Activation of RAGE (receptor for advanced glycation endproducts) plays a role in neuronal damage and neuroinflammation associated with brain ischemia, though the underlying mechanisms remain unclear. Poly(ADP-ribose) polymerase-1 (PARP-1) is a coactivator of the transcription factor NF-kB, that mediates inflammatory responses in cerebral ischemia. The PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide (PJ34) prevents IkB-alpha degradation, thus blocking NF-kB activation, and reduces brain damage following cerebral ischemia. In this study, we have investigated whether inhibition of PARP modulates RAGE expression in the cerebral cortex and soluble RAGE form (sRAGE) in male Wistar rats subjected to transient (1h) middle cerebral artery occlusion (tMCAo). After 24h of reperfusion, cortical RAGE expression was evaluated by western blotting, while circulating RAGE was quantified by ELISA. RAGE expression in the ischemic cortex and circulating sRAGE were significantly decreased after tMCAo as compared to sham-operated animals. This effect was abolished by systemic administration of PJ34. Our data demonstrate that neuroprotection by PJ34 is associated with modulation of RAGE expression in cerebral ischemia and that sRAGE levels may represent a useful peripheral marker for stroke.
BRAIN AND CIRCULATING LEVELS OF RAGE ARE MODULATED BY TRANSIENT FOCAL CEREBRAL ISCHEMA IN RAT: EFFECT OF PARP INHIBITION
AMANTEA, Diana;BAGETTA, Giacinto;
2012-01-01
Abstract
Activation of RAGE (receptor for advanced glycation endproducts) plays a role in neuronal damage and neuroinflammation associated with brain ischemia, though the underlying mechanisms remain unclear. Poly(ADP-ribose) polymerase-1 (PARP-1) is a coactivator of the transcription factor NF-kB, that mediates inflammatory responses in cerebral ischemia. The PARP inhibitor N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide (PJ34) prevents IkB-alpha degradation, thus blocking NF-kB activation, and reduces brain damage following cerebral ischemia. In this study, we have investigated whether inhibition of PARP modulates RAGE expression in the cerebral cortex and soluble RAGE form (sRAGE) in male Wistar rats subjected to transient (1h) middle cerebral artery occlusion (tMCAo). After 24h of reperfusion, cortical RAGE expression was evaluated by western blotting, while circulating RAGE was quantified by ELISA. RAGE expression in the ischemic cortex and circulating sRAGE were significantly decreased after tMCAo as compared to sham-operated animals. This effect was abolished by systemic administration of PJ34. Our data demonstrate that neuroprotection by PJ34 is associated with modulation of RAGE expression in cerebral ischemia and that sRAGE levels may represent a useful peripheral marker for stroke.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
