The AMPK-SIRT1-FoxO1-NF-κB signaling pathway participates in hesperetin-mediated neuroprotective effects against traumatic brain injury via the NLRP3 inflammasome

  • Immunopharmacol Immunotoxicol. 2022 Aug 8;1-14. doi: 10.1080/08923973.2022.2096464.
Hai Song  1 ,  Zhongyun Ding  1 ,  Jilin Chen  2 ,  Tingbao Chen  2 ,  Tinghua Wang  3 ,  Jin Huang  1
Affiliations
  • 1. Department of Neurosurgery, First Affiliated Hospital of Kunming Medical University, Kunming, China.
  • 2. Animal Zoology Department, Kunming Medical University, Kunming, China.
  • 3. Institute of Neuroscience, Basic Medical College, Kunming Medical University, Kunming, China.
PMID: 35786120 DOI: 10.1080/08923973.2022.2096464
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.

Keywords
Hesperetin; NLRP3; inflammation; microglial activation; traumatic brain injury.
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