Fighting Oxidative Stress: A Key to Slowing ALS Progression

Amyotrophic Lateral Sclerosis (ALS) is a complex and challenging disease that affects motor neurons, the nerve cells in the brain and spinal cord that control voluntary muscle movement. As these motor neurons deteriorate, people with ALS experience progressive muscle weakness, difficulty speaking, swallowing, and eventually breathing. While the exact cause of ALS is not fully understood, researchers have identified several factors that contribute to its development and progression. One key area of focus is the role of oxidative stress.

For patients, caregivers, and families facing ALS, understanding these biological processes can feel overwhelming. However, learning about factors like oxidative stress can provide valuable insight into the disease and potential strategies being explored to manage it.

What is Oxidative Stress?

Our bodies constantly undergo chemical processes that produce energy and allow cells to function. These processes naturally generate molecules called "free radicals." Free radicals are inherently unstable and can damage cells, proteins, and DNA if their levels become too high.

Think of it like rust forming on metal. Over time, exposure to oxygen and moisture causes damage. Similarly, free radicals can cause "oxidative damage" in our bodies.

Fortunately, our bodies also have a defense system made up of "antioxidants." Antioxidants are molecules that neutralize free radicals, preventing them from causing harm. Under normal conditions, there is a balance between free radicals and antioxidants.

Oxidative stress occurs when there is an imbalance – either too many free radicals are produced, or there aren't enough antioxidants to keep them in check. This excess of reactive molecules can lead to cellular damage throughout the body, including in the nervous system.

How Oxidative Stress Impacts Motor Neurons in ALS

Research strongly suggests that oxidative stress plays a significant role in the damage and death of motor neurons in ALS (Islam, 2017; Singh et al., 2019). Studies have shown that this imbalance contributes to several harmful processes within these vital cells:

• Protein Aggregation: Motor neurons in people with ALS often accumulate clumps of misfolded or damaged proteins, such as TDP-43 and SOD1 (Zuo et al., 2021; Kaur et al., 2016). Oxidative stress can promote the misfolding and clumping of these proteins, which are toxic to the cells (Zuo et al., 2021; Ratti et al., 2020).
• Mitochondrial Dysfunction: Mitochondria are the powerhouses of our cells, generating energy through a process called oxidative phosphorylation. This process naturally produces some free radicals. However, high levels of oxidative stress can damage mitochondria, making them inefficient energy producers and causing them to generate even more harmful reactive species (Islam, 2017; Singh et al., 2019; Bozzo et al., 2017). This creates a vicious cycle where mitochondrial problems worsen oxidative stress, further disrupting cellular balance (Zuo et al., 2021; Cilleros-Holgado et al., 2023).
• Damage to Cellular Components: The excess reactive species caused by oxidative stress can directly damage essential parts of the motor neuron, including its DNA, fats (lipids) that make up cell membranes, and other critical proteins (Singh et al., 2019). This widespread damage impairs cell function and can ultimately lead to cell death (Drechsel et al., 2012).
• Inflammation: Oxidative stress can also trigger inflammatory responses in the nervous system, which can further harm motor neurons.

Initially, the link between oxidative stress and ALS was particularly highlighted by the discovery of mutations in the SOD1 gene, which produces an enzyme that normally helps neutralize superoxide radicals (Kaur et al., 2016; Yamashita et al., 2019). While SOD1 mutations are responsible for a small percentage of ALS cases, the concept that impaired antioxidant function contributes to the disease has broadened to include oxidative stress as a factor in both familial and sporadic forms of ALS (Islam, 2017; Singh et al., 2019).

Targeting Oxidative Stress in ALS Treatment

Given the significant role of oxidative stress in the disease process, researchers have explored strategies to reduce it as a way to slow ALS progression.

One notable example is the drug edaravone (often known by the brand name Radicava®). Edaravone is an FDA-approved treatment for ALS. Its primary mechanism of action is believed to be its ability to scavenge (neutralize) free radicals, thereby alleviating oxidative stress (Supporting Info; Johnson et al., 2022; Yamashita et al., 2019).

Clinical trials and real-world studies on edaravone have yielded varied results. An initial study showed a statistically significant slowing of disease progression measured by the ALS Functional Rating Scale-Revised (ALSFRS-R) score in a specific subgroup of patients (Johnson et al., 2022). However, a large real-world study involving German patients did not find a significant difference in disease progression (ALSFRS-R) or survival compared to standard therapy alone (Witzel et al., 2022). Conversely, a retrospective analysis of US administrative claims data suggested that edaravone treatment was associated with prolonged overall survival compared to not using the drug (Brooks et al., 2022). These differing findings highlight the challenges in studying complex diseases like ALS and the need for ongoing research and careful evaluation of treatments.

It's important to remember that edaravone is administered intravenously, requiring regular infusions. Another formulation, taken orally, has also become available more recently.

Riluzole, another medication used to treat ALS, has a different mechanism, primarily affecting glutamate levels, though it also may indirectly influence oxidative pathways. It is often used alongside edaravone (Johnson et al., 2022).

