Linking Mechanisms of Lipoic Acid to Multiple Sclerosis: A Narrative Review

Introduction

Multiple sclerosis (MS) is a debilitating autoimmune disease that primarily affects the central nervous system (CNS), leading to the progressive destruction of myelin, the protective covering of nerve fibers.¹ The breakdown of myelin disrupts nerve signal transmission, resulting in a wide range of neurological symptoms, including visual disturbances, cognitive impairment, motor dysfunction, and autonomic dysfunction and MS is an autoimmune disorder, meaning that the immune system mistakenly attacks the body’s own tissues, in this case, the myelin sheaths. The disease’s progression is often marked by an initial phase of relapse-remission, followed by a more irreversible secondary progressive phase, leading to increasing disability over time.²

MS is particularly prevalent in young adults aged 20–40 years and can result in long-term neurological and physical impairments. However, the demographic landscape is shifting, and the incidence of MS among older adults, particularly those aged 55–64 years, is on the rise due to improved life expectancy and better diagnostic tools. MS significantly impacts patients’ quality of life and has profound social and economic consequences. It is estimated that over 2.8 million individuals worldwide suffer from MS, with the highest rates of prevalence observed in developed countries, such as the United States, where the disease is most commonly diagnosed in individuals between the ages of 55 and 64.³ Furthermore, MS’s impact is substantial in regions like Khuzestan, Iran, where there has been a marked increase in incidence rates over the past two decades, indicating a growing need for effective treatments.⁴

The symptoms of MS can vary greatly from person to person, depending on the extent of the damage to the CNS and the areas of the brain and spinal cord affected. Common symptoms include visual disturbances, muscle weakness, difficulty walking, fatigue, cognitive decline, sensory disturbances, bladder and bowel dysfunction, and depression.⁵ The heterogeneity of the disease means that MS can range from a relatively mild course, where patients can live independently for many years, to a severe, rapidly progressive form that results in complete physical and cognitive disability. The course of MS also varies based on age at onset, gender, and geographical location, with women being more likely to develop the disease than men.⁶

While disease-modifying therapies (DMTs) have shown some promise in managing MS, they often have limited effectiveness in preventing disease progression or alleviating symptoms in later stages of the disease. In light of this, dietary supplements such as vitamins D, E, A, and C, as well as antioxidants like curcumin, have been proposed as complementary therapeutic strategies.⁷

Lipoic acid (LA)(often called α-lipoic acid(ALA))⁸ is an endogenous organosulfur compound with potent antioxidant properties and is known to be an essential component for proper mitochondrial function. It exerts prominent anti-inflammatory and antioxidant effects by reducing ROS, inhibiting metal ions, and regulating pathways associated with oxidative stress and inflammation.⁹ ALA has a chiral center and exists in two isomers, R and S, as different enantiomers, each of which can have different biological and beneficial effects on health. The R-ALA isomer is the natural form of this compound and is found in food sources, especially meat and some vegetables and antioxidant activity are superior to S-ALA; while the S-ALA isomer is mainly produced through chemical synthesis.^10,11

Research has suggested that LA can reduce oxidative stress and inflammation, both of which are critical factors in the pathogenesis of MS.^12,13 Furthermore, LA has been shown to have the potential to stimulate myelin regeneration, which is essential for repairing the damage caused by MS. In this context, LA supplementation may offer an effective adjunctive treatment for MS patients, helping to reduce disease progression and improve overall quality of life.¹⁴ This Narrative review discusses the comprehensive mechanisms of α-lipoic acid in MS and assesses evidence of its effects on MS disease activity from various aspects in in vitro and in vivo studies.

Methods

This Narrative review article was conducted by searching for relevant studies from multiple reputable academic databases, including PubMed, Google Scholar, ScienceDirect, Scopus, and EMBASE. The focus of the narrative review was to identify studies that explored the impact of lipoic acid supplementation on MS, specifically its effects on oxidative stress, inflammation, and brain atrophy. The search strategy utilized the following keywords: “multiple sclerosis,” “lipoic acid,” “nutrition,” and “oxidative stress.” To ensure that only high-quality and relevant studies were included, articles published in peer-reviewed journals were selected, while case reports, studies with small sample sizes, and those from non-citable or predatory journals were excluded. In order to capture a broad spectrum of research, the narrative review included studies published in the English language, with no specific time restrictions and shown in PRISMA (Figure 1). By using this comprehensive approach, the narrative review aimed to provide a thorough and up-to-date synthesis of the existing literature on the topic.

Figure 1 Identification of studies via databases and registers.

The selected studies were then assessed based on their methodological rigor, the population studied, and the outcomes measured. The primary focus was on research that directly investigated the relationship between LA supplementation and its impact on MS symptoms, oxidative stress levels, inflammatory markers, and neurodegeneration. The results of these studies were synthesized to provide an overview of the potential benefits and limitations of LA as a therapeutic agent for MS^15,16 (Tables 1 and 2).

