Propane-2-sulfonic acid octadec-9-enyl-amide, a novel PPARα/γ dual agonist, protects against ischemia-induced brain damage in mice by inhibiting inflammatory responses
Copyright © 2017. Published by Elsevier Inc..
Propane-2-sulfonic acid octadec-9-enyl-amide (N15), an analogue of oleoylethanolamide (OEA), is a novel PPARα/γ dual agonist. Our previous studies verified the positive effects of OEA on the acute and delayed stages of cerebral ischemia. However, it is not clear whether N15 is effective against ischemic cerebral injury. In the present study, male Kunming mice were subjected to middle cerebral artery occlusion (MCAO). To evaluate its preventive effects, N15 (50, 100 or 200mg/kg, ip) was administered for 3days before ischemia. To evaluate its therapeutic effects, N15 (200mg/kg, ip) was administered 1h before reperfusion or 0, 1, 2 or 4h after reperfusion. Neurological deficit scores, infarct volume and the degree of brain oedema were determined at 24h after reperfusion. Blood brain barrier (BBB) disruption was evaluated by Evans blue (EB) and FITC-dextran leakages at 6h after reperfusion. The activation/inflammatory responses of microglia/macrophages were detected using immunohistochemistry and western blot. N15 pretreatment improved neurological dysfunction, reduced infarct volume and alleviated brain oedema in a dose-dependent manner; the most effective dose was 200mg/kg. The therapeutic time window was within 2h after reperfusion. N15 treatment preserved the BBB integrity and suppressed the activation of microglia/macrophages. N15 inhibited inflammatory cytokine expression not only in MCAO mice but also in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Additionally, N15 markedly decreased the phosphorylation levels of NF-κBp65, STAT3, and ERK1/2 both in vivo and in vitro. Furthermore, the PPARα antagonist MK886 or PPARγ antagonist T0070907 respectively partly abolished the anti-inflammatory effects of N15 in vitro. Our findings demonstrated that N15 can exert neuroprotective effects against cerebral ischemic insult. Moreover, the neuroprotective effects of N15 on cerebral ischemia may be attributed to its anti-inflammatory properties, at least in part, by enhancing PPARα/γ dual signaling and inhibiting the activation of the NF-κB, STAT3, and ERK1/2 signaling pathways. These findings suggest that N15 may be a potential therapeutic choice for the prevention and treatment of ischemic stroke.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2017 |
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| Erschienen: |
2017 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:66 |
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| Enthalten in: |
Brain, behavior, and immunity - 66(2017) vom: 01. Nov., Seite 289-301 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Ying [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 06.06.2018 Date Revised 06.06.2018 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bbi.2017.07.015 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM274108925 |
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| 245 | 1 | 0 | |a Propane-2-sulfonic acid octadec-9-enyl-amide, a novel PPARα/γ dual agonist, protects against ischemia-induced brain damage in mice by inhibiting inflammatory responses |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2017. Published by Elsevier Inc. | ||
| 520 | |a Propane-2-sulfonic acid octadec-9-enyl-amide (N15), an analogue of oleoylethanolamide (OEA), is a novel PPARα/γ dual agonist. Our previous studies verified the positive effects of OEA on the acute and delayed stages of cerebral ischemia. However, it is not clear whether N15 is effective against ischemic cerebral injury. In the present study, male Kunming mice were subjected to middle cerebral artery occlusion (MCAO). To evaluate its preventive effects, N15 (50, 100 or 200mg/kg, ip) was administered for 3days before ischemia. To evaluate its therapeutic effects, N15 (200mg/kg, ip) was administered 1h before reperfusion or 0, 1, 2 or 4h after reperfusion. Neurological deficit scores, infarct volume and the degree of brain oedema were determined at 24h after reperfusion. Blood brain barrier (BBB) disruption was evaluated by Evans blue (EB) and FITC-dextran leakages at 6h after reperfusion. The activation/inflammatory responses of microglia/macrophages were detected using immunohistochemistry and western blot. N15 pretreatment improved neurological dysfunction, reduced infarct volume and alleviated brain oedema in a dose-dependent manner; the most effective dose was 200mg/kg. The therapeutic time window was within 2h after reperfusion. N15 treatment preserved the BBB integrity and suppressed the activation of microglia/macrophages. N15 inhibited inflammatory cytokine expression not only in MCAO mice but also in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Additionally, N15 markedly decreased the phosphorylation levels of NF-κBp65, STAT3, and ERK1/2 both in vivo and in vitro. Furthermore, the PPARα antagonist MK886 or PPARγ antagonist T0070907 respectively partly abolished the anti-inflammatory effects of N15 in vitro. Our findings demonstrated that N15 can exert neuroprotective effects against cerebral ischemic insult. Moreover, the neuroprotective effects of N15 on cerebral ischemia may be attributed to its anti-inflammatory properties, at least in part, by enhancing PPARα/γ dual signaling and inhibiting the activation of the NF-κB, STAT3, and ERK1/2 signaling pathways. These findings suggest that N15 may be a potential therapeutic choice for the prevention and treatment of ischemic stroke | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Activated microglia/macrophages | |
| 650 | 4 | |a Focal cerebral ischemia | |
| 650 | 4 | |a Inflammation | |
| 650 | 4 | |a Mice | |
| 650 | 4 | |a Propane-2-sulfonic acid octadec-9-enyl-amide | |
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| 650 | 7 | |a Neuroprotective Agents |2 NLM | |
| 650 | 7 | |a PPAR alpha |2 NLM | |
| 650 | 7 | |a PPAR gamma |2 NLM | |
| 650 | 7 | |a STAT3 Transcription Factor |2 NLM | |
| 650 | 7 | |a Stat3 protein, mouse |2 NLM | |
| 650 | 7 | |a Sulfonic Acids |2 NLM | |
| 650 | 7 | |a propane-2-sulfonic acid octadec-9-enyl-amide |2 NLM | |
| 700 | 1 | |a Xu, Lanxi |e verfasserin |4 aut | |
| 700 | 1 | |a Zeng, Kaiyue |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Zhentian |e verfasserin |4 aut | |
| 700 | 1 | |a Suo, Daqin |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Lu |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Tong |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Zhiheng |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Wushuang |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Lichao |e verfasserin |4 aut | |
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