Repetitive transcranial magnetic stimulation ameliorates chronic unpredictable stress-induced depressive-like behaviors in rats model through enhancing hippocampal nuclearfactor-E2-related factor2 antioxidant signaling

Abstract

Objective To investigate the antidepressive-like effect of repetitive transcranial magnetic stimulation (rTMS) on the rats model exposing chronic unpredictable stress (CUS) and their nuclearfactor-E2-related factor2 (Nrf2) gene expression in hippocampus. Methods (1) SD rats were randomly assigned to the following 3 groups (n=8 for each group): Sham, CUS, CUS+ rTMS. The Sham group received only Sham stimulation. The rats in the CUS and CUMS+ rTMS group were subjected to CUS stimulus, followed by 5Hz rTMS or Sham rTMS for 7 days. 24 h after the last stimulation, rats were given a sucrose preference test, an open filed test and a forced swim test. Finally the gene expression of Nrf2, HO-1 and SOD-1 in the hippocampus were determined by real-time PCR and western blot. (2) SD rats were randomly assigned to another 3 groups (n=8 for each group): scramble+CUS, scramble+ CUS+ rTMS and shNrf2+ CUS+ rTMS. Rats were injected with scramble or shNf2 lentivirus into the dentate gyrus. Two weeks later, all rats were subjected to CUS followed by rTMS or Sham rTMS stimulus for 7 days. Finally rats were given the series behavior tests, and the gene expression of hippocampal Nrf2, HO-1 and SOD-1 were then determined after being sacrificed. Results (1) In comparison with Sham, the rat in CUS group showed significant lower sucrose preference ((77.31±4.69)% vs. (39.33±11.85)%; F2, 21=8.32, P<0.01) and shorter centre time ((52.49±1.07) s vs. (14.70±4.27) s; F2, 21=3.84, P<0.01)) in the open filed test, but longer freezing time in the forced swim test ((24.19±1.07 s vs. (38.70±4.27); F2, 21=10.31, P<0.05) ; the expression of Nrf2, HO-1 and SOD-1 in the hippocampus was inhibited in the CUS rats. (2) Compared with CUS group, the rat in CUS+rTMS group showed significant better sucrose preference (P<0.05), longer centre time (P<0.05 in open filed test), while shorter freezing time in the forced swim test (P<0.05); the expression of Nrf2, HO-1 and SOD-1 in the hippocampus in CUS+rTMS rats was up-regulated (P<0.05); (3) Rats in shNrf2+CUS+ rTMS group showed lower sucrose preference (P<0.05), shorter centre time (P<0.05) in the open filed test and longer freezing time in the forced swim test (P<0.05) and their expression of Nrf2, HO-1 and SOD-1 in the hippocampus (P<0.05) was down-regulated than rats in scramble+CUS+rTMS group. Conclusion rTMS administration may reverse depressive-like behaviors in rats under CUS paradigm and may restore the gene expression of Nrf2, HO-1 and SOD-1 in the hippocampus. Key words: Transcranial Magnetic Stimulation; Stress; Nuclearfactor-E2-related factor 2; Hemeoxygenase-1; Superoxide Dismutase-1