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Astrocytic N-Myc Downstream-regulated Gene-2 Is Involved in Nuclear Transcription Factor κB-mediated Inflammation
You-Liang Deng1, Yu-Long Ma, Zeng-Li Zhang
1From the Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China (Y.D., Y.M., P.Q., Y.H., Z.G., W.H.); Anesthesia and Operation Center, People's Liberation Army of China General Hospital, Beijing, China (Y.M.); Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China (Z.Z.); First Affiliated Hospital to People's Liberation Army of China General Hospital, Beijing, China (L.Z.); and Department of Anesthesiology, People's Liberation Army of China General Hospital, Beijing, China (H.G.).
Background:
Inflammation is a key element in the pathophysiology of cerebral ischemia. This study investigated the role of N-Myc downstream-regulated gene-2 in nuclear transcription factor κB-mediated inflammation in ischemia models.
Methods:
Mice (n = 6 to 12) with or without nuclear transcription factor κB inhibitor pyrrolidinedithiocarbamate pretreatment were subjected to global cerebral ischemia for 20 min. Pure astrocyte cultures or astrocyte-neuron cocultures (n = 6) with or without pyrrolidinedithiocarbamate pretreatment were exposed to oxygen-glucose deprivation for 4 h or 2 h. Astrocytic nuclear transcription factor κB and N-Myc downstream-regulated gene-2 expression, proinflammatory cytokine secretion, neuronal apoptosis and survival, and memory function were analyzed at different time points after reperfusion or reoxygenation. Proinflammatory cytokine secretion was also studied in lentivirus-transfected astrocyte lines after reoxygenation.
Results:
Astrocytic nuclear transcription factor κB and N-Myc downstream-regulated gene-2 expression and proinflammatory cytokine secretion increased after reperfusion or reoxygenation. Pyrrolidinedithiocarbamate pretreatment significantly reduced N-Myc downstream-regulated gene-2 expression and proinflammatory cytokine secretion in vivo and in vitro, reduced neuronal apoptosis induced by global cerebral ischemia/reperfusion (from 65 ± 4% to 47 ± 4%, P = 0.0375) and oxygen-glucose deprivation/reoxygenation (from 45.6 ± 0.2% to 22.0 ± 4.0%, P < 0.001), and improved memory function in comparison to vehicle-treated control animals subjected to global cerebral ischemia/reperfusion. N-Myc downstream-regulated gene-2 lentiviral knockdown reduced the oxygen-glucose deprivation-induced secretion of proinflammatory cytokines.
Conclusions:
Astrocytic N-Myc downstream-regulated gene-2 is up-regulated after cerebral ischemia and is involved in nuclear transcription factor κB-mediated inflammation. Pyrrolidinedithiocarbamate alleviates ischemia-induced neuronal injury and hippocampal-dependent cognitive impairment by inhibiting increases in N-Myc downstream-regulated gene-2 expression and N-Myc downstream-regulated gene-2-mediated inflammation.
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