Preston Williams

Multiple Sclerosis (MS) is an immune mediated, demyelinating disease that affects the central nervous system. Many times the initial symptoms are relatively minor, but MS can lead to severely debilitating effects later in its progression.8 Little is known about the causative factors of MS. Current therapies all act by suppressing or regulating the immune system and are oftentimes associated with serious side effects.9 Recent studies have begun to implicate reactive astrocytes in the neurodegeneration of MS.6 Dunham et al. revealed that there was enhanced expression of oxidative damage markers in inflammatory lesions in Experimental Autoimmune Encephalitis (EAE) in a marmoset model. They showed that ROS damage contributed to the lesion burden and that EAE in marmosets is an effective model to test new MS therapeutics.1 Gene β-1,4-galactosyltransferase 6 (B4GALT6) was determined to be associated with the chronic stage of EAE and to cause the synthesis of LacCer.2 LacCer acts in an autocrine manner to control astrocyte transcriptional programs that promote neurodegeneration. In addition, LacCer controls the recruitment and activation of microglia and CNS-infiltrating monocytes. Disease progression was suppressed with administration of B4GALT6 inhibitor D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol.2 Consequently, these findings in mice were validated when it was shown that human MS lesions also showed increased expression of LacSer and B4GALT6.2 LacSer also serves to increase inflammation with Arachidonic Acid synthesis via ROS. It was observed that the release of arachidonic acid was decreased when LacCer synthesis was inhibited.3 Excess ROS/RNS use LacCer to begin the phosphorylation cascade of group IVA Phospholipase A2, which releases arachidonic acid, increasing inflammation and the activity of T cells.3 ROS were also implicated in purveying damage via mitochondrial dysfunction causing an increase in generation of free radicals.4 Activated nuclear-factor-erythroid-related-factor 2 (NRF2) has already been clinically shown to cause protection from the effects of ROS in psoriasis. Evidence was also gathered in a separate study indicating that NRF2 knockout mice exhibited increased severity of EAE, further supporting the importance of NRF2 in protection against inflammation and oxidative stress.5 There is potential for new therapies using three aspects of reactive astrocyte mediated damage. B4GALT6 inhibition has already been shown to reduce disease progression and severity in mice. Targeting NRF2 activation would dispose of ROS and protect against oxidative damage. Finally, targeting antioxidants to the mitochondria would increase neutralization of ROS/RNS and prevent damage to the CNS.7

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2. Mayo L, Trauger S, Blain M et al. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med. 2014;20(10):1147-1156. doi:10.1038/nm.3681.
3. Nakamura H, Moriyama Y, Watanabe K et al. Lactosylceramide-Induced Phosphorylation Signaling to Group IVA Phospholipase A2 via Reactive Oxygen Species in Tumor Necrosis Factor-α-Treated Cells. J Cell Biochem. 2017;118(12):4370-4382. doi:10.1002/jcb.26091.
4. Rossi S, Motta C, Studer V et al. Tumor necrosis factor is elevated in progressive multiple sclerosis and causes excitotoxic neurodegeneration. Multiple Sclerosis Journal. 2013;20(3):304-312. doi:10.1177/1352458513498128.
5. Schulze-Topphoff U, Varrin-Doyer M, Pekarek K et al. Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2. Proceedings of the National Academy of Sciences. 2016;113(17):4777-4782. doi:10.1073/pnas.1603907113.
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7. Mitochondria-targeted Antioxidants as a Prospective Therapeutic Strategy for Multiple Sclerosis. Curr Med Chem. 2017;24(19). doi:10.2174/0929867324666170316114452.
8. Compston A, Coles A. Multiple sclerosis. The Lancet. 2008;372(9648):1502-1517. doi:10.1016/s0140-6736(08)61620-7.
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