Valproic acid inhibits the expressions of MMP-9 and AQP-4 proteins in the brain tissue of rats with traumatic brain injury / 医学研究生学报

ABSTRACT

Objective Few studies are reported on the protective effect of valproic acid (VPA) against traumatic brain injury (TBI) by down-regulating the protein expressions of matrix metalloproteinase-9 (MMP-9) and aquaporin-4 (AQP-4) in the brain tissue. This study aimed to investigate the neuroprotective effects of different doses of VPA against TBI in experimental rats. Methods We randomly divided 100 adult male rats into five groups of equal number, sham operation, TBI model, and low- (30 mg), medium- (150 mg) and high-dose (300 mg) VPA treatment. At 1, 3, 7 and 14 days after modeling by controlled cortex impact, we obtained the modified Neurological Severity Scores (mNSS), measured the VPA concentration in the venous blood, and then killed the rats and harvested the brain tissue for determination of the water content using the dry-wet method and the expressions of MMP-9 and AQP-4 by Western blot and immunohistochemistry. Results At 1, 3, 7 and 14 days after modeling, the mNSSs in the high-dose VPA group were 4.6 ± 1.3, 3.8 ± 1.3, 3.0 ± 0.7 and 1.8 ± 0.8, respectively, significantly lower than 8.4 ± 0.9, 7.0 ± 0.7, 5.8 ± 1.0 and 4.5 ± 1.3 in the TBI group (P < 0.05), decreasing in a time-dependent manner, with statistically significant difference between any two dose groups (P < 0.05). At 1, 3 and 7 days, the water contents in the brain tissue were (76.2 ± 0.7)%, (76.9 ± 1.7)% and (73.9 ± 1.3)% in the high-dose VPA group, significantly lower than (79.6 ± 0.8)%, (82.6 ± 0.8)% and (78.6 ± 0.7)% in the TBI group (P < 0.05), also decreasing in a time-dependent manner, with statistically significant difference between any two dose groups (P < 0.05). At 1 and 3 days, the expressions of MMP-9 and AQP-4 in the brain tissue were markedly down-regulated in the VPA groups in a dose-dependent manner as compared with those in the TBI group (P < 0.05), with statistically significant difference between any two dose groups (P < 0.05), and meanwhile immunohistochemistry showed large numbers of cells with positive expressions of MMP-9 and AQP-4, which were reduced with the increased dose of VPA. Conclusion VPA has a neuroprotective effect against TBI in rats by inhibiting the expressions of MMP-9 and AQP-4 proteins in the brain tissue and alleviating brain edema. Within the range of the doses studied, higher-dose VPA produces a better effect.