Cerebral hypoxia/ischemia rapidly induces inflammation in the brain, which is characterized by microglial activation and the release of inflammatory cytokines. We have previously demonstrated that miR-181c can directly regulate tumor necrosis factor (TNF)-a production post-transcriptionally. Here, we determined that hypoxia up-regulated TLR4 expression but down-regulated miR-181c expression in primary microglia. We also demonstrated that miR-181c suppresses TLR4 by directly binding its 3 0 -untranslated region. In addition, miR-181c inhibited NF-jB activation and the downstream production of proinflammatory mediators, such as TNF-a, IL1b, and iNOS. Knocking down TLR4 in microglia significantly decreased TLR4 expression and inhibited NF-jB activation and the downstream production of proinflammatory mediators, whereas ectopic TLR4 expression significantly abrogated the suppressed inflammatory response induced by miR-181c. Therefore, our study identified an important role for the miR-181c-TLR4 pathway in hypoxic microglial activation and neuroinflammation. This pathway could represent a potential therapeutic target for cerebral hypoxic diseases associated with microglial activation and the inflammatory response.

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SUMMARYPurpose: To evaluate efficacy and tolerability of levetiracetam (LEV; Keppra â ) as add-on therapy in Chinese patients with refractory partial-onset seizures. Methods: In this multicenter, double-blind, randomized, placebo-controlled trial, 206 patients aged 16-70 years with uncontrolled partial-onset seizures were randomized to receive LEV (n¼103) or placebo (n¼103); 202 patients (LEV, n¼102; placebo, n ¼ 100) comprised the intent-to-treat population. An 8-week historical baseline period confirmed eligibility according to seizure count. The 16-week treatment period consisted of a 4-week up-titration period (LEV, 1,000-3,000 mg/day in two equal divided doses) followed by a 12-week maintenance period. Efficacy assessments were based on weekly frequency of partial-onset seizures during the 16-week treatment period. Results: LEV significantly decreased weekly partial-onset seizure frequency over placebo by 26.8% (p < 0.001). Median percentage reductions in weekly partial-onset seizure frequency from historical baseline were 55.9% for LEV and 13.7% for placebo (p < 0.001). The ‡50% responder rates were 55.9% for LEV, compared with 26.0% for placebo (p < 0.001). Freedom from partial-onset seizures during treatment period was achieved by 11 LEV patients (10.8%) and 2 placebo patients (2.0%) (p ¼ 0.012). Adverse events were reported by 65 LEV-treated patients (63.1%) and 62 placebotreated patients (60.2%); most were of mildto-moderate intensity. The most common adverse events were somnolence (LEV, 17.5%; placebo, 17.5%), decreased platelet count (LEV, 9.7%; placebo, 9.7%), and dizziness (LEV, 7.8%; placebo, 13.6%). Discussion: Add-on LEV was effective and welltolerated in Chinese patients with refractory partial-onset seizures.

SCN1A, UGT2B7 and ABCC2 genetic polymorphisms are associated with OXC maintenance doses and may be useful for the personalization of OXC therapy in epileptic patients. Further studies are needed. Original submitted 6 June 2014; Revision submitted 5 September 2014.

SCN1A IVS5-91G>A gene polymorphism is potential genetic biomarker associated with the PK of CBZ.

This study suggested that SCN1A and ABCC2 polymorphisms may be associated with the response to CBZ/OXC in the Chinese Han population, indicating that they could serve as predictors of drug response. Original submitted 29 January 2014; Revision submitted 30 May 2014.