MicroRNAs change the games in central nervous system pharmacology

Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs’ World

“…In addition, the treatment with Natalizumab restored the expression levels of miR-26a and miR-155 [90], which were upregulated in PBMCs of MS patients, as well as in urine exosome, plasma, and in the spinal cord samples from EAE mice [82]. Notably, miR-155 plays a central role in many processes involved in the pathogenesis of MS, such as immune cell activation, neurodegeneration and permeabilization of the BBB [18]. Monocytes from RRMS patients receiving Natalizumab showed reduced expression of the proinflammatory miR-155, compared to untreated MS patients [91].…”

“…Two models of miRNA-mediated therapeutic effects have been proposed: direct and indirect. The first model reveals that most of the approved drugs for NDDs can directly restore the expression level of altered miRNAs and possibly contribute to their therapeutic effect [18]. The second model suggests that miRNAs may influence the drug efficacy by regulating the expression of genes involved in drug absorption, distribution, metabolism, and excretion (ADME) [32,33].…”

“…Fingolimod, an agonist of the sphingosine-1 phosphate receptor (S1P1) that prevents immune cell migration into the brain, showed a divergent pattern in patients who started the treatment, since the plasma levels of miR-150 decreased during the treatment, while the CSF levels remained unchanged [83]. Fingolimod was also reported to restore the blood levels of several miRNAs downregulated in MS patients, including miR-23a, a key regulator of myelination [18], miR-15b, a suppressor of Th17 differentiation, and miR-223, involved in inflammatory processes by targeting STAT5 [84]. Finally, Sáenz-Cuesta et al [85] demonstrated that the first dose of Fingolimod affects the circulating extracellular vesicles (EVs) in MS patients, where an elevated EV concentration with a dramatic change in their miRNA cargo resulted since the very early administration of the drug.…”

“…In the human brain, miRNAs act not only as fine-tuners but also as master regulators of neuronal circuit development, maturation, and function, and it is able to influence processes such as cell-fate determination, cell migration, neuronal polarization, cognition, synapse formation, and plasticity [17]. Of note, the discovery of miRNAs in body fluids (blood, saliva, urine, serum, and cerebrospinal fluid, CSF) proved to be particularly relevant in NDDs, in which the analysis of peripheral biomarkers could be helpful e.g., for a more accurate detection of a given disease onset [18]. More importantly, recent studies in the field of neurodegeneration showed unexpected miRNA-mediated mechanisms in the regulation of drug response and efficacy: (i) miRNAs can regulate the expression of pharmacology-related target genes and/or (ii) pharmacological therapies can restore altered miRNA expression levels [18,19].…”

“…Of note, the discovery of miRNAs in body fluids (blood, saliva, urine, serum, and cerebrospinal fluid, CSF) proved to be particularly relevant in NDDs, in which the analysis of peripheral biomarkers could be helpful e.g., for a more accurate detection of a given disease onset [18]. More importantly, recent studies in the field of neurodegeneration showed unexpected miRNA-mediated mechanisms in the regulation of drug response and efficacy: (i) miRNAs can regulate the expression of pharmacology-related target genes and/or (ii) pharmacological therapies can restore altered miRNA expression levels [18,19]. Indeed the involvement of miRNAs in response to drugs is part of an emerging branch of pharmacogenomics, which is referred to as pharmacoepigenomics [20].…”