Progesterone attenuates cerebral edema in neonatal rats with hypoxic-ischemic brain damage by inhibiting the expression of matrix metalloproteinase-9 and aquaporin-4

Abstract

The aim of this study was to investigate the effects of progesterone (PROG) on blood-brain barrier (BBB) permeability, cerebral edema and the expression of matrix metalloproteinase-9 (MMP-9) and aquaporin-4 (AQP-4) in neonatal rats with hypoxic-ischemic brain damage (HIBD) and to explore the mechanism of its neuroprotective effect. Sixty 7-day-old Wistar rats were divided into sham surgery, hypoxic ischemia (HI) and drug prophylaxis (PROG) groups. HIBD animal models were established. All the animals were sacrificed after 24 h. The BBB was assessed using Evans blue. Cerebral moisture capacity was determined using the dry-wet method. MMP-9 was detected in the brain tissues using enzyme-linked immunosorbent assay. The expression of AQP-4 and MMP-9 in the cerebral cortex was observed using immunohistochemistry and real-time polymerase chain reaction. The MMP-9 levels in the cortex, BBB permeability, cerebral moisture capacity and expression of AQP-4 and MMP-9 in the HI group were significantly higher compared with those in the sham surgery group (P<0.01), and they were significantly lower in the drug prophylaxis group compared with those in the HI group (P<0.05). In conclusion, PROG reduces BBB damage and cerebral edema and inhibits MMP-9 generation to protect rat brains against HIBD. The protective effect of PROG may be correlated with downregulated expression of AQP-4 and MMP-9 in the cerebral cortex.

Keywords: aquaporin; blood-brain barrier; cerebral edema; hypoxic-ischemic; matrix metalloproteinase; progesterone.

Figure 1.

Expression of matrix metalloproteinase (MMP)-9 and aquaporin (AQP)-4 was observed using immunohistochemistry [magnification, ×400; stained with SP (streptavidin-perosidase)]. MMP-9 expression in the (A) sham surgery, (B) hypoxic ischemia (HI) and (C) progesterone groups. AQP-4 expression in the (D) sham surgery, (E) HI and (F) progesterone groups, respectively.

Figure 2.

Expression of matrix metalloproteinase (MMP)-9 and aquaporin (AQP)-4 was detected using reverse transcription-polymerase chain reaction (RT-PCR). Lane 1, sham surgery group; lane 2, hypoxic ischemia (HI) group; lane 3, progesterone group.