ABSTRACT
Clinical advances in the treatment of intracranial hemorrhage (ICH) are restricted by the incomplete understanding of the molecular mechanisms contributing to secondary brain injury. Acrolein is a highly active unsaturated aldehyde which has been implicated in many nervous system diseases. Our results indicated a significant increase in the level of acrolein after ICH in mouse brain. In primary neurons, acrolein induced an increase in mitochondrial fragmentation, loss of mitochondrial membrane potential, generation of reactive oxidative species, and release of mitochondrial cytochrome c. Mechanistically, acrolein facilitated the translocation of dynamin-related protein1 (Drp1) from the cytoplasm onto the mitochondrial membrane and led to excessive mitochondrial fission. Further studies found that treatment with hydralazine (an acrolein scavenger) significantly reversed Drp1 translocation and the morphological damage of mitochondria after ICH. In parallel, the neural apoptosis, brain edema, and neurological functional deficits induced by ICH were also remarkably alleviated. In conclusion, our results identify acrolein as an important contributor to the secondary brain injury following ICH. Meanwhile, we uncovered a novel mechanism by which Drp1-mediated mitochondrial oxidative damage is involved in acrolein-induced brain injury.
ABSTRACT
Clinical advances in the treatment of intracranial hemorrhage (ICH) are restricted by the incomplete understanding of the molecular mechanisms contributing to secondary brain injury. Acrolein is a highly active unsaturated aldehyde which has been implicated in many nervous system diseases. Our results indicated a significant increase in the level of acrolein after ICH in mouse brain. In primary neurons, acrolein induced an increase in mitochondrial fragmentation, loss of mitochondrial membrane potential, generation of reactive oxidative species, and release of mitochondrial cytochrome c. Mechanistically, acrolein facilitated the translocation of dynamin-related protein1 (Drp1) from the cytoplasm onto the mitochondrial membrane and led to excessive mitochondrial fission. Further studies found that treatment with hydralazine (an acrolein scavenger) significantly reversed Drp1 translocation and the morphological damage of mitochondria after ICH. In parallel, the neural apoptosis, brain edema, and neurological functional deficits induced by ICH were also remarkably alleviated. In conclusion, our results identify acrolein as an important contributor to the secondary brain injury following ICH. Meanwhile, we uncovered a novel mechanism by which Drp1-mediated mitochondrial oxidative damage is involved in acrolein-induced brain injury.
ABSTRACT
AIM: To investigate the role of reactive oxygen species ( ROS)-mediated mitochondrial oxidative injury in isonicotinyl hydrazide ( INH)-induced DNA damage and the protective effect of quercetin on L-02 cells.ME-THODS:The injury model of hepatocyte L-02cells in vitro induced by INH was established .The cells were divided into control group, INH group, low-dose quercetin group and high-dose quercetin group.The DNA damage of L-02 cells was evaluated by the comet test .The mitochondrion was prepared , and the level of mitochondrial ROS and the value of mitochondrial membrane potential (ΔΨm ) were detected by fluorescent probes DCFH-DA and rhodamine 123.The content of MDA was measured by TBA method .The activity of SOD was assessed with the xanthine oxidase method .The protein expression of Bcl-2 and Bax was determined by Western blotting , and the value of Bax/Bcl-2 was calculated .RESULTS:INH induced obvious DNA damage , increased the level of mitochondrial ROS , the content of MDA and the value of Bax/Bcl-2, and markedly reduced the value of ΔΨm and the activity of SOD in the L-02 cells.Quercetin attenuated DNA dam-age, reduced the level of mitochondrial ROS , elevated the value of ΔΨm , declined the content of MDA , increased the ac-tivity of SOD and decreased the value of Bax/Bcl-2 in the L-02 cells.CONCLUSION:INH induces DNA damage in L-02 cells by generation of mitochondrial oxidative stress .Quercetin has a protective effect on L-02 cells to attenuate the INH-in-duced DNA damage by inhibiting ROS-mediated mitochondrial oxidative damage .