2. Academic Validation
  3. HET0016 inhibits neuronal pyroptosis in the immature brain post-TBI via the p38 MAPK signaling pathway

HET0016 inhibits neuronal pyroptosis in the immature brain post-TBI via the p38 MAPK signaling pathway

  • Neuropharmacology. 2023 Aug 12;239:109687. doi: 10.1016/j.neuropharm.2023.109687.
Xiaoli Chen 1,  Yalei Ning 2,  Bo Wang 3,  Jun Qin 1,  Changhong Li 3,  Ruobing Gao 3,  Zhihui Ma 1,  Yuanguo Zhou 2,  Ping Li 2,  Yan Zhao 2,  Yan Peng 3,  Xing Chen 3,  Nan Yang 3,  Shiyu Shu 4
Affiliations

Affiliations

  • 1 Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
  • 2 Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China; Institute of Brain and Intelligence, Army Medical University, Chongqing, 400038, China.
  • 3 Department of Army Occupational Disease, State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Daping Hospital, Army Medical University, Chongqing, 400042, China.
  • 4 Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China. Electronic address: [email protected].
PMID: 37579871 DOI: 10.1016/j.neuropharm.2023.109687
Abstract

Traumatic brain injury (TBI) is a serious health threat worldwide, especially for the younger demographic. Our previous study demonstrated that HET0016 (a specific inhibitor of 20-hydroxyeicosatetraenoic acid synthesis) can decrease the lesion volume in the immature brain post-TBI; however, its mechanism of action and its association with Pyroptosis post-TBI are unclear. In this study, we established a controlled cortical impact (CCI) injury rat model (postnatal day 9-10) and observed that increased expression of indicators for Pyroptosis, including NLR family pyrin domain containing 3 (NLRP3), Caspase-1 and gasdermin D (GSDMD) proteins and interleukin (IL)-18/IL-1β mRNA during the acute phase of TBI, especially on post-injury day (PID) 1. Additionally, we found that Caspase-1 was primarily expressed in the neurons and microglia. HET0016 (1 mg/kg/d, ip, 3 consecutive days since TBI) reduced the lesion volume; neuronal death; expression of NLRP3, Caspase-1, and GSDMD; and expression of IL-18/IL-1β mRNA. Bioinformatics analysis suggested involvement of mitogen-activated protein kinase (MAPK) signaling pathway in the HET0016-mediated neuroprotective role against TBI in the immature brain. Western blot analysis revealed reduced expression of p-p38 MAPK and nuclear factor-kappa B (NF-κB) p65 in the neurons and microglia upon HET0016 treatment in TBI rats. In cultured primary cortical neurons subjected to oxygen-glucose deprivation/re-oxygenation (OGD) + (lipopolysaccharide) LPS, HET0016-induced the reduction of p-p38 MAPK, NLRP3, cleaved-caspase-1, GSDMD, IL-18, and IL-1β was reversed by co-treatment with p38 MAPK Activator as well as NLRP3 Agonist. Therefore, we conclude that Pyroptosis is involved in neuronal death in the immature brains post-TBI and that HET0016 administration can alleviate neuronal Pyroptosis possibly via inhibiting the phosphorylation of p38 MAPK.

Keywords

20-Hydroxyeicosatetraenoicacid (20-HETE); Immature brain; N-hydroxy-N-4-Butyl-2-methylphenylformamidine (HET0016); Pyroptosis; Traumatic brain injury (TBI).

Figures
Products