Current Pharmaceutical Design - Volume 28, Issue 6, 2022

There are few diseases where as much therapeutic progress has been made in recent years as in multiple sclerosis. Nine different drug classes with more than a dozen approved therapies are now available. Similarly, there have been unimaginable advances in understanding neuromyelitis optica (now neuromyelitis optica spectrum disorder [NMOSD]) over the past 15 years. Building on the knowledge gained, the first therapies have been approved in recent years. In this review, we aim to present all therapies approved for the treatment of MS or NMOSD. The different forms of application, different approval criteria and most important side effects will be presented. This work is intended for physicians who are interested in MS and NMOSD therapies and want to get a first overview and does not replace the respective guidelines of the regulatory authorities.

Significant progress has been made to understand the immunopathogenesis of multiple sclerosis (MS) over recent years. Successful clinical trials with CD20-depleting monoclonal antibodies have corroborated the fundamental role of B cells in the pathogenesis of MS and reinforced the notion that cells of the B cell lineage are an attractive treatment target. Therapeutic inhibition of Bruton's tyrosine kinase (BTK), an enzyme involved in B cell and myeloid cell activation and function, is regarded as a next-generation approach that aims to attenuate both errant innate and adaptive immune functions. Moreover, brain-penetrant BTK inhibitors may impact compartmentalized inflammation and neurodegeneration within the central nervous system by targeting brain-resident B cells and microglia, respectively. Preclinical studies in animal models of MS corroborated an impact of BTK inhibition on meningeal inflammation and cortical demyelination. Notably, BTK inhibition attenuated the antigen-presenting capacity of B cells and the generation of encephalitogenic T cells. Evobrutinib, a selective oral BTK inhibitor, has been tested recently in a phase 2 study of patients with relapsing-remitting MS. The study met the primary endpoint of a significantly reduced cumulative number of Gadolinium-enhancing lesions under treatment with evobrutinib compared to placebo treatment. Thus, the results of ongoing phase 2 and 3 studies with evobrutinib, fenobrutinib, and tolebrutinib in relapsing-remitting and progressive MS are eagerly awaited. This review article introduces the physiological role of BTK, summarizes the pre-clinical and trial evidence, and addresses the potential beneficial effects of BTK inhibition in MS.

For decades, the headache was not considered a typical symptom of multiple sclerosis (MS) and was construed as a “red flag” for important differential diagnoses such as cerebral vasculitis. Meanwhile, several studies have demonstrated an increased prevalence of headaches in MS compared to the general population. This is due to the heterogeneity of headache genesis with frequent occurrence of both primary and secondary headaches in MS. On the one hand, MS and migraine are often comorbid. On the other hand, secondary headaches frequently occur, especially in the course of MS relapses. These are often migraine-like headaches caused by inflammation, which can improve as a result of MS-specific therapy. Headaches are particularly common in the early stages of chronic inflammatory CNS disease, where inflammatory activity is the greatest. In addition, headaches can also occur as a side effect of disease-modifying drugs (DMDs). Headache can occur with most DMDs and is most frequently described with interferon-beta therapy. The aim of this work is to present the prevalence of headaches and describe the heterogeneity of possible causes of headaches in MS. In addition, important therapeutic aspects in the treatment of MS patients, in general, will be presented as well as different approaches to the treatment of headaches in MS depending on the etiological classification.

Identification of patients with antibody-mediated encephalitis poses a diagnostic challenge, and any delay in that aspect will increase the interval until the initiation of immunotherapy and may negatively affect the patient´s clinical outcome. Within this review, we focus on therapeutic strategies in antibody-mediated encephalitis and propose how to proceed with patients who are suspected of having encephalitis of unknown origin. We further briefly outline differences in the treatment of paraneoplastic and antibody-mediated encephalitis according to its pathomechanisms.

