Blood Brain Barrier Compromise with Endothelial Inflammation may Lead to Autoimmune Loss of Myelin during Multiple Sclerosis

Abstract

Multiple sclerosis is an autoimmune disease characterized by multifocal areas of inflammation and demyelination within the central nervous system. The mechanism that triggers the disease remains elusive. However, recent findings may indicate that multiple sclerosis, at its source, could be a hemodynamic disorder. It has been found that multiple sclerosis patients exhibit significant stenoses in extracranial veins draining the central nervous system (in azygous and internal jugular veins), which are associated with significant pressure gradients measured across strictures. Such anatomic venous abnormalities were not found in the control group of healthy subjects. In this review, it is hypothesized that pathological refluxing venous flow in the cerebral and spinal veins increases the expression of adhesion molecules, particularly intercellular adhesion molecule-1 (ICAM-1), by the cerebrovascular endothelium. This, in turn, could lead to the increased permeability of the blood-brain barrier. Inflamed and activated endothelium could secrete proinflammatory cytokines, including GM-CSF and TGF-beta In these settings, monocytes could transform into antigen-presenting cells and initiate an autoimmune attack against myelin-containing cells. Consequently, a potential therapeutic option for multiple sclerosis could be pharmacotherapy with either substances that strengthen the tight-junctions barrier, or with agents that reduce the expression of adhesion molecules. In addition, surgical correction could be an option in some anatomical variants of pathologic venous outflow. We are optimistic that a hemodynamic approach to the multiple sclerosis pathogenesis can open a new chapter of investigations and treatment of this debilitating neurologic disease.

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

“…Key to this barrier are endothelial cells of the CNS blood vessels forming tight junctions, facilitating exclusion of constituents of the systemic circulation from entry into the CNS. It is noteworthy that only recently has it been hypothesized that endothelial cells of the blood-brain barrier might contribute to immune signaling within the CNS (Quan et al, 2003;Simka, 2009). After a tissue insult and the ensuing release of peripheral or central immune signals, the tight junctions become leaky, exposing the CNS to peripheral immune signals (Stamatovic et al, 2003;Song and Pachter, 2004;Bennett et al, 2010).…”

Efficient In Vivo Delivery of siRNA Into Brain Capillary Endothelial Cells Along With Endogenous Lipoprotein

“…Inflammatory cell adhesion molecules, such as the intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and selectins, are potential target molecules for the treatment of brain ischemia and MS. This is because the adhesion of activated leukocytes to BCECs induces secondary neuronal injury after reperfusion 4,5 and immune-mediated demyelination in MS. 6,7 In Alzheimer's disease (AD), inhibition of the receptor for advanced glycation end products (RAGE) can be expected to alleviate AD pathology, because RAGE expressed in BCECs mediates an influx transport of the neurotoxic amyloid-β peptide (Aβ) from the blood into the brain. 8,9 RNA interference is a powerful tool to achieve post-transcriptional gene silencing.…”

Hypercapnia and hypoxaemia due to impaired venous blood draining and significant improvement after endovascular treatment in patients with chronic cerebrospinal venous insufficiency

“…A number of studies have demonstrated an association of CCSVI with MS [1,6,7,16], and it was hypothesised that impaired cerebral venous drainage may lead to local venous hypertension and dysfunction of the bloodbrain barrier, which in turn may evoke autoimmune reaction and neurodegeneration [17]. Still, an association of CCSVI with MS was not confirmed by many authors, probably not only because of the different diagnostic protocols used, but primarily due to much a more complex relationship between CCSVI and MS than was initially believed [18].…”