Chrysophanol facilitates long-term neurological recovery through limiting microglia-mediated neuroinflammation after ischemic stroke in mice

Background: Inflammation plays an important role in ischemic brain injury and affects brain recovery and neuroplasticity. Chrysophanol (CHR), has attracted attention for its protective effects through immunomodulatory and anti-inflammatory properties. However, the effect of CHR for brain recovery and neuroplasticity is not clear. The current study aimed to investigate the effect of CHR in the chronic phase of stroke in mice, and to elucidate the underlying mechanisms.Methods: C57BL/6 mice were subjected to treatment with Vehicle or CHR immediately through intraperitoneal injection daily for 14 d after distal middle cerebral artery occlusion (dMCAO). Neurological deficits were monitored up to 28 days after stroke. Nissl and Golgi stain, neural plasticity, and microglia-associated inflammatory cytokines were detected. Primary cortical neuron and BV2 microglia cell lines were employed to explore the underlying mechanism in vitro.Results: Compared with Vehicle group, CHR mitigated the histological damage, facilitated the neural plasticity and improved the neurological function up to 4 weeks after stroke. In vitro, CHR promoted the complexity of neurons and the spine density by modulating microglial polarization and reducing the expression of microgliaassociated inflammatory cytokines, especially IL-6. In vivo, microglia activation and inflammatory cytokines were significantly increased after dMCAO and downregulated by CHR. Further investigation showed STAT3 is the major downstream effector of IL-6 signaling.Conclusions: CHR ameliorated microenvironment for neural plasticity and exhibited neuroprotection via arresting microglia toward pro-inflammatory phenotype and downregulation of the expressions of pro-inflammatory cytokines, especially of IL-6. IL-6-STAT3 signaling might be CHR's therapeutic target for neuroinflammatory responses after stroke.

Automated summary

This study aimed to investigate the effect of Chrysophanol (CHR) in the chronic phase of stroke and its underlying mechanisms. The results showed that CHR alleviated tissue damage, promoted neural plasticity, and improved neurological function. In vitro experiments revealed that CHR enhanced the complexity of neurons and spine density by modulating microglial polarization and reducing the expression of microglia-associated inflammatory cytokines, particularly IL-6. In vivo experiments demonstrated that CHR inhibited microglia activation and downregulated inflammatory cytokines. Further investigation suggested that IL-6-STAT3 signaling played a significant role in this process.