In the case of serious cardiovascular diseases, such as refractory heart failure, heart transplantation is the only possible intervention. Currently, the modes of organ transport in hypothermic cardioplegic solution do not allow the implantation of the heart beyond 4-5 hours from the explant. The heart being an organ with a greater consumption of oxygen and high metabolism than the brain, its transport in hypothermic cardioplegic solutions presents critical issues in terms of time and conservation. An ambitious goal of many researchers and clinicians is to minimize the hypoxia of the explanted heart and extend the permanence time in cardioplegic solution without damage from hypoxia. Adequately oxygenating the explanted organs may extend the usability time of the explanted organ. This challenge has been pursued for years with approaches that are often expensive, risky, and/or difficult to use. We propose to consider oxygenated nanocarriers releasing oxygen for a long time. In this way, it will also be possible to use organs from distant countries with respect to the recipient, thus exceeding the canonical 4-5 hours tolerated up to now. In addition to the lack of oxygen, the transplanted organ can undergo the accumulation of catabolites due to the lack of perfusion during transport. Therefore, nanocarriers can also be perfused in adequate solution during organ transportation. A better oxygenation improving the postoperative recovery of the transplanted heart will improve the recipient's quality of life.

The discovery of microRNAs (miRNAs) has been one of the revolutionary developments and has led to the advent of new diagnostic and therapeutic opportunities for the management of cancer. In this regard, miRNA dysregulation has been shown to play a critical role in various stages of tumorigenesis, including tumor invasion, metastasis as well as angiogenesis. Therefore, miRNA profiling can provide accurate fingerprints for the development of diagnostic and therapeutic platforms. This review discusses the recent discoveries of miRNA- based tools for early detection of cancer as well as disease monitoring in cancers that are common, like breast, lung, hepatic, colorectal, oral and brain cancer. Based on the involvement of miRNA in different cancers as oncogenic miRNA or tumor suppressor miRNA, the treatment with miRNA inhibitors or mimics is recommended. However, the stability and targeted delivery of miRNA remain the major limitations of miRNA delivery. In relation to this, several nanoparticle-based delivery systems have been reported which have effectively delivered the miRNA mimics or inhibitors and showed the potential for transforming these advanced delivery systems from bench to bedside in the treatment of cancer metastasis and chemoresistance. Based on this, we attempted to uncover recently reported advanced nanotherapeutic approaches to deliver the miRNAs in the management of different cancers.

Mitophagy plays an important role in maintaining mitochondrial quality and cell homeostasis through the degradation of damaged, aged, and dysfunctional mitochondria and misfolded proteins. Many human diseases, particularly neurodegenerative diseases, are related to disorders of mitochondrial phagocytosis. Exploring the regulatory mechanisms of mitophagy is of great significance for revealing the molecular mechanisms underlying the related diseases. Herein, we summarize the major mechanisms of mitophagy, the relationship of mitophagy with human diseases, and the role of traditional Chinese medicine (TCM) in mitophagy. These discussions enhance our knowledge of mitophagy and its potential therapeutic targets using TCM.

Background: Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common diseases that result in limb disability and a decrease in quality of life. The major symptoms of OA and RA are pain, swelling, stiffness, and malformation of joints, and each disease also has unique characteristics. Objective: To compare the pathological mechanisms of OA and RA via weighted correlation network analysis (WGCNA) and immune infiltration analysis and find potential diagnostic and pharmaceutical targets for the treatment of OA and RA. Methods: The gene expression profiles of ten OA and ten RA synovial tissue samples were downloaded from the Gene Expression Omnibus (GEO) database (GSE55235). After obtaining differentially expressed genes (DEGs) via GEO2R, WGCNA was conducted using an R package, and modules and genes that were highly correlated with OA and RA were identified. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and protein-protein interaction (PPI) network analyses were also conducted. Hub genes were identified using the Search Tool for the Retrieval of Interacting Genes (STRING) and Cytoscape software. Immune infiltration analysis was conducted using the Perl program and CIBERSORT software. Results: Two hundred ninety-nine DEGs, 24 modules, 16 GO enrichment terms, 6 KEGG pathway enrichment terms, 10 hub genes (CXCL9, CXCL10, CXCR4, CD27, CD69, CD3D, IL7R, STAT1, RGS1, and ISG20), and 8 kinds of different infiltrating immune cells (plasma cells, CD8 T cells, activated memory CD4 T cells, T helper follicular cells, M1 macrophages, Tregs, resting mast cells, and neutrophils) were found to be involved in the different pathological mechanisms of OA and RA. Conclusion: Inflammation-associated genes were the top differentially expressed hub genes between OA and RA, and their expression was downregulated in OA. Genes associated with lipid metabolism may have upregulated expression in OA. In addition, immune cells that participate in the adaptive immune response play an important role in RA. OA mainly involves immune cells that are associated with the innate immune response.