Therapeutic Plasma Exchange and Multiple Sclerosis Dysregulations: Focus on the Removal of Pathogenic Circulatory Factors and Altering Nerve Growth Factor and Sphingosine-1-Phosphate Plasma Levels

Abstract

Multiple sclerosis (MS) is predominantly an immune-mediated disease of the central nervous system (CNS) of unknown etiology with a possible genetic predisposition and effect of certain environmental factors. It is generally accepted that the disease begins with an autoimmune inflammatory reaction targeting oligodendrocytes followed by a rapid depletion of their regenerative capacity with subsequent permanent neurodegenerative changes and disability. Recent research highlights the central role of B lymphocytes and the corresponding IgG and IgM autoantibodies in newly forming MS lesions. Thus, their removal along with the modulation of certain bioactive molecules to improve neuroprotection using therapeutic plasma exchange (TPE) becomes of utmost importance. Recently, it has been proposed to determine the levels and precise effects of both beneficial and harmful components in the serum of MS patients undergoing TPE to serve as markers for appropriate TPE protocols. In this review we discuss some relevant examples, focusing on the removal of pathogenic circulating factors and altering the plasma levels of nerve growth factor and sphingosine-1-phosphate by TPE. Altered plasma levels of the reviewed molecular compounds in response to TPE reflect a successful reduction of the pro-inflammatory burden at the expense of an increase in anti-inflammatory potential in the circulatory and CNS compartments.

Oxidative Stress and the Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) Pathway in Multiple Sclerosis: Focus on Certain Exogenous and Endogenous Nrf2 Activators and Therapeutic Plasma Exchange Modulation

“…Most patients received three TPE procedures in LVPE mode (patients 1, 2, 3, 5), whereas one of them received four nanomembrane-based TPE procedures in LVPE mode (patient 4). We observed an elevation in NGF plasma levels in all patients (Figure 7) [143]. The measurement of OS markers (ROS and isoprostanes) showed that the application of TPE leads to a reduction in the OS level (Figures 8 and 9) [17], which is favorable for the general and neurological status of patients.…”

“…Translating the results of this preclinical model to the real clinical setting is achievable through the application of TPE in the treatment of acute exacerbations of MS. Through this non-pharmacological therapeutic approach, both an increase in circulating levels of NGF and a modulation of OS can be achieved [17,143]. Evidence for this will be presented in the next section.…”

“…Last but not least, NGF antibodies have been observed to exacerbate the neuropathological signs of EAE [140]. This suggests not only the importance of NGF in decreasing the EAE lesions [141], but also offers new possibilities for increasing the anti-inflammatory potential of NGF in MS patients by removing these antibodies using TPE [142,143].…”

“…In addition, NGF synthesis is elevated in brain endothelial cells, and NGF is secreted into the brain parenchyma, activating the NGF/TrkA/PI3K/Akt/Nrf2 pathway, which stimulates the expression of antioxidant genes in the CNS. Another possibility is that peripheral NGF enters the CNS directly, as suggested in the 1980s by Levi-Montalcini [156], which may occur with a permeable BBB, as is the case in acute exacerbations of MS [135,143]. Translating the results of this preclinical model to the real clinical setting is achievable through the application of TPE in the treatment of acute exacerbations of MS.…”

“…The use of saline to replace the removed plasma is in agreement with the so-called low-volume plasma exchange (LVPE), which ranges from 350 mL to 2 l plasma volume removal for each separate procedure [166][167][168][169]. We performed a nanomembrane-based TPE treatment in steroid-refractory MS in five patients with a relapsing-remitting MS [18,143,164]. Most patients received three TPE procedures in LVPE mode (patients 1, 2, 3, 5), whereas one of them received four nanomembrane-based TPE procedures in LVPE mode (patient 4).…”