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Hanada M.,Hamamatsu University School of Medicine | Shinjo R.,Nagoya University | Miyagi M.,Hamamatsu University School of Medicine | Yasuda T.,Hamamatsu University School of Medicine | And 6 more authors.
Journal of the Neurological Sciences | Year: 2014

Background Arundic acid (ONO-2506) inhibits the production and release of S100 protein from astrocytes. While numerous studies have assessed the effect of ONO-2506 in the diseased brain, to the best of our knowledge, no study has examined the effect of ONO-2506 in spinal cord injury (SCI). In this study, we administered ONO-2506 to rats with SCI in order to evaluate its effectiveness in improving motor function and protecting against histological injury. Methods All rats underwent laminectomy with SCI at the 10th thoracic vertebra. Rats were divided into 3 groups that received different concentrations of ONO-2506 as follows: 10 mg/kg (Group I) and 20 mg/kg (Group II). The third group (control group) was administered only saline. ONO-2506 or saline was administered by intravenous injection for a week after SCI. Recovery of motor function was assessed by determining the Basso, Beattie, and Bresnahan (BBB) scores and using the %grip test. Using immunohistochemistry, S100 protein and glial fibrillary acidic protein expression was assessed at week 12 post SCI. Results The BBB score of Group II was significantly better than that of the control group. At week 12 post SCI, the %grip was 43.0% in Group II and 20.3% in Group I. The score for the %grip test was greater for Group II than for the control group (7.0%); thus, motor function improvement appeared to be dose dependent. Regarding immunostaining evaluation, S100 protein staining was lower in Group II compared to the control group, and the astrocytic morphology resembled that of normal spinal cord sections. The SCI lesion expanded from the injured site to both proximal and distal sites in the control group and in Group I. However, despite the presence of cavitation, secondary expansion of the SCI lesion was prevented in Group II as a result of inhibition of S100 protein. Conclusions Administration of ONO-2506 (20 mg/kg) improves motor function and inhibits expansion of secondary injury in SCI rats. © 2013 Elsevier B.V. Source

Hanada M.,Hamamatsu University School of Medicine | Tsutsumi K.,Kitasato University | Arima H.,Hamamatsu University School of Medicine | Shinjo R.,Nagoya University | And 5 more authors.
Journal of the Neurological Sciences | Year: 2014

Results Motor function recovery, BBB score, and the %grip test were significantly higher in the tranilast-treated groups than in the control group. At week 1 after SCI, inflammatory-cell invasion was more severe and Iba1 expression was significantly higher in the control group. At week 8, although the number of GFAP-positive cells increased greatly from the impaction site to the proximal and distal sites in the control group, these cells were confined around a cavity in the tranilast-treated groups. GFAP distribution coincided with that of fibronectin. Anti-CS antibody level in the tranilast-treated groups was significantly lower than that in the control group.Conclusions Tranilast inhibits inflammation in the acute phase of SCI and reduces glial and fibrotic scars and could present a new method for treating SCI.Background Glial and fibrotic scars inhibit neural regeneration after spinal cord injury (SCI). N-[3,4-dimethoxycinnamoyl]-anthranilic acid (tranilast) inhibits transforming growth factor β, alleviates allergic reactions, and decreases hypertrophic skin scars. We evaluated its ability to improve motor function and inhibit the spread of tissue damage in rats with SCI.Methods Rats with SCI were divided into groups that received tranilast (30 mg/[kg·day]) by intravenous administration (group IV), tranilast (200 mg/[kg·day]) by oral administration (group OR), and saline injections (control). Motor functions were assessed by determining Basso, Beattie, and Bresnahan (BBB) scores and %grip tests for 8 weeks after SCI. Histological evaluation of ionized calcium binding adaptor molecule 1 (Iba1) at 1 week after SCI and glial fibrillary acidic protein (GFAP), fibronectin, and chondroitin sulfate (CS) at week 8 was performed. © 2014 Elsevier B.V. All rights reserved. Source

Kobayashi T.,National Health Research Institute | Shimabukuro-Demoto S.,National Health Research Institute | Yoshida-Sugitani R.,National Health Research Institute | Furuyama-Tanaka K.,National Health Research Institute | And 12 more authors.
Immunity | Year: 2014

SLC15A4 is a lysosome-resident, proton-coupled amino-acid transporter that moves histidine and oligopeptides from inside the lysosome to the cytosol of eukaryotic cells. SLC15A4 is required for Toll-like receptor 7 (TLR7)- and TLR9-mediated type I interferon (IFN-I) productions in plasmacytoid dendritic cells (pDCs) and is involved in the pathogenesis of certain diseases including lupus-like autoimmunity. How SLC15A4 contributes to diseases is largely unknown. Here we have shown that B cell SLC15A4 was crucial for TLR7-triggered IFN-I and autoantibody productions in a mouse lupus model. SLC15A4 loss disturbed the endolysosomal pH regulation and probably the v-ATPase integrity, and these changes were associated with disruption of the mTOR pathway, leading to failure of the IFN regulatory factor 7 (IRF7)-IFN-I regulatory circuit. Importantly, SLC15A4's transporter activity was necessary for the TLR-triggered cytokine production. Our findings revealed that SLC15A4-mediated optimization of the endolysosomal state is integral to a TLR7-triggered, mTOR-dependent IRF7-IFN-I circuit that leads to autoantibody production. © 2014 Elsevier Inc. Source

Takenouchi T.,Keio University | Sugiura Y.,Keio University | Sugiura Y.,JST Precursory Research for Embryonic Science and Technology PRESTO Project | Morikawa T.,Keio University | And 20 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2015

Although therapeutic hypothermia is known to improve neurologic outcomes after perinatal cerebral hypoxia-ischemia, etiology remains unknown. To decipher the mechanisms whereby hypothermia regulates metabolic dynamics in different brain regions, we used a two-step approach: a metabolomics to target metabolic pathways responding to cooling, and a quantitative imaging mass spectrometry to reveal spatial alterations in targeted metabolites in the brain. Seven-day postnatal rats underwent the permanent ligation of the left common carotid artery followed by exposure to 8% O 2 for 2.5 hours. The pups were returned to normoxic conditions at either 38°C or 30°C for 3 hours. The brain metabolic states were rapidly fixed using in situ freezing. The profiling of 107 metabolites showed that hypothermia diminishes the carbon biomass related to acetyl moieties, such as pyruvate and acetyl-CoA; conversely, it increases deacetylated metabolites, such as carnitine and choline. Quantitative imaging mass spectrometry demarcated that hypothermia diminishes the acetylcholine contents specifically in hippocampus and amygdala. Such decreases were associated with an inverse increase in carnitine in the same anatomic regions. These findings imply that hypothermia achieves its neuroprotective effects by mediating the cellular acetylation status through a coordinated suppression of acetyl-CoA, which resides in metabolic junctions of glycolysis, amino-acid catabolism, and ketolysis. © 2015 ISCBFM. Source

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