Neurodegeneration in Multiple Sclerosis: Symptoms of Silent Progression, Biomarkers and Neuroprotective Therapy—Kynurenines Are Important Players

Abstract

Neurodegeneration is one of the driving forces behind the pathogenesis of multiple sclerosis (MS). Progression without activity, pathopsychological disturbances (cognitive impairment, depression, fatigue) and even optic neuropathy seems to be mainly routed in this mechanism. In this article, we aim to give a comprehensive review of the clinical aspects and symptomology, radiological and molecular markers and potential therapeutic targets of neurodegeneration in connection with MS. As the kynurenine pathway (KP) was evidenced to play an important role in the pathogenesis of other neurodegenerative conditions (even implied to have a causative role in some of these diseases) and more and more recent evidence suggest the same central role in the neurodegenerative processes of MS as well, we pay special attention to the KP. Metabolites of the pathway are researched as biomarkers of the disease and new, promising data arising from clinical evaluations show the possible therapeutic capability of KP metabolites as neuroprotective drugs in MS. Our conclusion is that the kynurenine pathway is a highly important route of research both for diagnostic and for therapeutic values and is expected to yield concrete results for everyday medicine in the future.

Symptom Interconnectivity in Multiple Sclerosis: A Narrative Review of Potential Underlying Biological Disease Processes

“…As our understanding of the biological pathways leading to, and connecting, symptoms of interest increases, it may become possible to identify potential novel therapeutic and non-pharmacological strategies that target several of these symptoms at once. Future therapeutics that could plausibly alleviate multiple symptoms simultaneously include neuro-restorative agents [ 301 ], kynurenine metabolites and analogues [ 317 ], and agents that regulate the HPA axis.…”

Exosomes-Based Nanomedicine for Neurodegenerative Diseases: Current Insights and Future Challenges

“…It is considered the most prevalent chronic inflammatory disease of the CNS, affecting more than 2 million people worldwide [ 150 ]. Although MS is not categorized as a purely neurodegenerative disease, its pathological processes lead to the irreversible destruction of neural tissue [ 151 , 152 , 153 ]. Several authors have studied the therapeutic potential of exosomes in MS in relation to the demyelination process by targeting the neuroinflammation cascade.…”

Proteomics in Multiple Sclerosis: The Perspective of the Clinician

“…Regarding the second inflammatory process, the key players are the CD20+ B cells. These cells can be found in the connective tissue in the CNS as well, mainly in the meninges and the Virchow-Robin spaces forming inflammatory aggregates, so-called "ectopic germinal centers", there [28][29][30]. The activation of these cells leads to a diffuse damage in the normal-appearing white and grey matter, and the subpial cortical regions [29,30].…”

“…Biomarkers were defined by the World Health Organization as "any substance, structure, or process that can be measured in the body or its products and influence or predict the incidence of outcome or disease" [61]. This broad definition allows any type of quan-tifiable attribute to become a biomarker; however, in molecular medicine, the molecules that are viewed as potential biomarkers are those that can reliably differentiate between a physiological and a pathophysiological process or predict or monitor a certain outcome in a given condition [30]. There is an abundance of molecular biomarkers routinely utilized in everyday medical practice: considering a routine blood test, C-reactive protein and procalcitonin levels are markers of inflammation, the liver transaminase levels measure the metabolic state of the liver, creatinine and urea levels measure kidney functions and the list goes on.…”

“…In addition, in 2015, a high quality assessment compared the serum proteome of "benign" MS patients and "aggressive" MS patients. Though there is more than one definition for both entities, they utilized the definition of EDSS score ≤ 3 points after ≥20 years of disease duration for "benign" MS and EDSS score ≥ 6 points within 10 years of the disease onset for "aggressive" MS [30,180,181]. They identified 11 proteins, of which 7 had increased levels in the aggressive phenotype (thrombospondin-1, platelet basic protein, insulin-like growth factor-binding protein 3, cholinesterase, protein S100-A9, platelet glycoprotein V and ficolin-2) and 4 in the benign phenotype (leucine-rich α-2-glycoprotein, corticosteroidbinding globulin, iter-α-trypsin inhibitor heavy chain H4 and lipopolysaccharide-binding protein) [180].…”