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Peer-reviewedCC BYBiochemistry and biophysics reports

TPPU, a soluble epoxide hydrolase inhibitor, mitigates Aβ-induced neurotoxicity via dual modulation of mitochondrial stabilization and JNK suppression.

  • Jingfang Song1
  • Ailan He2
  • Shuyu Li2
  • Qiong Wu3
  1. 1Department of General Surgery, Wuyi Hospital of Traditional Chinese Medicine, Jiangmen, 529000, China.
  2. 2Department of Clinical Medicine, Guangdong Jiangmen Chinese Medicine College, Jiangmen, 529000, China.
  3. 3Department of Basic Medicine, Guangdong Jiangmen Chinese Medicine College, Jiangmen, 529000, China.
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Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, primarily driven by β-amyloid (Aβ) aggregation and neuronal apoptosis. This study aims to investigate the neuroprotective effects of soluble epoxide hydrolase (sEH) inhibition against Aβ-induced cytotoxicity in PC-12 cells, focusing on cell viability, apoptosis, and the c-Jun N-terminal kinase (JNK) signaling pathway. Western blotting and fluorometric assays revealed elevated sEH expression and activity in Aβ1-42-treated PC-12 cells compared to untreated controls. Treatment with N-[1-(1-Oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl]urea (TPPU), a potent sEH inhibitor, significantly attenuated Aβ-induced apoptosis in PC-12 cells and enhanced cell viability. These findings were corroborated by CCK-8 assays and flow cytometry analyses. Furthermore, TPPU reversed Aβ-induced cleaved Caspase-3 dysregulation and restored mitochondrial membrane potential. Notably, exogenous administration of epoxyeicosatrienoic acids partially mimicked the protective effects of TPPU, primarily by preserving mitochondrial function. Western blot analysis confirmed that TPPU pretreatment suppressed the phosphorylation of JNK, thereby contributing to its anti-apoptotic effects. Collectively, these findings demonstrate that TPPU attenuates Aβ-induced neurotoxicity via dual mechanisms-restoring mitochondrial function and suppressing JNK activation-highlighting its potential as a therapeutic agent for AD.

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Cite

BibTeXRIS
BibTeX
@article{song2026tppu,
  title = {{TPPU, a soluble epoxide hydrolase inhibitor, mitigates Aβ-induced neurotoxicity via dual modulation of mitochondrial stabilization and JNK suppression.}},
  author = {Jingfang Song and Ailan He and Shuyu Li and Qiong Wu},
  journal = {Biochemistry and biophysics reports},
  year = {2026},
  month = oct,
  doi = {10.1016/j.bbrep.2026.102806},
  url = {https://europepmc.org/article/MED/42903448},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - TPPU, a soluble epoxide hydrolase inhibitor, mitigates Aβ-induced neurotoxicity via dual modulation of mitochondrial stabilization and JNK suppression.
AU  - Jingfang Song
AU  - Ailan He
AU  - Shuyu Li
AU  - Qiong Wu
PY  - 2026
DA  - 2026/10/12
JO  - Biochemistry and biophysics reports
DO  - 10.1016/j.bbrep.2026.102806
UR  - https://europepmc.org/article/MED/42903448
AB  - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, primarily driven by β-amyloid (Aβ) aggregation and neuronal apoptosis. This study aims to investigate the neuroprotective effects of soluble epoxide hydrolase (sEH) inhibition against Aβ-induced cytotoxicity in PC-12 cells, focusing on cell viability, apoptosis, and the c-Jun N-terminal kinase (JNK) signaling pathway. Western blotting and fluorometric assays revealed elevated sEH expression and activity in Aβ1-42-treated PC-12 cells compared to untreated controls. Treatment with N-[1-(1-Oxopropyl)-4-piperidinyl]-N'-[4-(trifluoromethoxy)phenyl]urea (TPPU), a potent sEH inhibitor, significantly attenuated Aβ-induced apoptosis in PC-12 cells and enhanced cell viability. These findings were corroborated by CCK-8 assays and flow cytometry analyses. Furthermore, TPPU reversed Aβ-induced cleaved Caspase-3 dysregulation and restored mitochondrial membrane potential. Notably, exogenous administration of epoxyeicosatrienoic acids partially mimicked the protective effects of TPPU, primarily by preserving mitochondrial function. Western blot analysis confirmed that TPPU pretreatment suppressed the phosphorylation of JNK, thereby contributing to its anti-apoptotic effects. Collectively, these findings demonstrate that TPPU attenuates Aβ-induced neurotoxicity via dual mechanisms-restoring mitochondrial function and suppressing JNK activation-highlighting its potential as a therapeutic agent for AD.
SN  - 2405-5808
ER  -