earticle

영어

Heme oxygenase-1 (HO-1) gene is an anti-apoptotic gene and has been widely investigated as a therapeutic gene for ischemic diseases (1-2). In this research, a co-delivery carrier of dexamethasone and heme oxygenase-1 (HO-1) gene was developed by conjugation of dexamethasone to polyethylenimine (2 kDa, PEI2k) for the treatment of ischemic stroke. In vitro transfection assays showed that the tumor necrosis factor-α (TNF-α) level was decreased more efficiently by pDNA/PEI2k-Dexa complex than dexamethasone only in hypoxia activated Raw264.7 macrophage cells, suggesting that pDNA/PEI2k-Dexa complex increased the delivery efficiency of dexamethasone. In addition, the transfection efficiency of PEI2k-Dexa was higher than lipofectamine in Neuro2A cells. The stroke animal model was produced by middle cerebral artery occlusioin (MCAO). The HO-1 gene was delivered to the focal ischemic brain of the MCAO model using PEI2k-Dexa as a gene carrier. The pEmpty/PEI2k, pEmpty/PEI2k-Dexa and pSV-HO-1/PEI2k-Dexa complexes were injected into a transient focal ischemia animal model. The results showed that the injection of the pEmpty/PEI2k-Dexa complex reduced infarct size significantly, compared with the control and pEmpty/PEI2k injection groups. This suggests that dexamethsone of PEI-Dexa protected the brain cells under ischemia-reperfusion condition. The infarct size of the pSV-HO-1/PEI-Dexa injection group was further reduced, compared with the pEmpty/PEI2k-Dexa injection group, suggesting that HO-1 had a synergistic effect with PEI2k-Dexa in reducing inflammatory response in ischemic brain. Magnetic resonance imaging and microPET studies confirmed the therapeutic effect of pSV-HO-1/PEI2k-Dexa complex at 10 days after the injection. Therefore, pSV-HO-1/PEI2k-Dexa complexes may be useful for the treatment of ischemic diseases such as stroke.