TY - JOUR
T1 - Role of interleukin-10 in the neuroprotective effect of the Angiotensin Type 2 Receptor agonist, compound 21, after ischemia/reperfusion injury
AU - Fouda, Abdelrahman Y.
AU - Pillai, Bindu
AU - Dhandapani, Krishnan M.
AU - Ergul, Adviye
AU - Fagan, Susan C.
N1 - Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017
Y1 - 2017
N2 - Introduction We and others have shown that the angiotensin type 2 (AT2) receptor agonist, compound 21 (C21), provides neuroprotection and enhances recovery in rodent stroke models yet the mechanism involved is not known. Moreover, C21 treatment is associated with an anti-inflammatory response. Here we tested the hypothesis that C21 mediates neuroprotection by upregulating the neuroprotective and anti-inflammatory cytokine, interleukin (IL)−10. Methods Wistar rats were subjected to 3 h-middle cerebral artery suture occlusion and treated at reperfusion with C21 (0.03 mg/kg)±IL-10 neutralizing antibody (0.1 mg/kg) both given i.p. Infarct size, behavioral outcomes, and molecular analysis were performed at 24 h post-injury. Primary rat neurons were used to test the direct neuroprotective effect of C21 in vitro. Results C21 treatment reduced infarct size, improved functional outcome and decreased the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α) in the ischemic hemisphere compared to saline. Anti-IL-10 co-treatment blocked the C21-induced reduction in infarct size and inflammation, and the improvement in behavioral outcome. In vitro, C21 treatment increased neuron survival and reduced cell apoptosis after oxygen glucose deprivation (OGD) and OGD/reoxygenation. These effects were mediated through AT2R stimulation. Conclusion C21 provides direct neuroprotection as well as indirect protection through IL-10.
AB - Introduction We and others have shown that the angiotensin type 2 (AT2) receptor agonist, compound 21 (C21), provides neuroprotection and enhances recovery in rodent stroke models yet the mechanism involved is not known. Moreover, C21 treatment is associated with an anti-inflammatory response. Here we tested the hypothesis that C21 mediates neuroprotection by upregulating the neuroprotective and anti-inflammatory cytokine, interleukin (IL)−10. Methods Wistar rats were subjected to 3 h-middle cerebral artery suture occlusion and treated at reperfusion with C21 (0.03 mg/kg)±IL-10 neutralizing antibody (0.1 mg/kg) both given i.p. Infarct size, behavioral outcomes, and molecular analysis were performed at 24 h post-injury. Primary rat neurons were used to test the direct neuroprotective effect of C21 in vitro. Results C21 treatment reduced infarct size, improved functional outcome and decreased the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α) in the ischemic hemisphere compared to saline. Anti-IL-10 co-treatment blocked the C21-induced reduction in infarct size and inflammation, and the improvement in behavioral outcome. In vitro, C21 treatment increased neuron survival and reduced cell apoptosis after oxygen glucose deprivation (OGD) and OGD/reoxygenation. These effects were mediated through AT2R stimulation. Conclusion C21 provides direct neuroprotection as well as indirect protection through IL-10.
KW - And Interleukin 10
KW - Angiotensin Type 2 Receptor
KW - Compound 21
KW - Neuroprotection
KW - Stroke
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U2 - 10.1016/j.ejphar.2017.02.016
DO - 10.1016/j.ejphar.2017.02.016
M3 - Article
C2 - 28192099
AN - SCOPUS:85012940606
SN - 0014-2999
VL - 799
SP - 128
EP - 134
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
ER -