Table 1 Summary of Included Study on Lipoic Acid in MS Patients

Table 2 Summary of Included Animal Study on Lipoic Acid in MS Patients

Mechanisms of MS Pathology

The exact cause of MS remains largely unknown, but multiple factors have been identified as potential contributors to the disease’s onset and progression. Genetic predisposition plays a significant role, as certain gene variants increase susceptibility to the disease.⁴ In addition, environmental factors such as viral infections, smoking, high-fat diets, and vitamin D deficiency are believed to influence the development and exacerbation of MS. Gender is another factor, with women being more likely to develop MS than men, possibly due to hormonal influences on immune function. Although genetic factors cannot be controlled, the influence of environmental factors can be mitigated through lifestyle changes, including smoking cessation and dietary modification.²⁴

MS is characterized by the activation of the immune system, particularly autoreactive T cells, which mistakenly attack the myelin in the CNS and this immune response triggers inflammation, demyelination, and axonal damage.²⁵ Oxidative stress is another key factor in MS pathology, as it leads to further cellular damage and mitochondrial dysfunction. The combination of inflammation, oxidative stress, and neuronal damage results in the progressive neurological impairments seen in MS patients, As the disease advances, myelin regeneration becomes more difficult, and axonal loss leads to irreversible functional impairments.²⁶ Understanding these underlying mechanisms is critical for developing effective treatments that target the root causes of the disease.

Lipoic Acid Supplementation in MS

Effect of Lipoic Acid on Mechanisms of MS Symptoms Such as Brain Atrophy

Brain atrophy, particularly in gray and white matter, is a hallmark feature of MS and is associated with disease progression and functional decline.²⁷ Longitudinal studies have shown that MS patients experience significant reductions in brain volume, which are linked to cognitive impairment and worsening physical disability. Brain atrophy in MS patients typically begins early in the disease course and can be observed even in the absence of overt lesions on MRI scans. This has prompted researchers to investigate potential therapies that could slow or prevent brain atrophy.²⁸

Lipoic acid has shown promise in this regard. Preclinical studies have suggested that LA can protect against neurodegeneration by modulating key cellular pathways involved in inflammation, oxidative stress, and neuronal survival.^29,30 In experimental models of MS, LA supplementation has been shown to reduce the rate of brain volume loss, particularly in patients with secondary progressive MS (SPMS), a stage of the disease that is characterized by more rapid progression and irreversible disability.^17,23 MRI studies in SPMS patients have demonstrated that LA supplementation may help preserve brain structure and function by reducing brain atrophy. However, these findings are preliminary, and further studies are needed to determine the long-term effects of LA on brain atrophy in MS patients.^29,31

Effect of Lipoic Acid on Mechanisms of MS Pathogenesis Such As

Oxidative Stress

Oxidative stress is a key contributor to the pathophysiology of MS, as it can damage neurons, myelin, and other critical structures in the CNS. The brain is particularly vulnerable to oxidative stress because it consumes a significant amount of oxygen during energy production, generating free radicals as by products.^27,28 LA acts as a potent antioxidant, neutralizing these free radicals and protecting against oxidative damage. It has been shown to increase the activity of other antioxidants, such as glutathione, and can regenerate other antioxidants like vitamin C, further reducing oxidative stress. LA’s ability to cross the blood-brain barrier is crucial for its potential as a therapeutic agent for MS, as it can directly target oxidative damage in the CNS²⁵ (Figure 2).

Figure 2 The possible mechanisms of alpha-lipoic acid in multiple sclerosis include antioxidant and anti-inflammatory roles. This compound acts by reducing oxidative stress, inhibiting inflammatory processes, decreasing brain atrophy, neutralizing free radicals, and restricting cell damage.

Several studies have investigated the effects of LA on oxidative stress in MS. These studies suggest that LA supplementation may help reduce oxidative markers in the serum and cerebrospinal fluid of MS patients, which could potentially slow the progression of the disease.^29,30 Additionally, LA has been shown to enhance total antioxidant capacity (TAC), which is an important indicator of the body’s ability to counteract oxidative stress. Despite these promising results, the findings are not entirely consistent, with some studies failing to demonstrate significant improvements in oxidative stress markers.^17,23 This inconsistency may be due to differences in study designs, patient populations, or dosages of LA used, indicating the need for more standardized research to confirm its efficacy.^17,27

Inflammation

Inflammation plays a central role in the pathogenesis of MS.³² The entry of autoreactive T cells into the CNS triggers a cascade of immune responses that result in the activation of microglia, astrocytes, and other immune cells, leading to further inflammation and neuronal damage. This inflammatory process contributes to the formation of MS lesions and accelerates disease progression. In addition to T cells, B cells, macrophages, and other myeloid cells are also involved in the inflammatory response in MS.³³

