AAV/BBB-Mediated Gene Transfer of CHIP Attenuates Brain Injury Following Experimental Intracerebral Hemorrhage

Cell death is a hallmark of secondary brain injury following intracerebral hemorrhage (ICH). The E3 ligase CHIP has been reported to play a key role in mediating necroptosis—an important mechanism of cell death after ICH. However, there is currently no evidence supporting a function of CHIP in ICH. In the present study, we aimed to determine whether CHIP plays an essential role in brain injury after ICH. Our findings indicated that CHIP expression was increased in the peri-hematomal area in rat models of ICH. The AAV/BBB viral platform enables non-invasive, widespread, and long-lasting global neural expression of target genes. Treatment with AAV/BBB-CHIP ameliorated brain injury and inhibited neuronal necroptosis and inflammation in wild type (WT) rats following ICH. Furthermore, rats with CHIP deficiency experienced severe brain injury and increased levels of neuronal necroptosis and inflammation relative to their WT counterparts. However, treatment with AAV/BBB-CHIP attenuated the effects of CHIP deficiency after ICH. Collectively, our results demonstrate that CHIP inhibits necroptosis and pathological inflammation following ICH, and that overexpression of CHIP may represent a therapeutic intervention for ICH. Moreover, the AAV/BBB viral platform may provide a novel avenue for the treatment of brain injury.