We used the PubMed and ScienceDirect databases with the keywords based on MeSH terms: photobiomodulation, low-level laser therapy, multiple sclerosis, autoimmune encephalomyelitis, demyelination, and progressive multiple sclerosis. Data search was limited from 2012 to June 2024. This study followed the guideline of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (25). Two evaluators made the evaluations, and disagreements were resolved by consensus.

The search strategy included experimental and clinical studies using PBM in MS. We included original in vitro and clinical articles written in English.

For data extraction, we used an individualized data form (26), in which articles were subdivided according to the author, subjects, light source, PBM parameters (center wavelength, operation mode, average radiant power, irradiance at aperture, beam spot size, exposure duration, radiant exposure, number of points irradiated, number of sessions, total radiant energy) and outcomes. The data are presented in the Results section.

The initial database search resulted in 126 studies. Of these, 68 articles were removed due to duplicity, 50 were screened out, and 8 studies were included in the systematic review. The process of selecting the articles is illustrated in Figure 1.

Four articles reported experiments in mice (27–30), of which 2 were on female C57BL/6 (29, 30) and 2 were on male C57BL/6 (27, 28) (Table 1). In these studies, the age of animals varied from 6 to 10 weeks old. In humans, 4 articles reported a randomized clinical trial in men and women aged 18–60 diagnosed with MS (31–34) (Table 2). In all studies, the subjects received PBM treatment. The studies aimed to analyze the effects of PBM on the damages caused by MS, inflammatory response and oxidative stress, mitochondrial activity, demyelination, microglial modulation, and apoptosis.

Studies show that the laser improves clinical signs in patients with MS (31–33). In the study conducted by Seada et al. (33), the laser treatment performed three times per week on consecutive days (24 sessions) reduced trigeminal pain and increased mouth opening, masseter, and temporalis muscles. In another study, Kubsik et al. (31) observed that, after PBM treatment with 21 sessions, MS patients improved their functional status based on Expanded Disability Status Scale (EDSS) of Kurtzke and Barthel Index. Also, Rouhani et al. (32) noted an improvement in force recovery of patients treated with 4 sessions of PBM treatment. These therapeutic effects of PBM have also been observed in laboratory animals (27–29). Among the models studied in the literature are: experimental autoimmune encephalomyelitis (EAE) and cuprizone intoxication (35–38). In these models, the onset and progression of the disease are determined by a clinical score based on the progressive appearance of paralysis, the origin of locomotor deficits, and the gradual disability of the pathology (35, 36). In the study conducted by Gonçalves, thirty sessions of PBM (660 nm and 904 nm) were able to reduce clinical score and delay the disease onset in EAE mice. Also, a body weight gain was observed in the animals from the laser group. In the study by Duarte (27), cuprizone-induced MS model animals that received six sessions of laser treatment (808 nm) applied on three consecutive days for 2 weeks showed an improvement in motor performance. These data suggest that PBM improves the clinical signs of MS.

The diagnosis of MS is established in conjunction with the clinical presentation and inflammatory lesions (39). In this sense, studies performed on patients (34) and animal models of MS (27, 28, 30) show that PBM modulates the levels of inflammatory markers. For example, after 24 sessions of PBM twice a week, the expression of IL-10 increased significantly in MS patients (34). It is known that the expression of pro-inflammatory cytokines is inhibited by the secretion of IL10 (40). These data are interesting, given that patients with MS exhibit reduced levels of IL-10 in mononuclear cells (41). In animal models of MS, it is also possible to observe the anti-inflammatory properties of PBM (27–29). For example, after PBM, a decrease was observed in the levels of pro-inflammatory cytokines, such as interferon and tumor necrosis factor-alpha (TNF-α), and an increase in IL-4 and IL-10 (anti-inflammatory cytokines) (29). Goncalves et al. (28) noted that EAE mice showed profound infiltration of inflammatory cells into the CNS, particularly in the white matter region, and a pronounced increase in IL-17, interferon gamma (IFN-γ), and IL-1b levels. However, PBM reduced the infiltration of inflammatory cells into the CNS of EAE mice. In addition, PBM inhibited the upregulation of IL-17, IFN-γ, and IL-1b. These findings are essential since the secretion of pro-inflammatory cytokines such as IFN-γ and TNF-α initiates and propagates a pro-inflammatory response, generating demyelination of CNS axons by multiple mechanisms, including cytokine-mediated demyelination (42). In this sense, Duarte et al. (27) observed that PBM attenuated the degree of demyelination in the corpus callosum of cuprizone-induced MS model animals, accompanied by a better clinical outcome. In addition, the authors investigated microglial and astrocyte activation. They noted a reduced severity of astrogliosis (GFAP) and microglia (IBA-1) immunoreactivity in the corpus callosum of the cuprizone-induced MS model submitted to PBM treatment. Glial cell activation and inflammatory response are critical hallmarks of MS in humans and animal models (43). About high levels of GFAP, it is known that these high levels in CSF are associated with the progression of MS (44–46) and with clinical disability (44, 46).

Studies show that levels of oxidative stress markers are increased in MS model animals (47–49). However, it is suggested that reduction of oxidative stress prevents the progression of MS, mainly by protecting against apoptosis (50–52). In this sense, in the studies conducted by Muili et al. (30) and Goncalves et al. (28), it was shown that animal models of MS submitted to treatment with PBM exhibit a decrease in oxidative stress markers, such as: nitric oxide (NO), inducible nitric oxide (iNOS) and nitrite. In addition, animal models of MS that received PBM treatment exhibited up-regulation of the Bcl-2 anti-apoptosis gene, an increased Bcl-2: Bax ratio, and reduced apoptosis in the spinal cord (30).

Our systematic review presents limitations, mainly because it only analyzed 4 studies with MS patients. The research highlighted in this review shows the therapeutic potential of PBM on MS. However, the lack of details about the PBM parameters used in each work make it difficult to replicate these approaches. Standardization of the PBM protocols would facilitate comparison between the findings of the studies.