Lipoic acid has been shown to have potent anti-inflammatory effects, which could make it a valuable therapeutic agent for MS.³⁴ By inhibiting key inflammatory pathways, including the NF-κB pathway, LA can reduce the production of pro-inflammatory cytokines such as TNF-α, IL-6, and INF-γ.^35–37 These cytokines are implicated in the development and progression of MS lesions.³⁸ Several studies have demonstrated that LA supplementation can decrease the secretion of these inflammatory markers and reduce immune cell activation, suggesting that LA may help modulate the immune response in MS patients.³⁹ Furthermore, LA has been shown to enhance the production of cAMP, a molecule that plays a key role in regulating immune responses and inflammation.^40–42 By increasing cAMP levels, LA may inhibit the activation of inflammatory pathways and help to reduce the autoimmune response in MS.^31,43

According to animal studies, similar results have been shown to decrease inflammation and oxidative stress²³ and improve the myelin repair.¹⁴

Discussion

LA presents as a promising neuroprotective and anti-inflammatory agent for patients with multiple sclerosis (MS).¹⁸ The compound’s antioxidant properties can help mitigate oxidative stress, a major factor contributing to the progression of MS.⁴⁴ Additionally, LA’s ability to modulate inflammatory responses and protect against brain atrophy makes it a potential complementary therapy for MS management.^19,20 Results from a 2014 study by Khalili et al showed that daily intake of 1200 mg LA significantly improved total antioxidant capacity in patients with MS, although other markers of oxidative stress were not affected.²¹ While another randomized clinical trial conducted by Khalili et al in 2017, daily intake of 1200 mg of ALA helped reduce plasma Asymmetric dimethylarginine (ADMA) levels in patients with multiple sclerosis and prevented progression of Expanded Disability Status Scale (EDSS) score. However, no significant change was observed compared to the control group and larger studies are needed to confirm its clinical effects.²² In a clinical trial conducted by Spain et al¹⁷ in 2017 over a two-year period in patients with secondary progressive MS, daily administration of 1200 mg of LA reduced the rate of whole-brain atrophy and showed signs of improvement in motor function. This effect may be related to the duration of this study. In another study, oral administration of LA was well tolerated in patients with multiple sclerosis and resulted in reduced serum levels of matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (sICAMP-1), indicating potential anti-inflammatory and inhibitory effects on T cell migration into the central nervous system. These findings suggest a possible role for LA in reducing inflammation and limiting demyelinating damage in MS.¹⁹ Given that LA exists in different forms, a study showed that pure RLA caproate was better gastrointestinally tolerated and provided similar serum absorption than the racemic R, S-LA mixture. These findings suggest that the choice of LA form can influence the safety and clinical acceptability of the supplement, and that the use of R-LA may be a suitable option for long-term treatment.¹⁸ Nonetheless, daily administration of 1200 mg of lipoic acid in patients with progressive multiple sclerosis in a study improved walking performance, indicating the potential effect of LA in preserving motor function and reducing the progression of physical limitations in secondary progressive multiple sclerosis (SPMS).²⁰ The potential mechanisms of the neuroprotective and anti-inflammatory effects of LA in animal models of MS are also reflected in the results of studies that LA can alter the activity of primary mouse microglia, including inhibition of phagocytosis, actin rearrangement, and formation of membrane blebs, and also reduce brain atrophy.²³ In another animal study, ALA supplementation demonstrated myelin regenerative activity and indicated neuroprotective and regenerative effects by reducing oxidative stress, neuroinflammation, and increasing the expression of major myelin proteins (MBP and PLP). These findings underscore the potential of ALA to stimulate remyelination and neuroprotection in MS.¹⁴

While evidence from preclinical and clinical studies suggests that LA supplementation may offer benefits, the findings are not entirely consistent, and further research is required to confirm its effectiveness and some supplements may be harmful and have the opposite results.³⁷ Long-term, multicenter, well-designed studies are necessary to determine the optimal dosages, administration methods, and potential combination therapies that could improve outcomes for MS patients.⁴⁵

Strength and Limitations

Despite the promising effects of lipoic acid in clinical and animal studies, the results of some studies have been inconsistent. The differences may be due to variability in dose, duration of administration, type of LA form (R-LA or racemic mixture), patient population, and study design. Also, clinical studies often have small sample sizes and short durations, and animal and cellular models are unable to fully represent the complexity of human MS. These limitations make interpretation of the effects of LA cautious.

Research Gaps and Novelty

Given the limitations, future research should focus on large-scale, long-term, multicenter clinical trials to determine the optimal dose, appropriate form (R-LA or R, S-LA), and combination strategies with conventional therapies. The long-term effects of LA on myelin repair, motor function, microglial activity, and central immune responses also need to be investigated. Clarification of these issues may clarify the true role of LA in reducing disease progression and neuroprotection in MS.