What Can Patients Do? Supportive Strategies

While medication prescribed by your neurologist is the primary approach for managing ALS, adopting healthy lifestyle habits that support your body's natural antioxidant defenses may be beneficial as part of a comprehensive care plan. It is crucial to discuss any changes to diet, supplements, or activity levels with your healthcare team to ensure they are safe and appropriate for your individual situation.

General strategies that support overall cellular health and may help manage oxidative stress include:

• Nutrition: Eating a balanced diet rich in fruits, vegetables, nuts, and seeds provides a wide array of vitamins and antioxidants. Specific nutrients like Vitamin C, Vitamin E, selenium, and compounds found in colorful produce are known antioxidants.
• Exercise: Regular, appropriate exercise (as recommended by your medical team and physical therapist) can improve circulation and cellular health, potentially supporting antioxidant systems.
• Avoiding Toxins: Limiting exposure to known sources of free radicals, such as cigarette smoke (both active and passive) and excessive alcohol, is important for overall health.
• Managing Stress: Chronic psychological stress can contribute to oxidative stress in the body. Techniques like mindfulness, meditation, or gentle hobbies may help manage stress levels.

These lifestyle approaches are supportive measures and should not be considered a replacement for prescribed ALS treatments.

Future Directions

Research continues into the complex interplay between oxidative stress, mitochondrial function, protein handling, and other cellular pathways in ALS (Bozzo et al., 2017; Deng et al., 2020). Scientists are exploring various potential therapeutic avenues, including:

• Developing new drugs that specifically target oxidative stress pathways or enhance the body's antioxidant defenses.
• Investigating compounds that can improve mitochondrial health and function (Zhou et al., 2023; Cilleros-Holgado et al., 2023).
• Exploring how to prevent the formation or promote the clearance of toxic protein aggregates (Zuo et al., 2021; Ratti et al., 2020).
• Studying existing compounds with known antioxidant or neuroprotective properties for their potential in ALS, such as Tauroursodeoxycholic acid (TUDCA) (Khalaf et al., 2022).

Understanding the genetic factors involved in ALS (Nijs et al., 2024), including those related to oxidative stress like SOD1 mutations (Kaur et al., 2016; McCampbell et al., 2018), is also paving the way for more personalized treatment approaches.

Conclusion

Oxidative stress is a significant factor contributing to the damage and loss of motor neurons in ALS. By creating an imbalance between harmful free radicals and protective antioxidants, it fuels processes like protein aggregation and mitochondrial dysfunction. Targeting this oxidative imbalance is a key strategy in the development of ALS treatments, as exemplified by the FDA-approved drug edaravone.

While research continues to unravel the intricate mechanisms of ALS and refine therapeutic approaches, understanding the role of oxidative stress empowers patients and families with knowledge about one facet of the disease and highlights the importance of ongoing scientific efforts to find effective treatments. Combining prescribed medical therapies with supportive lifestyle choices, always in consultation with your healthcare team, remains the best approach to managing ALS.

References

• Bozzo, F., Mirra, A., & Carrì, M. T. (2017). Oxidative stress and mitochondrial damage in the pathogenesis of ALS: New perspectives. Molecular Neurobiology, 54(6), 4269-4281.
• Brooks, B. R., Berry, J. D., Ciepielewska, M., Liu, Y., Suarez Zambrano, G., Zhang, J., & Hagan, M. (2022). Intravenous edaravone treatment in ALS and survival: An exploratory, retrospective, administrative claims analysis. Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration, 23(5-6), 390-399.
• Cilleros-Holgado, P., Gómez-Fernández, D., Piñero-Pérez, R., Romero-Domínguez, J. M., Reche-López, D., López-Cabrera, A., ... & Sánchez-Alcázar, J. A. (2023). Mitochondrial Quality Control via Mitochondrial Unfolded Protein Response (mtUPR) in Ageing and Neurodegenerative Diseases. International Journal of Molecular Sciences, 24(19), 14555.
• Deng, Z., Lim, J., Wang, Q., Purtell, K., Wu, S., Palomo, G. M., ... & Yue, Z. (2020). ALS-FTLD-linked mutations of SQSTM1/p62 disrupt selective autophagy and NFE2L2/NRF2 anti-oxidative stress pathway. Autophagy, 16(11), 1973-1991.
• Drechsel, D. A., Estévez, A. G., Barbeito, L., & Beckman, J. S. (2012). Nitric oxide-mediated oxidative damage and the progressive demise of motor neurons in ALS. Nitric Oxide, 26(4), 207-213.
• Islam, M. T. (2017). Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders. Neurological Sciences, 38(3), 403-416.
• Johnson, S. A., Fang, T., De Marchi, F., Neel, D., Van Weehaeghe, D., Berry, J. D., & Paganoni, S. (2022). Pharmacotherapy for Amyotrophic Lateral Sclerosis: A Review of Approved and Upcoming Agents. Drugs, 82(12), 1251-1269.
• Kaur, S. J., McKeown, S. R., & Rashid, S. (2016). Mutant SOD1 mediated pathogenesis of Amyotrophic Lateral Sclerosis. Gene, 577(2), 1