The HDAC3 inhibitor RGFP966 ameliorated ischemic brain damage by downregulating the AIM2 inflammasome.

Histone deacetylases 3 (HDAC3) modulates the acetylation state of histone and non-histone proteins and could be a powerful regulator of the inflammatory process in stroke. Inflammasome activation is a ubiquitous but poorly understood consequence of acute ischemic stroke. Here, we investigated the potential contributions of HDAC3 to inflammasome activation in primary cultured microglia and experimental stroke models. In this study, we documented that HDAC3 expression was increased in microglia of mouse experimental stroke model. Intraperitoneal injection of RGFP966 (a selective inhibitor of HDAC3) decreased infarct size and alleviated neurological deficits after the onset of middle cerebral artery occlusion (MCAO). In vitro data indicated that LPS stimulation evoked a time-dependent increase of HDAC3 and absent in melanoma 2 (AIM2) inflammasome in primary cultured microglia. Interestingly, AIM2 was subjected to spatiotemporal regulation by RGFP966. The ability of RGFP966 to inhibit the AIM2 inflammasome was confirmed in an experimental mouse model of stroke. As expected, AIM2 knockout mice also demonstrated significant resistance to ischemia injury compared with their wild-type littermates. RGFP966 failed to exhibit extra protective effects in AIM2-/- stroke mice. Furthermore, we found that RGFP966 enhanced STAT1 acetylation and subsequently attenuated STAT1 phosphorylation, which may at least partially contributed to the negative regulation of AIM2 by RGFP966. Together, we initially found that RGFP966 alleviated the inflammatory response and protected against ischemic stroke by regulating the AIM2 inflammasome.

Inhaled budesonide protects against chronic asthma-induced neuroinflammation in mouse brain.

Chronic asthma is one of the most common respiratory diseases, characterized by airway inflammation. However, little is known whether asthma-induced airway inflammation might influence the brain. We found that chronic asthma not only resulted in peripheral inflammation, but also induced neuroinflammation which was characterized by microglial activations and increased levels of TNFα and IL-1ß in the hippocampus and prefrontal cortex. Simultaneously, we found that there was significant neuronal loss in the asthmatic mouse brain. Inhaled budesonide, the classic therapeutic drug for chronic asthma, could inhibit asthma-induced microglial activation, down-regulate TNFα and IL-1ß but up-regulate TGFß and IL-10 of mouse brain, and thereby attenuate neuronal loss. Further study showed that chronic asthma increased the expressions of TLR4 and p65/NFκB in the brain, which could be reversed by budesonide treatment. Therefore, the present study reveals that inhaled budesonide protects against asthma-induced neuroinflammation in mouse brain, which might be contributed to attenuate neuronal loss.