Parthenolide ameliorates neurological deficits and neuroinflammation in mice with traumatic brain injury by suppressing STAT3/NF-κB and inflammasome activation

Traumatic brain injury (TBI) triggers a set of complex inflammation that results in secondary injury. Parthenolide (PTN) is a sesquiterpene lactone extracted from the herb Tanacetum parthenium (Feverfew) and has potent anti-inflammatory, anti-apoptosis and anti-oxidative stress effects in the central nervous system (CNS)-related diseases. This study focuses on investigating the potential neuroprotective effect of PTN on TBI and the related mechanism.Bv2 microglia, primary microglia were stimulated by LPS, and HT22 neuron cells were stimulated by OGD/R, and they were treated with different doses of PTN. The expression profiles of pro-inflammatory cytokines, proteins, oxidative stress mediators, STAT3/NF-κB pathway, inflammasomes were detected. Forty male/female C57BL/6 mice were randomly divided into the sham, PTN, TBI, and TBI + PTN groups (10 mice per group). A mouse TBI model was set up with a controlled cortical impact (CCI) device. The modified nerve severity score (mNSS) was implemented to check short-term neurological impairment in mice, and the mice's memory and learning were assessed by the Morris water maze test. The water content in the mice's brains was measured by the dry-wet method. Hematoxylin-eosin (H&E) staining, Nissl staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay were applied for neuronal apoptosis.PTN dramatically alleviated LPS-induced inflammation in microglia, and OGD-mediated neuronal apoptosis and oxidative stress. In addition, PTN repressed LPS- or OGD-modulated STAT3/NF-κB and NLR family pyrin domain containing 1 (NLRP1), NLRP3, NLR family CARD domain containing 4 (NLRC4) inflammasomes activation. Administering the STAT3 inhibitor Stattic or NF-κB inhibitor Bay 11-7082 attenuated PTN-mediated effects. In vivo, PTN treatment relieved neural function deficits, brain edema and neuron apoptosis and improved the memory and learning function of TBI mice. Additionally, PTN impeded microglial activation and reduced the production of pro-inflammatory cytokines in brain lesions of TBI mice. Furthermore, PTN hindered STAT3/NF-κB and inflammasome activation.PTN can curb microglial activation and neuron apoptosis by dampening the STAT3/NF-κB pathway, thus exerting neuroprotective effects in TBI mice.