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      Zafirlukast in combination with pseudohypericin attenuates spinal cord injury and motor function in experimental mice

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          Abstract

          Background

          Biosynthesis of leukotriene (LT) by arachidonic acid involves 5-lipoxygenase (5-LO) as an important precursor. Here, we evaluated the role of pseudohypericin (PHP) for its postulated 5-LO inhibitory activity along with a Cys-LT receptor antagonist zafirlukast (ZFL) against inflammatory response and tissue injury in mice.

          Materials and methods

          The spinal injury was induced by two-level laminectomy of T6 and T7 vertebrae. The inflammation was assessed by histology, inflammatory mediators by enzyme-linked immunosorbent assay, apoptosis by Annexin-V, FAS staining, terminal deoxynucleoti-dyltransferase-mediated UTP end labeling (TUNEL) assay and expression of Bax and Bcl-2 by Western blot. Effect on motor recovery of hind limbs was evaluated for 10 days postinjury.

          Results

          The spinal injury resulted in tissue damage, apoptosis, edema, infiltration of neutrophils with increased expression of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). The spinal tissue showed elevated levels of prostaglandin E 2 (PGE2), and LTB 4 and increased phosphorylation of injured extracellular signal-regulated kinase-1/2 (ERK1/2). The PHP, ZFL and combination decreased inflammation, tissue injury and infiltration of neutrophils. Treatment also decreased the levels of PGE 2, phosphorylation of extracellular signal-regulated kinase-1/2 (pERK 1/2), LT, TNF-α and COX-2 with a marked reduction in apoptosis and improved the motor function.

          Conclusion

          The present study confirmed 5-LO antagonist activity of PHP and established its neuroprotective role along with ZFL.

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          Most cited references 34

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          Myeloperoxidase activity as a quantitative assessment of neutrophil infiltration into ischemic myocardium.

          The infiltration of neutrophils into ischemic myocardium exacerbates myocardial damage upon reperfusion, whereas drugs that inhibit neutrophil activity or function reduce infarct size. Consequently, it is important to accurately assess the myocardial neutrophil content. Histologic sections and radiolabeled cells have been used, but have major limitations. We have developed a method to measure the neutrophils present in cardiac tissue by utilizing a spectrophotometric assay for the neutrophil-specific myeloperoxidase enzyme (MPO) (Bradley et al., 1982a). Coronary artery occlusion and reperfusion in the anesthetized dog induces neutrophil accumulation into the ischemic heart, which shows a linear relationship with time. An increase in activity from 0.014 +/- 0.001 units (u) MPO/100 mg tissue to 0.091 +/- 0.02 u MPO/100 mg is already apparent at the end of the 90-min occlusion period. This activity increases over 5 hr reperfusion to 0.32 +/- 0.018 u MPO/100 mg tissue. Histologic analyses confirmed the temporal association of neutrophil accumulation. Moreover, there is a correlation between infarct size and tissue MPO activity. Measuring the MPO content in preparations of canine neutrophils, which is directly correlated with cell number, allows units of MPO activity to be converted into a tissue neutrophil content. This assay is simple, sensitive, and provides a quantitative index of myocardial neutrophil accumulation that can be used to study the relationship between leukocyte infiltration and myocardial injury.
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            Degenerative and regenerative mechanisms governing spinal cord injury.

            Spinal cord injury (SCI) is a major cause of disability, and at present, there is no universally accepted treatment. The functional decline following SCI is contributed to both direct mechanical injury and secondary pathophysiological mechanisms that are induced by the initial trauma. These mechanisms initially involve widespread haemorrhage at the site of injury and necrosis of central nervous system (CNS) cellular components. At later stages of injury, the cord is observed to display reactive gliosis. The actions of astrocytes as well as numerous other cells in this response create an environment that is highly nonpermissive to axonal regrowth. Also manifesting important effects is the immune system. The early recruitment of neutrophils and at later stages, macrophages to the site of insult cause exacerbation of injury. However, at more chronic stages, macrophages and recruited T helper cells may potentially be helpful by providing trophic support for neuronal and non-neuronal components of the injured CNS. Within this sea of injurious mechanisms, the oligodendrocytes appear to be highly vulnerable. At chronic stages of SCI, a large number of oligodendrocytes undergo apoptosis at sites that are distant to the vicinity of primary injury. This leads to denudement of axons and deterioration of their conductive abilities, which adds significantly to functional decline. By indulging into the molecular mechanisms that cause oligodendrocyte apoptosis and identifying potential targets for therapeutic intervention, the prevention of this apoptotic wave will be of tremendous value to individuals living with SCI.
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              Cell death in models of spinal cord injury.

              Current treatments for acute spinal cord injury are based on animal models of human spinal cord injury (SCI). These models have shown that the initial traumatic injury to cord tissue is followed by a long period of secondary injury that includes a number of cellular and biochemical cascades. These secondary injury processes are potential targets for therapies. Continued refinement of rat and mouse models of SCI, along with more detailed analyses of the biology of the lesion in these models, points to both necrotic and apoptotic mechanisms of cell death after SCI. In this chapter, we review recent evidence for long-term apoptotic death of oligodendrocytes in long tracts undergoing Wallerian degeneration following SCI. This process appears to be related closely to activation of microglial cells. It is has been thought that microglial cells might be the source of cytotoxic cytokines, such as tumor necrosis factor-alpha (TNF-alpha), that kill oligodendrocytes. However, more recent evidence in vivo suggests that TNF-alpha by itself may not induce necrosis or apoptosis in oligodendrocytes. We review data that suggests other possible pathways for apoptosis, such as the neurotrophin receptor p75 which is expressed in both neurons and oligodendrocytes after SCI in rats and mice. In addition, it appears that microglial activation and TNF-alpha may be important in acute SCI. Ninety minutes after a moderate contusion lesion, microglia are activated and surround dying neurons. In an 'atraumatic' model of SCI, we have now shown that TNF-alpha appears to greatly potentiate cell death mediated by glutamate receptors. These studies emphasize that multiple mechanisms and interactions contribute to secondary injury after SCI. Continued study of both contusion models and other new approaches to studying these mechanisms will be needed to maximize strategies for acute and chronic therapies, and for neural repair.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                01 August 2018
                : 12
                : 2389-2402
                Affiliations
                [1 ]Department of Orthopedics, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu 223300, People’s Republic of China, xopfix493051@ 123456163.com
                [2 ]Department of Gynaecology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu 223300, People’s Republic of China
                Author notes
                Correspondence: Xiao-Gang Chen, Department of Orthopedics, Huai’an First People’s Hospital, Nanjing Medical University, No 6, Beijing West Road, Huai’an, Jiangsu 223300, People’s Republic of China, Email xopfix493051@ 123456163.com
                Article
                dddt-12-2389
                10.2147/DDDT.S154814
                6078184
                © 2018 Chen et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                mice, pseudohypericin, cys-lt, 5-lipoxygenase, zafirlukast

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