Gene transfer of extracellular superoxide dismutase increases superoxide dismutase activity in cerebrospinal fluid

Background and Purpose-Copper-zinc superoxide dismutase (CuZnSOD) is expres sed intracellularly, while extracellular SOD (EC-SOD) is released from cell s. The purpose of this study was to determine whether gene transfer of CuZn SOD increases SOD activity predominantly in tissues, and gene transfer of E C-SOD increases SOD activity in cerebrospinal fluid (CSF). We also determin ed whether heparin or dextran sulfate releases EC-SOD into CSF. Methods-We injected recombinant adenoviruses expressing EC-SOD (AdEC-SOD), CuZnSOD (AdCuZnSOD), or beta -galactosidase (Ad beta -gal) into the cistern a magna of rabbits. Results-Total SOD activity in CSF was 39+/-11 U/mL (mean+/-SE) before virus injection. Three days later, total SOD activity in CSF increased to 148+/- 22 U/mL after AdEC-SOD and 92+/-10 U/mL after AdCuZnSOD (P<0.05 versus AdEC -SOD), with no change after Ad<beta>-gal (49+/-5 U/mL). EC-SOD protein was detected in CSF after AdEC-SOD but not AdCuZnSOD or Ad beta -gal. Injection of heparin or dextran sulfate into the cisterna magna increased total SOD activity 27-fold and 32-fold over basal values, respectively, in CSF of rab bits that received AdEC-SOD. In contrast to effects in CSF, total SOD activ ity in basilar artery and meninges was significantly higher after AdCuZnSOD and tended to be higher after AdEC-SOD than after Ad beta -gal. Conclusions-We have developed a method for intracranial gene transfer of Cu ZnSOD and EC-SOD. After gene transfer, CuZnSOD was expressed mainly in tiss ues, and EC-SOD was released into the CSF, especially after injection of he parin or dextran sulfate. Gene transfer of different isoforms of SOD may be useful in studies of cerebral vascular physiology and pathophysiology.