INTRODUCTION:

Neurodegenerative disorders pose a serious risk to human health¹. Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Multiple sclerosis (MS)are the most common form of neurodegenerative disorders among several other forms². These age-related conditions are becoming more common in recent decades¹. Despite MS being a neurodegenerative disease, it can be diagnosed at a faster rate when compared to other neurodegenerative diseases. Still, effective treatment strategies have not been developed yet³. More than two million individuals worldwide have been reported to be diagnosed withMS⁴. Among them, almost one million cases of MS were reported from the United States (US), as per current research directed by the National Multiple Sclerosis Society (NMSS)^5,6.

The most common non-traumatic debilitating illness influencing young adults is MS⁷. It is a persistent autoimmune, inflammatory neurological disorder of the central nervous system (CNS)^8,9 thatdamages the myelinated axons to varying degrees^10,11. Axonal damage and further disruption of neuronal integration occurs primarily in white tissues, basal ganglia, and brain stem due to autoimmune reactions^12,13,14,15. This causes several physical, mental and psychological issues^16,17,18,19. The cause of the condition remains unclear but tends to include an association of genetic susceptibility and non-genetic triggers (viruses, metabolism, or environmental factors), both of which contribute to a self-sustaining autoimmune disorder, leading to frequent CNS immune attacks^20,21. In this condition, multiple plaques are formed in grey and white matter of the brain and spinal cord²². Based on the course of the disease, there are several forms of MS disorders, such as relapsing-remitting (RRMS)²³, secondary progressive (SPMS), primary progressive (PPMS), and progressive relapsing (PRMS) multiple sclerosis^9,24,25. The symptoms of MS include sensory deprivation, visual impairment, diplopia, muscle weakness, confusion, and loss of balance, which can significantly reduce the quality of life in individuals²⁶. The related clinical symptoms are caused by demyelination plaques in the CNS with relative axon persistence. Indeed, to relay communication between areas within the CNS, the myelin sheath around the axons is essential^27,28. Accordingly, MS has also been correlated with major depressive disorder²⁹.

The pathology of many neurological disorders such as migraine³⁰, epilepsy³¹, PD³², MS^33,34 and amyotrophic lateral sclerosis (ALS)(35), and other disorders such as attention-deficit hyperactivity disorder (ADHD)³⁶, and autism spectrum disorder (ASD)³⁷ is currently assumed to be correlated with changes in the level of serotonin. Studies suggest that the main cause of MS is decreased level of serotonin and increased level of proinflammatory cytokines (TNF-α and IL-1β)³⁸. Interestingly, in recent years, the research mainly focuses on the serotonergic system for MS by activating 5HT₇ receptors. Therefore, enhanced 5HT levels may exert both anti-inflammatory and immunosuppressive activity. Hence, this review aims to understand the mechanism behind serotonin abnormalities and their relation with pro-inflammatory cytokines in MS.

SEROTONINERGIC SYSTEM:

Serotonin is a neurotransmitter,mitogen, and hormone that has complex effects in the CNS and the periphery. It is more prevalent in the animal kingdom³⁹. Around 95 percent of 5-HT in the human body is produced in GI mucosa enterochromaffin (EC) cells and the residual 5 percent is formed by serotonergic CNS neurons⁴⁰. The amount of serotonin in the whole blood and plasma ranges from 65 -250 ng/ml and 5.6 - 23.9 ng/ml respectively⁴¹.

5-HT receptors are involved in a wide range of serotonin effects. The classification has grown into a consensus that identifies seven subgroups of 5-HT receptors(5‐HT_1–7)⁴². Approximately 25% of the three main subtypes, 5HT₁, 5HT₂, and 5HT₃, are homologous⁴³. Except for 5-HT₃, which is an ionotropic receptor, all other 5-HT receptor subtypes are members of G- protein couples receptor superfamily⁴⁴. Metabotropic serotonin receptor subgroups contain seven transmembrane domains and are classified into four types based on the G-protein form to which they are connected. The 5-HT1 receptor (5-HT1AR, 5-HT1BR, 5-HT1DR, 5-HT1ER, 5-HT1FR) bind to Gαi/Gαo proteins, while the 5-HT2 receptors (5-HT2AR, 5-HT2BR, 5-HT2C) bind to Gαq proteins and the 5-HT4R, 5-HT6R, and 5-HT7R bind to Gαs proteins⁴⁵.

