Astrocytic N-Myc Downstream-regulated Gene–2 Is Involved in Nuclear Transcription Factor κB–mediated Inflammation Induced by Global Cerebral Ischemia

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Abstract

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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