Synthetic gelatinases inhibitor attenuates electromagnetic pulse-induced blood–brain barrier disruption by inhibiting gelatinases-mediated ZO-1 degradation in rats

Previously we found that exposure to electromagnetic pulse (EMP) induced an increase in blood–brain-barrier (BBB) permeability and the degradation of tight junction protein ZO-1 in rats. Matrix metalloproteinases (MMPs), in particular gelatinases (MMP-2 and MMP-9), play a key role in degradation of tight junction proteins, are known mediators of BBB compromise. We hypothesized that the degradation of ZO-1 by gelatinases contributed to EMP-induced BBB opening. To test this hypothesis, the mRNA level of ZO-1, protein levels of MMP-2, MMP-9 and tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) were detected in rat cerebral cortex after exposing rats to EMP at 200 kV/m for 200 pulses. It was found that the mRNA level of ZO-1 was unaltered at different time points after EMP exposure. The protein levels of MMP-2 and MMP-9 significantly increased at 3 h and 0.5 h, respectively. However, TIMP-1 (inhibitor of MMP-9) and TIMP-2 (inhibitor of MMP-2) only moderately increased after EMP exposure. In addition, in situ zymography results showed that the gelatinase activity increased in cerebral microvessels at 3 h after EMP exposure. When rats were treated with gelatinases inhibitor (SB-3CT) before EMP exposure, the EMP-induced BBB opening was attenuated and the ZO-1 degradation was reversed. Our results suggested that EMP-induced BBB opening was related to gelatinase mediated ZO-1 degradation.

► Blood-brain-barrier (BBB) disruption was induced by Electromagnetic pulse (EMP).
► BBB tight junction protein ZO-1 level decreased after EMP exposure.
► Gelatinases activity increased in BBB after EMP exposure.
► Gelatinases inhibitor attenuated EMP-induced BBB disruption and ZO-1 degradation.
► EMP-induced BBB disruption contributed to the degradation of ZO-1 by gelatinases.