathophysiology of diabetic neuropathy.

Altered expression of IRS2 and GRB2 in demyelination of peripheral neurons: Implications in diabetic neuropathy.

Demyelination of the peripheral nerves and dysfunction of Schwann cells (SCs) are the chronic complications involved in the development of peripheral neuropathy among diabetic patients. Insulin signaling plays an important role in restoring the myelin proteins in diabetic peripheral neuropathy (DPN). Since insulin levels are altered in diabetes, it becomes of great interest to appreciate the role and regulation of docking and adaptor protein, how these proteins respond to variations in the levels of insulin as experienced in juvenile diabetes. Tyrosine phosphorylation of receptor protein kinases provides a docking site for the activation of adaptor proteins which are the key regulators of insulin signaling pathway. In this report, we studied the long term effect of insulin as a neurotrophic factor and identified the isoform of receptor substrate involved in the propagation of insulin signal in SCs. We also studied the ability of insulin to regulate the expression of different receptor substrates like insulin receptor substrate-1 (IRS1), insulin receptor substrate-2 (IRS2) and growth factor receptor-bound protein-2 (GRB2) that propagate the insulin signaling and also their variation in hyperglycemic SCs and sciatic nerve of the diabetic rats. Results confirmed that IRS2 is the key receptor substrate involved in insulin signal transduction. But, a radical increase in the phosphorylation of IRS2 at serine 731 prevents the recruitment of GRB2 adaptor protein which may fail further to connect the Ras and other pathways required to the cell for its survival and to maintain integrity. These findings prove that SCs and sciatic nerve express IRS proteins that are altered by diabetes and thereby insulin signaling downstream is impaired and that contribute to the pathogenesis of DPN.

Insulin influenced expression of myelin proteins in diabetic peripheral neuropathy.

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.