Novel therapeutic approaches for treatment of COVID-19

To date, there is no licensed treatment or approved vaccine to combat the coronavirus disease of 2019 (COVID-19), and the number of new cases and mortality multiplies every day. Therefore, it is essential to develop an effective treatment strategy to control the virus spread and prevent the disease. Here, we summarized the therapeutic approaches that are used to treat this infection. Although it seems that antiviral drugs are effective in improving clinical manifestation, there is no definite treatment protocol. Lymphocytopenia, excessive inflammation, and cytokine storm followed by acute respiratory distress syndrome are still unsolved issues causing the severity of this disease. Therefore, immune response modulation and inflammation management can be considered as an essential step. There is no doubt that more studies are required to clarify immunopathogenesis and immune response; however, new therapeutic approaches including mesenchymal stromal cell and immune cell therapy showed inspiring results. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature

Anti-inflammatory effect of KW-2449 on autoimmune encephalomyelitis: An experimental study on mice

Background: The KW-2449 is a novel multikinase inhibitor that inhibits FLT3, ABL, ABL-T315I, and Aurora A. FLT3 and Aurora A kinases play an important role in the pathogenesis of multiple sclerosis (MS). KW-2449 could modulate immune cells, but the immunomodulatory effects of KW-2449 on experimental autoimmune encephalomyelitis (EAE) have not been investigated yet. The aim of the present study is to investigate the effects of KW-2449 on EAE mouse model. Methods: In this study, C57BL/6 EAE mice were orally treated with (10 mg/kg/day) KW-2449 solution and compared with EAE and control mice. Following the treatment, histological analyses were performed on the brain and cerebellum to evaluate the pathological score. The gene expression levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2) were measured using qRT-PCR. The serum levels of TNF-α, IL-6, CCL-2 and MMP-2 were determined by using quantitative enzyme-linked immunosorbent assay (ELISA). Results: The results indicated that the clinical score, the infiltration of inflammatory cells and the demyelination in EAE mice treated with KW-2449 decreased significantly compared to control groups. KW-2449 also decreased TNF-α, IL-6, CCL-2 inflammatory cytokines, and MMP-2 in both brain mRNA expressions and serum levels of EAE mice. Conclusion: The KW-2449, aging as a multi-kinase inhibitor, modulates the inflammatory responses of cytokine cascades either in the brain or in plasma and reduces EAE pathogenesis manifestation

Anti-inflammatory effect of KW-2449 on autoimmune encephalomyelitis: An experimental study on mice

Background: The KW-2449 is a novel multikinase inhibitor that inhibits FLT3, ABL, ABL-T315I, and Aurora A. FLT3 and Aurora A kinases play an important role in the pathogenesis of multiple sclerosis (MS). KW-2449 could modulate immune cells, but the immunomodulatory effects of KW-2449 on experimental autoimmune encephalomyelitis (EAE) have not been investigated yet. The aim of the present study is to investigate the effects of KW-2449 on EAE mouse model. Methods: In this study, C57BL/6 EAE mice were orally treated with (10 mg/kg/day) KW-2449 solution and compared with EAE and control mice. Following the treatment, histological analyses were performed on the brain and cerebellum to evaluate the pathological score. The gene expression levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2) were measured using qRT-PCR. The serum levels of TNF-α, IL-6, CCL-2 and MMP-2 were determined by using quantitative enzyme-linked immunosorbent assay (ELISA). Results: The results indicated that the clinical score, the infiltration of inflammatory cells and the demyelination in EAE mice treated with KW-2449 decreased significantly compared to control groups. KW-2449 also decreased TNF-α, IL-6, CCL-2 inflammatory cytokines, and MMP-2 in both brain mRNA expressions and serum levels of EAE mice. Conclusion: The KW-2449, aging as a multi-kinase inhibitor, modulates the inflammatory responses of cytokine cascades either in the brain or in plasma and reduces EAE pathogenesis manifestation. © 2021 Bentham Science Publishers

The effects of D-aspartate on neurosteroids, neurosteroid receptors, and inflammatory mediators in experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is a widely used model for multiple sclerosis. The present study has been designed to compare the efficiencies of oral and intraperitoneal (IP) administration of D-aspartate (D-Asp) on the onset and severity of EAE, the production of neurosteroids, and the expression of neurosteroid receptors and inflammatory mediators in brain of EAE mice.Objective: Experimental autoimmune encephalomyelitis (EAE) is a widely used model for multiple sclerosis. The present study has been designed to compare the efficiencies of oral and intraperitoneal (IP) administration of D-aspartate (D-Asp) on the onset and severity of EAE, the production of neurosteroids, and the expression of neurosteroid receptors and inflammatory mediators in the brain of EAE mice. Methods: In this study, EAE was induced in C57BL/6 mice treated with D-Asp orally (D-Asp-Oral) or by IP injection (D-Asp-IP). On the 20th day, brains (cerebrums) and cerebellums of mice were evaluated by histological analyses. The brains of mice were analyzed for: 1) Neurosteroid (Progesterone, Testosterone, 17β-estradiol) concentrations; 2) gene expressions of cytokines and neurosteroid receptors by reverse transcription polymerase chain reaction, and 3) quantitative determination of D-Asp using liquid chromatography-tandem mass spectrometry. Further, some inflammatory cytokines and matrix metalloproteinase-2 (MMP-2) were identified in the mouse serum using enzyme-linked immunosorbent assay kits. Results: Our findings demonstrated that after D-Asp was administered, it was taken up and accumulated within the brain. Further, IP injection of D-Asp had more beneficial effects on EAE severity than oral gavage. The concentration of the testosterone and 17β-estradiol in D-Asp-IP group was significantly higher than that of the control group. There were no significant differences in the gene expression of cytokine and neurosteroid receptors between control, D-Asp-IP, and D-Asp-Oral groups. However, IP treatment with D-Asp significantly reduced C-C motif chemokine ligand 2 and MMP-2 serum levels compared to control mice. Conclusion: IP injection of D-Asp had more beneficial effects on EAE severity, neurosteroid induction and reduction of inflammatory mediators than oral gavage