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      Downregulation of Matrix Metalloproteinases 2 and 9 is Involved in the Protective Effect of Trehalose on Spinal Cord Injury

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          Abstract

          Upregulation of matrix metalloproteinases (MMPs), in particular MMP-2 and MMP-9 contributes to secondary pathogenesis of spinal cord injury (SCI) via promoting inflammation. Recently, we have reported that trehalose suppresses inflammatory responses following SCI. Therefore, we investigated the effect of trehalose on MMP-2 and MMP-9 expression in SCI. A weight-drop contusion SCI was induced in male rats. Then, the animals received trehalose at three doses of 10 (T10), 100 (T100) and 1000 (T1000) mM intrathecally. MMP-2 and MMP-9 transcripts were then measured in damaged spinal cord at 1, 3 and 7 days after trauma, and compared with vehicle and sham groups. Additionally, behavioral analysis was conducted for 1 week using Basso-Beattie-Bresnahan (BBB) locomotor rating scale. Our data showed an early upregulation of MMP-9 at 1 day post-SCI. However, MMP-2 expression was increased at 3 days after trauma. Treatment with 10 mM trehalose significantly reduced MMP-2 expression in 3 and 7 days (P< 0.01) and MMP-9 expression in 1, 3, and 7 days (P< 0.05) post-damage compared with vehicle. Nonetheless, downregulation of both MMPs was not observed in T100 and T1000 groups. In addition, T10 group showed more rapid recovery of hind limb strength compared with T100 and T1000 groups. We propose that the neuroprotective effect of low dose trehalose is mediated by attenuation of MMP-2 and MMP-9 expression.

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          Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events.

          Staci Goussev, Stephen Donovan, Zena Werb … (2002)
          Inflammation in general and proteinases generated as a result are likely mediators of early secondary pathogenesis after spinal cord injury. We report that matrix metalloproteinase-9 (MMP-9) plays an important role in blood-spinal cord barrier dysfunction, inflammation, and locomotor recovery. MMP-9 was present in the meninges and neurons of the uninjured cord. MMP-9 increased rapidly after a moderate contusion spinal cord injury, reaching a maximum at 24 hr, becoming markedly reduced by 72 hr, and not detectable at 7 d after injury. It was seen in glia, macrophages, neutrophils, and vascular elements in the injured spinal cord at 24 hr after injury. The natural tissue inhibitors of MMPs were unchanged over this time course. MMP-9-null mice exhibited significantly less disruption of the blood-spinal cord barrier, attenuation of neutrophil infiltration, and significant locomotor recovery compared with wild-type mice. Similar findings were observed in mice treated with a hydroxamic acid MMP inhibitor from 3 hr to 3 d after injury, compared with the vehicle controls. Moreover, the area of residual white matter at the lesion epicenter was significantly greater in the inhibitor-treated group. This study provides evidence that MMP-9 plays a key role in abnormal vascular permeability and inflammation within the first 3 d after spinal cord injury, and that blockade of MMPs during this critical period attenuates these vascular events and leads to improved locomotor recovery. Our findings suggest that early inhibition of MMPs may be an efficacious strategy for the spinal cord-injured patient.
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            Acute inflammatory response in spinal cord following impact injury.

            Stephen Parrish, K Doty, Michelle Dossett … (1998)
            Numerous factors are involved in the spread of secondary damage in spinal cord after traumatic injury, including ischemia, edema, increased excitatory amino acids, and oxidative damage to the tissue from reactive oxygen species. Neutrophils and macrophages can produce reactive oxygen species when activated and thus may contribute to the lipid peroxidation that is known to occur after spinal cord injury. This study examined the rostral-caudal distribution of neutrophils and macrophages/microglia at 4, 6, 24, and 48 h after contusion injury to the T10 spinal cord of rat (10 g weight, 50 mm drop). Neutrophils were located predominantly in necrotic regions, with a time course that peaked at 24 h as measured with assays of myeloperoxidase activity (MPO). The sharpest peak of MPO activity was localized between 4 mm rostral and caudal to the injury. Macrophages/microglia were visualized with antibodies against ED1 and OX-42. Numerous cells with a phagocytic morphology were present by 24 h, with a higher number by 48 h. These cells were predominantly located within the gray matter and dorsal funiculus white matter. The number of cells gradually declined through 6 mm rostral and caudal to the lesion. OX-42 staining also revealed reactive microglia with blunt processes, particularly at levels distant to the lesion. The number of macrophages/microglia was significantly correlated with the amount of tissue damage at each level. Treatments to decrease the inflammatory response are likely to be beneficial to recovery of function after traumatic spinal cord injury. Copyright 1998 Academic Press.
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              The trehalose myth revisited: introduction to a symposium on stabilization of cells in the dry state.

              J Crowe, L M Crowe, A Oliver … (2001)
              This essay is an introduction to a series of papers arising from a symposium on stabilization of cells in the dry state. Nearly all of these investigations have utilized the sugar trehalose as a stabilizing molecule. Over the past two decades a myth has grown up about special properties of trehalose for stabilization of biomaterials. We review many of such uses here and show that under ideal conditions for drying and storage trehalose has few, if any, special properties. However, under suboptimal conditions trehalose has some distinct advantages and thus may remain the preferred excipient. We review the available mechanisms for introducing trehalose into the cytoplasm of living cells as an introduction to the papers that follow. Copyright 2001 Elsevier Science (USA).
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Mol Cell Med
                Journal ID (iso-abbrev): Int J Mol Cell Med
                Journal ID (publisher-id): IJMCM
                Title: International Journal of Molecular and Cellular Medicine
                Publisher: Babol University of Medical Sciences (Babol, Iran )
                ISSN (Print): 2251-9637
                ISSN (Electronic): 2251-9645
                Publication date (Print): Winter 2018
                Publication date (Electronic): 23 March 2018
                Volume: 7
                Issue: 1
                Pages: 8-16
                Affiliations
                [1 ] Department of Clinical Biochemistry, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman , Iran.
                [2 ] Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran.
                [3 ] Endocrinology  and Metabolism Research Center,  Institute  of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Iran.
                Author notes
                [* ]Corresponding author: Neuroscience Research Center, Institute of Neuropharmacology; Department of Clinical Biochemistry, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran. Email: mnazari@kmu.ac.ir
                Article
                DOI: 10.22088/IJMCM.BUMS.7.1.8
                PMC ID: 6134419
                SO-VID: 16f74cf6-1a55-4b53-9d01-8f7ebdcac46f
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, ( http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 6 December 2017
                Date accepted : 17 March 2018
                Categories
                Subject: Original Article

                Keywords: spinal cord injury,trehalose,matrix metalloproteinases
                Data availability:
                Keywords: spinal cord injury, trehalose, matrix metalloproteinases

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