The Serotonin 1 and 5 receptors are negatively coupled to adenylyl cyclase, and their activation reduces cyclic adenosine monophosphate (cAMP) regulation. The 5HT₂ receptor causes intracellular Ca²⁺ release by increasing the regulation of the inositol triphosphate and diacylglycerol pathways. The cAMP's function is improved by 5HT₄ and 5HT₇ receptors. Sodium-potassium cation channel correlated with 5HT₃ induces depolarization of the plasma membrane^46,39. Among several other 5HT receptors, the 5-HT7R is one of the recently identified receptors and is involved in both physiological and pathological central nervous system processes.As a result, this receptor is a more effective as a therapeutic target for CNS disorders⁴⁷. The activity of the receptor has anti-inflammatory and immunosuppressive properties⁴⁸, where autoimmune and inflammatory responses play an important role in determining disease severity.

PROINFLAMMATORY CYTOKINES IN MS:

To cause lymphocyte migration across the blood-brain barrier (BBB), proinflammatory cytokines must be regulated. Among several other proinflammatory cytokines, TNF-α and interleukin-1β have been detected in MS plaques at both the protein and mRNA levels⁴⁹.

TNF-α regulates homeostasis, immunity, and inflammation. The homeostatic actions of TNF-α include pathogen defense, lymphoid organ architecture formation, inflammation resolution, regeneration of tissues, immune control, tumor growth suppression, and its pathogenic roles include inflammation, vascular endothelial activation, immune cell proliferation, and tissue damage^50,51. It is formed in the periphery by macrophages, lymphocytes (T and B), NK cells, DC cells, and monocytes under physiological conditions⁵², whereas in the CNS by microglia, neurons, and astrocytes^51,52,53,54. TNF-α improves host defense mechanisms against intracellular pathogens, especially mycobacteria, and has favorable homeostatic effects in tissues at lower concentrations⁵⁵, but at high concentrations, it can cause inflammation and organ damage⁵⁶. Animal studies and human clinical trials, including the failure of an anti-TNF clinical trial, shows that TNF plays a dynamic, and probably multifaceted, function in the immunopathogenesis of MS^57,58,59.

In the CNS, IL-1β is a pro-inflammatory cytokine with neuroimmunological and neurophysiological functions. The IL-1 family consists of eleven members, the most well-studied of which are IL-1α and IL-1β. Despite being formed by different genes, both the proteins have a 25% sequence similarity at the protein level⁶⁰. Several cellular types in the peripheral and central immune systems, including blood monocytes and tissue macrophages, develop them as large precursor proteins^61,62. IL-1β levels are very low in a healthy brain, but they rise in response to a variety of conditions, including injury and peripheral inflammation^63,64. Interleukin (IL-1β) has a significant role in the development of MS⁶⁵. 5HT₇ agonist by activation through its receptor decreases the level of TNF-α and IL-1β which plays an imperative role in MS.

SEROTONIN LEVEL IN MS:

5-HT levels in the blood and platelets are lower in MS patients⁵. To better understand this phenomenon, researchers looked into the availability of 5-HT transporters (SERT) in this population (.According to a 45-person study conducted in 2014, patients with RRMS had lower transporter availability in the limbic system than healthy volunteers. SERT expression is higher in PPMS patients' prefrontal areas⁶⁶. Despite the limited sample size, this study offered a starting point for future research.After four years with the sample size of 200, a group of researchers attempted to emphasize the mechanism of SERT gene polymorphism in controlling serotonin levels. There was no difference between MS patients and healthy individuals, indicating that other pathways could be involved in this phase⁶⁷.

High latitudes have been linked to an increased risk of developing the disease and a decrease in tryptophan (TRP) intake³⁸. As a result, the lower levels of the neurotransmitter can be explained by the amino acid's limited availability. Finally, both animal and human experiments have shown that the neurons important for 5-HT synthesis in the bulbospinal region are destroyed⁶⁸. In general, several processes that influenceneurotransmitter modulation have been identified. Future studies with larger sample sizes will reveal the precise mechanisms underlying the anomalies in 5-HT levels in MS patients.

RELATION BETWEEN SEROTONIN AND PROINFLAMMATORY CYTOKINE IN THE PATHOGENESIS OF MS:

Macrophages are one of the many inflammatory cells found in MS lesions, and they play an important role. The most frequently defined subtypes are M1 and M2. M1 is a pro-inflammatory subtype that reacts to IFN- γ, and lipopolysaccharide (LPS) by releasing toxic metabolites that aggravate the inflammatory response. M2, on the other hand, is a regulatory subtype that is activated by cytokines such as interleukin-4 (IL-4) and releases anti-inflammatory mediators that prevent foci from spreading. As the condition worsens, the M1 macrophage becomes more prominent⁶⁹. On macrophages, several 5-HT receptors have been identified. Among them, activation of 5-HT7 receptors increases macrophage polarization toward the M2 subtype³⁸.

The key targets of the immune attack on MS patients are oligodendrocytes and neurons. They play a significant role in the central nervous system's myelination in the neurons⁷⁰. 5HT1A/7 receptors are found on immune cells such as monocytes and dendritic cells, and the receptor activity has been linked to anti-inflammatory effects⁷¹.

