Abstract
Background
Traumatic brain injury (TBI) induces inflammations that lead to secondary damage. Hesperetin (Hes) exerts anti-inflammatory activities against central nervous system (CNS) diseases. This article probes the possible neuroprotective effect and mechanism of Hes on TBI-induced acute cerebral damage.
Methods
Male C57BL/6J mice were subjected to controlled cortical impingement (CCI) and Hes (50 mg/kg) treatment after the surgery. Short-term neurological deficits were assessed with the modified neurological severity score (mNSS) and the Rota-rod test. The brain edema was tested by the wet/dry method. Neuron apoptosis was evaluated by Nissl staining and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining. The blood-brain barrier (BBB) integrity was measured by Evans’ blue staining, and immunohistochemistry (IHC) was conducted to study BV2 microglial activation. BV2 microglia and HT22 neuronal cells were stimulated by oxygen-glucose deprivation followed by recovery (OGD/R) and processed with Hes. Quantitative real-time-polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were implemented to gauge the expression of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-β (IL-1-β) and interleukin-6 (IL-6). Western blot (WB) was performed to check AMPK-SIRT1-FoxO1 both in vitro and in vivo.
Results
Hes eased neurological deficits, cerebral edema, and neuronal apoptosis in mice following TBI. Hes hampered microglial activation and pro-inflammatory cytokines production. Hes promoted AMPK and SIRT1 expression, whereas repressed the phosphorylation of FoxO1-NF-κB, and inhibited NLRP3 expression. The AMPK inhibitor Compound C markedly reversed Hes-mediated anti-inflammatory and neuron-protective effects.
Conclusion
Hes curbs microglial activation-mediated inflammation via the AMPK-SIRT1-FoxO1-NF-κB axis, thereby improving neurobehavioral function after TBI.
GRAPHICAL ABSTRACT
Correction Statement
This article has been corrected with minor changes. These changes do not impact the academic content of the article.
Ethical approval
Our study was approved by the Animal Care and Experiment Committee of Kunming Medical University.
Disclosure statement
The authors declare that they have no competing interests.
Data availability statement
The data sets used and analyzed during the current study are available from the corresponding author on reasonable request.