Sodium tanshinone IIA sulfonate alleviates neuroinflammation-induced damage to hippocampal neurons by activating SIRT1 in mice with sepsis-associated encephalopathy.

Abstract

ETHNOPHARMACOLOGICAL RELEVANCE: Sepsis-associated encephalopathy (SAE) is a diffuse cerebral dysfunction caused by sepsis. Danshen (Salvia miltiorrhiza Bunge) is a traditional Chinese herb utilized to treat cardiovascular and neurological disorders. However, the therapeutic effects and underlying mechanisms of Danshen on sepsis-associated encephalopathy remain unclear. AIM OF THE STUDY: This study aims to investigate whether sodium tanshinone IIA sulfonate (STS), a lipid-soluble extract from Danshen, could alleviate neuroinflammatory-induced hippocampal neuronal injury and explore the mechanisms involved. METHODS: SAE model was generated by cecal ligation and puncture (CLP), along with HT22 cells treated with activated BV2-derived conditioned medium (Ac-BV2-CM). The effects of STS on SAE were assessed by behavioral tests, histopathology, immunostaining, RT-qPCR, western blotting, and RNA-seq. Mitochondria dysfunction was evaluated by detecting membrane potential, mitochondria reactive oxygen species (ROS) and ATP, and by mitochondria complex activity assays. RESULTS: STS significantly reduced the mortality rate of CLP mice over a 7-day period, ameliorated cognitive and emotional dysfunction, and prevented neuronal damage in the hippocampal CA1 region. STS effectively inhibited neuroinflammatory responses mediated by microglial activation and pyroptosis in the hippocampus of CLP mice. Ac-BV2-CM, mimicking neuroinflammatory responses in vivo, induced damage to HT22 cells, a mouse hippocampal neuronal cell line. RNA-seq and validation analysis demonstrated that STS improved mitochondria dysfunction induced by Ac-BV2-CM, thereby preventing neuroinflammatory response-induced hippocampal neuronal damage. In addition, STS enhanced the SIRT1/PGC-1α/NRF1/TFAM pathway in the hippocampus of CLP mice and Ac-BV2-CM treated HT22 cells. Finally, STS inhibited neuroinflammatory-induced hippocampal neuron apoptosis, leading to improved synaptic plasticity; these effects were achieved through the enhancement of SIRT1. CONCLUSIONS: The SIRT1/PGC-1α/NRF1/TFAM pathway regulates mitochondrial dysfunction and constitutes the underlying mechanism by which STS mitigates neuroinflammation-induced damage to hippocampal neurons in SAE.