BackgroundMicroglial polarization with M1/M2 phenotype shifts and the subsequent neuroinflammatory responses are vital contributing factors for spinal cord injury (SCI)-induced secondary injury. Nuclear factor-κB (NF-κB) is considered the central transcription factor of inflammatory mediators, which plays a crucial role in microglial activation. Lysine acetylation of STAT1 seems necessary for NF-kB pathway activity, as it is regulated by histone deacetylases (HDACs). There have been no studies that have explained if HDAC inhibition by valproic acid (VPA) affects the NF-κB pathway via acetylation of STAT1 dependent of HDAC activity in the microglia-mediated central inflammation following SCI. We investigated the potential molecular mechanisms that focus on the phenotypic transition of microglia and the STAT1-mediated NF-κB acetylation after a VPA treatment.MethodsThe Basso-Beattie-Bresnahan locomotion scale, the inclined plane test, the blood-spinal cord barrier, and Nissl staining were employed to determine the neuroprotective effects of VPA treatment after SCI. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and interferon (INF)-γ was used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of VPA treatment. Immunofluorescent staining and Western blot analysis were used to detect HDAC3 nuclear translocation, activity, and NF-κB signaling pathway activation to evaluate the effects of VPA treatment. The impact of STAT1 acetylation on NF-kB pathway and the interaction between STAT1 and NF-kB were assessed to evaluate anti-inflammation effects of VPA treatment and also whether these effects were dependent on a STAT1/NF-κB pathway to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after SCI.ResultsThe results showed that the VPA treatment promoted the phenotypic shift of microglia from M1 to M2 phenotype and inhibited microglial activation, thus reducing the SCI-induced inflammatory factors. The VPA treatment upregulation of the acetylation of STAT1/NF-κB pathway was likely caused by the HDAC3 translocation to the nucleus and activity. These results indicated that the treatment with the VPA suppressed the expression and the activity of HDAC3 and enhanced STAT1, as well as NF-κB p65 acetylation following a SCI. The acetylation status of NF-kB p65 and the complex with NF-κB p65 and STAT1 inhibited the NF-kB p65 transcriptional activity and attenuated the microglia-mediated central inflammatory response following SCI.ConclusionsThese results suggested that the VPA treatment attenuated the inflammatory response by modulating microglia polarization through STAT1-mediated acetylation of the NF-κB pathway, dependent of HDAC3 activity. These effects led to neuroprotective effects following SCI.

In recent years, it has become mandatory for many pharmaceutical companies to conduct country‐specific clinical studies which are needed for obtaining regulatory approvals for their drugs. Such studies are important to delineate possible racial or environmental (lifestyle) differences which could not have been predicted from data obtained in other populations. A double‐blind, randomized, double‐dummy, multiclinic, comparative trial examined the tolerance and efficacy of misoprostol (200 μg QID) and cimetidine (200 mg QID) for the treatment of duodenal ulcers in the People's Republic of China. The trial characteristics and monitoring complied with the standards in the United States of America and the People's Republic of China. Two hundred consenting outpatients of either sex, aged 18–75 years, who had duodenal ulcers (not less than 0.3 cm in longest diameter and not more than 2 ulcers) were enrolled. Endoscopy, physical examination, and laboratory assessments wereperformed on entry and after 4 weeks of treatment. The effects of the treatment on ulcer healing, dyspeptic symptoms, tolerance, and adverse drug reactions were determined. Both treatment groups were well matched for demographic characteristics and disease severity at entry to the study. Misoprostol showed equal efficacy to cimetidine in inducing ulcer healing (60.7% vs. 67.9% for misoprostol and cimetidine, respectively, P > 0.05) and resolving dyspeptic pain. The extent of duodenal ulcer healing achieved by misoprostol in this study is essentially similar to the ulcer healing rates noted in many other worldwide studies, indicating the absence of racial differences in response to misoprostol. The adverse effects observed for misoprostol and cimetidine were also very similar. Both drugs were very well tolerated; however, slightly more patients experienced transient diarrhea with misoprostol (6.4%) than with cimetidine (3.8%). In conclusion, this trial supports the world‐ wide efficacy and tolerance of misoprostol for the treatment of duodenal ulcers and indi‐ cates the absence of racial influences on the safety and efficacy of misoprostol. © 1992 Wiley‐Liss, Inc.