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 immunemodulatory 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.

T Lymphocyte Serotonin 5-HT7 Receptor Is Dysregulated in Natalizumab-Treated Multiple Sclerosis Patients

“…The neuroprotective role of serotonin [ 3 ] is associated with its ability to modulate the inflammatory response of lymphocytes [ 6 ] involved in MS disease course [ 15 ], but the knowledge of the receptors involved is limited. Moreover, several studies reported an important activation of immune cells in peripheral blood from MS patients, including changes in surface phenotype [ 16 ].…”

“…Thus, 5-HT was shown to play an immune-modulatory role in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS) [ 3 ], without understanding precisely the molecular events involved.…”

“…Recent studies demonstrated the anti-inflammatory role of 5-HT 1A and 5-HT 2B receptors on the CD4 + T cell surfaces in MS [ 6 , 7 ]. Nevertheless, the mechanisms by which 5-HT modifies autoimmune responses remain poorly understood [ 3 , 8 ].…”

A gut‐centric view of aging: Do intestinal epithelial cells contribute to age‐associated microbiota changes, inflammaging, and immunosenescence?

“…Older humans also have increased numbers of enterochromaffin cells (Yu et al, 2016 ), which secrete the hallmark hormone serotonin. Altered levels of and signaling by serotonin play a role in a variety of neurodegenerative disorders including Parkinson's disease (Fox et al, 2009 ; Politis & Niccolini, 2015 ), multiple sclerosis (Malinova et al, 2018 ; San Hernandez et al, 2020 ), and Alzheimer's disease (Mdawar et al, 2020 ; Smith et al, 2017 ). The impact of aging on enteroendocrine cells remains understudied but given the role of this IEC subtype in the sensing of and response to luminal contents and the microbiota, and their systemic effects, these cells may represent major players in the regulation of aging process and age‐associated comorbidities.…”

Therapeutic Potentials of Poly (ADP‐Ribose) Polymerase 1 (PARP1) Inhibition in Multiple Sclerosis and Animal Models: Concept Revisiting

“…Activation [ 54,55] ERK1/2 activation promotes OL differentiation and myelination, [56] enhances microglial and astroglial activation, presumably augmenting neuroinflammation, [57] promotes neuronal survival or death in a context-dependent manner [ 55,58] Neurotransmitter serotonin (5-HT) Activation [59] Serotonin levels are diminished in MS patients/5-HT may exert immunosuppressive and neuroprotective effects [60] Tumor necrotic factor alpha (TNF𝛼) Activation [61] Tumour necrosis factor alpha (TNF𝛼), upregulated in MS patients and animal models, is required for oligodendroglial remyelination, [62] regulates neuroinflammation, [63] and exerts neuroprotection [64] Neuronal activity, molecularly mediated by phospholipase C (PLC) and calmodulin-dependent kinase II (CaMKII)…”