One suitable approach to enhancing multiple sclerosis (MS) treatment is combination of available medications to provide more desirable outcomes. Immunomodulatory effects of atorvastatin and/or all-trans retinoic acid (ATRA) were determined in previous studies. The present study was set out to investigate the synergistic effects of combination therapy by suboptimal doses of atorvastatin and ATRA in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE was induced by MOG_35–55 in female C57BL/6 mice. Therapies were initiated at day 12 post immunization when the mice developed a disability score and continued throughout the study until the day 33 when animals were sacrificed. Therapeutic treatment with half doses of atorvastatin and ATRA in combination has synergistic benefits causing the regression of clinical and neuropathological features of EAE more favorable than treatment with full doses of either drug alone. Without any advantage in anti-proliferative effect, combination treatment significantly reduced the secretion of pro-inflammatory cytokine interleukin-17 and conversely, increased the production of anti-inflammatory cytokine interleukin-10 more prominent than either drug alone. Furthermore, FoxP3⁺Treg cells were significantly increased only in combination treatment. In conclusion, combined atorvastatin and ATRA have immunomodulatory synergistic benefits and this pharmacological approach may be as a useful strategy to control MS.

Collectively, caffeine treatment of MSCs appeared to augment the instruction of anti-inflammatory macrophages by conditioned medium of MSCs. These findings might offer new insight into the potential mechanisms that underlie the immunomodulatory and anti-inflammatory effects of caffeine.

Experimental autoimmune encephalomyelitis (EAE) in rats through immunization with guinea pig spinal cord homogenate (GPSCH) produces a chronic disease with a relapsing pattern such as multiple sclerosis (MS) in humans. In previous studies, the immunomodulatory benefits of mesenchymal stem cells (MSCs) and nicotine have already been determined. Thus, this research was conducted to assess the additional benefits of the combination therapy of MSCs and nicotine in a rat model of MS. EAE was induced by GPSCH and complete Freund’s adjuvant (CFA) in female Wistar rats. The therapies were initiated at day 12 post-immunization (p.i.), when the rats developed a neurological disability score. The symptoms were recorded daily until day 33, when the rats were sacrificed. Finally, the splenocytes were evaluated by Enzyme-linked immunosorbent assay (ELISA) for cytokine production. The therapeutic treatment in the EAE rats with a combination of MSCs and nicotine exhibited a more desirable outcome, causing the regression of the average mean clinical score and neuropathological features to be more favorable than the treatment with either therapy alone. The combination therapy led to a significant reduction in the cumulative disease disability from day 21. For the EAE rats treated with nicotine and MSCs, this period was started from day 22 and 28 p.i., respectively. Besides the increase in the levels of IL-10, the combined therapy significantly reduced the splenocytes production of pro-inflammatory IL-17 as well as TNF-α more profoundly than either of the medications alone. In conclusion, the combination of MSCs and nicotine can be suggested as a promising strategy for further MS therapeutics improvement.