Effect of activation of nuclear factor-κB/hypoxia-inducible factor-1α pathway on the hippocampal neurodegeneration caused by status epilepticus in rats

Abstract

Objective To observe the roles of nuclear factor-κB(NF-κB) and hypoxia-inducible factor-1α (HIF-1α) in hippocampal neurodegeneration of status epilepticus (SE) rats, and explore whether HIF-1α activation is regulated by NF-κB. Methods A total of 110 male Sprague-Dawley rats were randomly divided into seven groups: (1) Control group treated with saline (control, n=15), (2) sham group implanted cannula into lateral ventricle and treated with saline (sham, n=15), (3) SE group treated with pilocarpine (SE, n=20), (4) NF-κB activity inhibitor pyrrolidine dithiocarbamate (PDTC) group treated only with PDTC (PDTC, n=15), (5) SE+ PDTC group treated with pilocarpine plus PDTC (SE+ PDTC, n=15), (6) SE+ HIF-1α siRNA group implanted cannula into lateral ventricle and treated with pilocarpine plus HIF-1α siRNA (SE+ HIF-1α siRNA, n=15), (7) SE+ control siRNA group implanted cannula into lateral ventricle and treated pilocarpine plus control siRNA(n=15). SE was induced by injecting lithium chloride and pilocarpine. The seizure of rats was observed. The protein expressions of NF-κB and HIF-1α in hippocampus of rats were examined by Western blotting. The degenerating neurons in hippocampus were detected by Fluoro-Jade C (FJC) staining. Results Twenty-four hours after termination of SE, the nuclear protein expressions of NF-κB and HIF-1α in hippocampus of rats were increased in SE group (0.57±0.06, 0.47±0.07) compared with those in control group (0.23±0.03, 0.20±0.03; P<0.05); and compared with SE group PDTC significantly decreased the nuclear protein expressions of NF-κB and HIF-1α in SE+ PDTC group (0.23±0.03, 0.14±0.03; P<0.05); in SE+ PDTC group the numbers of FJC positive cells in CA1 area (28.33±5.03) were decreased compared with that in SE group (76.67±13.32); HIF-1α siRNA injected into lateral ventricle of rats significantly decreased the expression of HIF-1α in hippocampus (0.22±0.03) and the number of FJC positive cell in CA1 area (27.34±7.02) in SE+ HIF-1α siRNA group compared with those in SE group (0.39±0.06, 76.67±13.32; P<0.05). Conclusions These data suggest that SE can result in activation of NF-κB/HIF-1α pathway in brain. Inhibition of the pathway can attenuate hippocampal neurodegeneration caused by SE, which has the brain protective effect. Key words: Status epilepticus; Hippocampus; Neurons; Transcription factor relA; Hypoxia-inducible factor 1, alpha subunit; Rats