Multiple Sclerosis and Serotonin: Potential Therapeutic Applications

Abstract

Multiple sclerosis (MS) is a neurodegenerative disease with a complex autoimmune component, and it has a high prevalence among middle-aged females. The manifestations of the disease range from episodic somatosensory dysfunction to progressive and permanent central nervous system (CNS) damage. Due to a high prevalence of psychiatric comorbidities and proven abnormalities in serotonin (5-HT) levels among MS patients, they are usually on drugs that modify the serotonergic system. Through a comprehensive literature review of studies published in the last 10 years related to 5-HT in MS and its therapeutic applications, we aimed to elucidate the mechanism behind the neurotransmitter (NT) levels' abnormalities. Most importantly, we endeavored to gather the most up-to-date information about the full therapeutic potential of agents acting on this system. We discovered that multiple processes cause low levels of 5-HT in MS patients. The varying levels of the availability of the 5-HT transporter (SERT) in the CNS decreasing overall tryptophan (TRP) levels, and diversion of the amino acid away from its synthetic pathway constitute some of those. Studies in animals have shown that 5-HT levels' elevations could cause immune-modulating effects and could probably slow down the disease progression rate. Human studies have shown a more diverse and complex response. Promising results have been obtained in the last 10 years regarding 5-HT's immune-modulatory role in MS patients and its therapeutic applications. Human studies with a larger population and feasible designs are still needed to fully ascertain the effects of serotonin on the immune system and disease progression in patients with MS.

Keywords: chemistry of multiple sclerosis; multiple sclerosis; multiple sclerosis and serotonin; serotonin.

Figure 1. Tryptophan metabolism in MS patients

The figure highlights one of the plausible mechanisms causing decreased levels of serotonin in MS patients. The diagram on the left represents normal tryptophan metabolism. A synthetic pathway using tryptophan hydroxylase (TPH) allows serotonin formation, while enzymes IDO and TDO degrade tryptophan into various products. The diagram on the right highlights the diversion of tryptophan into this catabolic pathway through induction of the enzyme IDO by inflammatory cytokines like IL-1, TNF-α, and IFN-γ present in high levels during inflammatory periods in MS patients MS: multiple sclerosis; IDO: indoleamine 2,3-dioxygenase; TDO: tryptophan dioxygenase; IL-1: interleukin-1; TNF-α: tumor necrosis factor alpha; IFN-γ: interferon gamma; TPH: tryptophan hydroxylase

Figure 2. Serotonin's effects on the immune system

The figure summarizes the findings of previous studies about the effects of serotonin on the immune system. Overall, 5-HT decreases the proliferation of WBC, suppresses the synthesis of inflammatory cytokines like IFN-γ, IL-17, and IL-22 by TH1 and Th2 cells, respectively. The NT also enhances the synthesis of IL-10, a regulatory cytokine, from CD4+ cells and acts on macrophages, enhancing its polarization into the M2 subset, a population that secretes regulatory mediators to control inflammation. Finally, the addition of 5-HT to WBCs increases their migration through the BBB into the inflammatory foci 5-HT: serotonin; IFN-γ: interferon gamma; IL: interleukin; WBC: white blood cells; NT: neurotransmitter