Lower Trp induces a reduction in 5-HT, which contributes to increased sensitivity to MS; this represents a potential connection between serotonin and MS⁷². Tryptophan, a precursor of serotonin, is found in people with MS at lower levels in both plasma and cerebrospinal fluids^73,74,75. Monaco et al.⁷³ discovered that not only is the volume of Trp decreasing, but so is the amount of other amino acids including leucine and valine. In MS, the ratio of neutral amino acids to Tryptophan was discovered to be considerably higher than in other neurological diseases. Trp levels in cerebrospinal fluid and plasma in patients with multiple sclerosis are consistent with decreased 5-HT brain synthesis^76,77,78. Reduction of 5-HT brain synthesis in MS has been shown to cause local 5-HT deficiency⁷⁹. According to Markianos et al.⁸⁰, the rate of impairment accumulation has a greater influence on the turnover of 5-HT than on disability itself. Axonal failure may be caused by decreased serotonergic activity. Interferon-gamma initiation of class II MHC in astrocytes is blocked by increased intracellular cyclic adenosine monophosphate levels. In MS, astrocytes produced by major histocompatibility complex (MHC) class II typically function as antigen-presenting cells and participate in inflammation⁸¹. Changes in 5-HT action have been associated not only with the manifestation of MS but also with psychological changes⁸².

Several clinical studies have found correlations between higher 5-HT levels and better health in MS patients. According to a 2016 study, physical exercise reduces the fatigue intensity scale (FSS), and this effect was linked to an increase in 5-HT levels in the same population⁸³. Similarly, a randomized controlled trial conducted in 2019 discovered that aerobic exercise enhanced 5-HT levels, which linked to improved sleep quality in participants⁸⁴. Even though both types of research had a limited sample size, the findings are promising for potential serotonergic-targeted therapies to improve the overall health and quality of life of MS patients.

Decreased inflammation may aid in MS neuroprotection because pro-inflammatory cytokines promote the production of neurotoxins such as the glutamate agonist quinolinic acid, which contributes to oligodendrocyte and neuron apoptosis⁸⁵.

The major cause of MS is due to a low level of Serotonin which is related directly or indirectly with the increased pro-inflammatory cytokines (TNFα and IL-1β). The level of serotonin is low when the cytokines are high⁸⁶. Psychiatric comorbidities, particularly those due to inappropriate 5-HT levels, are common in people with MS⁵. Serotonergic drugs used in MS induce not only symptomatic relief but also a degree of neuroprotection is achieved⁸⁷. The causes and consequences of abnormal 5-HT levels are still not well known in patients with MS⁵.

Treatment with SSRIs or increasing 5-HT reduces the severity of the disease and is linked to decreased T cell proliferation, inflammatory infiltration, and IFN production⁸⁸. T cells, along with macrophages and DC cells, are commonly recognized as key roles in MS pathogenesis.The progression of the disease can be delayed by rising 5HT levels. The elevated 5-HT levels have anti-inflammatory and immunosuppressive properties⁵.

In MS, a decrease in serotonin levels stimulates the macropage, resulting in the production of more proinflammatory cytokines (TNF-α and IL-1β). These responses cause oligodendrocyte toxicity, which leads to severe neuronal demyelination. The activation of 5HT7 receptors by its agonist inhibits macrophage activation, decreases proinflammatory cytokines and increases serotonin level and thereby prevents demyelination of neurons.

CONCLUSION:

The MS pathology encompasses both degenerative and immune processes. In the context of the immune process, the pro-inflammatory cytokines must be activated to regulate lymphocyte movement through the BBB. On the other hand in MS, reducing inflammation may indirectly lead to neuroprotection since high levels of pro-inflammatory cytokines encourage the creation of neurotoxins.Approaches to regulate pro-inflammatory cytokines in the disease require selective tuning and specificity to ensure that protective signaling outcomes are not jeopardized. Many critical questions, such as how multiple aspects and compounds regulate pro-inflammatory cytokine signaling in homeostasis and how this cytokine signaling interacts with other innate and adaptive immune pathways, remain unanswered. Future research should concentrate on gaining a thorough understanding of how the proinflammatory cytokines relate to MS pathology, as this may provide further cues for the production of treatment interventions in MS disorder.

ACKNOWLEDGEMENT:

The authors acknowledge the research infrastructure and generous support by JSS Academy of Higher Education and Research, Mysuru, India.

CONFLICT OF INTEREST:

The author declares no conflict of interest.

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Received on 15.11.2021 Modified on 19.03.2022

Research J. Pharm. and Tech 2023; 16(3):1514-1520.

DOI: 10.52711/0974-360X.2023.00248