Antioxidant effect may benefit multiple sclerosis
One of life’s conundrums is that the oxygen we need to live is also life-threatening. Oxygen drives the body’s metabolism, but that same metabolic activity produces oxygen products that are highly damaging to the tissues of the body. These products include ‘free radicals’, such as the hydroxyl radical (think of a water molecule [H2O] with an ‘H’ missing); and ‘reactive oxygen species’ (ROS) such as hydrogen peroxide, which is sold in pharmacies as an antiseptic or to bleach hair.
Despite their bad reputation, oxidants are needed by the body. For example, the free radical nitric oxide is an important signalling molecule and is ‘weaponized’ by immune cells, which release it to kill bacteria (Knight JA. Ann Clin Lab Sci 2000;30:145-158). So what is important is to maintain an oxidant/antioxidant balance. The body has in-built antioxidant mechanisms to achieve this balance. When the balance is upset, it creates a condition called oxidative stress.
Oxidative stress is often misrepresented as everyday ‘stress’ by people selling antioxidant products but the two terms are quite different. The brain, with all its thinking and processing, has high metabolic activity and so it is highly vulnerable to oxidative stress. However, there is very little evidence to suggest psychological stress (overwork, depression, etc.) is a cause or consequence of oxidative stress (Irie and colleagues. Int Arch Occup Environ Health 2001;74:153-157. Irie and colleagues. Biochem Biophys Res Commun 2003;311:1014-1018).
Oxidative stress is emerging as an important topic in MS. During an inflammatory flare-up, immune cells in the brain (called microglia) become activated and release large amounts of ROS. While the body’s antioxidant mechanisms should neutralize these ROS, a number of studies have suggested that the antioxidant machinery is dysregulated in people with neurodegenerative diseases such as MS (Ohl and colleagues. Exp Neurol 2016;277:58-67). This means that the brain is unable to detoxify the tissue-damaging effects of inflammation. Some researchers have even suggested that ROS are one of the main contributors to the formation of lesions in the brain and spinal cord (Barnett & Prineas. Ann Neurol 2004;55:458-468).
The central component in the antioxidant machinery is called Nrf2 (for nuclear factor [erythroid-derived 2]-like 2). Nrf2 acts like a regulator switch: it is usually turned off but will switch on if it detects oxidative stress. Once it gets turned on, it drives Nrf2 genes that re-regulate the inflammatory response. Nrf2 activity slows during normal aging, leaving the body more susceptible to tissue damage (the basis for antioxidant creams that claim to be anti-aging).
The Nrf2 switch also seems to be impaired in MS, which means that inflammatory flare-ups are more damaging than they need to be. An interest finding in recent years is that the disease-modifying therapies (DMT) used to treat MS may act in part by switching on the antioxidant machinery. For example, laboratory studies have shown that Tecfidera boosts the level of Nrf2, which in turn increases the release of antioxidants in the brain (Albrecht and colleagues. J Neuroinflamm 2012;9:163). Tecfidera also appears to promote the release of oxygen scavengers that mop up ROS in the brain (Huang and colleagues. Redox Biology 2015;5:169-175). Treatment also appears to dampen the antioxidant effects of immune cells that enter the brain in MS (Liebmann and colleagues. Brain 2021:144;3126-3141).
Other DMTs also appear to have an impact on different aspects of the antioxidant response. Tysabri has been shown to reduce oxidative damage in MS (Perez-Herrera and colleagues. Pharmacol Rep 2013;65:624-631). Gilenya appears to have antioxidant effects that come into play after three months of continuous treatment (Yevgi and colleagues. Clin Neurol Neurosurg 2021;202:106500). Mavenclad has also been shown to boost antioxidant levels in people with secondary-progressive MS (Jamroz-Wisniewska and colleagues. Oxid Med Cell Longev 2020;2020:1654754).
These findings suggest that targeting the antioxidant machinery may provide another approach to preventing some of the tissue damage that occurs in MS.
Re-regulating the antioxidant response may also have unexpected benefits in these COVID times. A recent study found that the CoV-2 virus that causes COVID-19 has the ability to suppress Nrf2; it seems that the virus has a better chance of survival if the cellular machinery is impaired (Olagnier D. Nature Comm 2020;11:4938). However, proliferation of the CoV2 virus (as well as other viruses such as Herpes simplex and Zika) was inhibited when Tecfidera switched Nrf2 back on. This may help to explain the case reports of people on Tecfidera developing only mild COVID symptoms (Mantero and colleagues. J Neurol 2021;268:2023-2025. Capone and colleagues. J Neurol 2021;268:3132-3134).
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