Sodium houttuyfonate attenuates neurological defects after traumatic brain injury in mice via inhibiting NLRP3 inflammasomes

Abstract

Sodium houttuyfonate (SH) is a chemical compound synthesized by houttuynin and sodium bisulfite. As it has antinflammatory effects, SH has been widely used to treat autoimmune diseases, including post events following traumatic brain injury (TBI).Meanwhile, NOD-like receptor with pyrin domain containing-3 (NLRP3) inflammasomes in microglia may play a central role in TBI. But to date, the intracellular mechanisms involved in the anti-inflammatory effects of SH in TBI remain unknown, especially whether regulating NLRP3. To gain an insight into this possibility, we conducted cell culture and biochemical studies on the effect of SH on NLRP3 inflammasome in microglia. The results showed that SH inhibited TLR4 and NLRP3 inflammasome activation in the microglia cell. In parallel, phosphorylation of ERK and NF-κB p65, which play a key role in NLRP3 inflammasome formation, was decreased. Intraperitoneal injection of SH into TBI mice significantly reduced the modified neurological severity score (mNSS), as well as the degree of microglia apoptosis post-controlled cortical impact (CCI). Immunohistochemistry, Western blot analysis, and reverse-transcription polymerase chain reaction (RT-PCR) revealed that SH markedly reduced NLRP3 inflammasome activation, TLR4 activity, phosphorylation of ERK and NF-κB. Moreover, SH significantly inhibited microglia activation post-CCI, but effectively promoted the astrocyte activation and angiopoiesis.Taken together, our research provides evidence that SH attenuated neurological deficits post TBI through inhibiting NLRP3 inflammasome activation, via influencing the TLR4/NF-κB signaling pathway. These findings explain the intracellular mechanism of the anti-inflammatory activity caused by SH treatment following TBI.

Reactive Astrocytes in Central Nervous System Injury: Subgroup and Potential Therapy

“…Sodium houttuyfonate effectively inhibited the activation of microglia cells while promoting the activation of astrocytes and angiogenesis (Yao et al, 2021 ). Ferrostatin-1 alleviated astrocytes inflammation and ferroptosis by suppressing the ROS levels and activating the Nrf2/HO-1 signaling pathway (Li S. et al, 2021 ).…”

Sodium houttuyfonate derived fromHouttuynia cordataThunb improves intestinal malfunctionviamaintaining gut microflora stability inCandida albicansovergrowth aggravated ulcerative colitis

“…62 Indeed, there have been several reports on the efficacy of SH in brain repair. 63,64 Mounting evidence shows a decreased abundance of Firmicutes and increased ratios of Bacteroidetes and Proteobacteria in colitis. 65,66 In this study, the DSS group displays an increased proportion of Proteobacteria in comparison with the sham group, but the gavage of C. albicans inhibited the abundance of Proteobacteria in the non-cohabitation pattern.…”

Toll-like receptor-mediated neuroinflammation: relevance for cognitive dysfunctions

“…Trauma (e.g., from accidental falls, construction and car accidents, violence, sport) results in brain edema, hypoxia/ischemia, and neuroinflammation (referred to as secondary injury) that lead to long-lasting deficits in memory, attention, and executive functions in >50% of patients [60]. TLR2 and TLR4 are upregulated in the injured cortex and promote (i) M1 neurotoxic phenotypes through the NF-κB-p65/pERK/NLRP3 pathway [61], and (ii) the recruitment of reactive astrocytes to the injury site, with detrimental effects on synapses and neurological outcomes [62]. Interestingly, TLR2/TLR4 activation also interferes with OPC survival, thus impairing the remyelination of injured axons [63].…”