2. Academic Validation
  3. Inhibition of 12/15-LOX hyperactivation mitigates cognitive decline in a chronic cerebral hypoperfusion mouse model and in H2O2-induced HT22 cells: therapeutic effects of brozopine

Inhibition of 12/15-LOX hyperactivation mitigates cognitive decline in a chronic cerebral hypoperfusion mouse model and in H2O2-induced HT22 cells: therapeutic effects of brozopine

  • J Enzyme Inhib Med Chem. 2025 Dec;40(1):2547259. doi: 10.1080/14756366.2025.2547259.
Xuening Wang 1 2 3,  Zhizai Lu 1 2,  Qiuji Shao 4,  Yi Wang 1 2,  Zixin Zhang 1 2,  Zhiyu Wang 1 2,  Qingran Jia 1 2,  Jinpeng Zhu 1 2,  Yiran Song 1 2,  Lingxu Yuan 1 2,  Yiming Wang 1 2,  Shaoyang Xu 1 2,  Lirou He 1 2,  Junbiao Chang 5,  Yuan Gao 1 2
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medicine, Zhengzhou University, Zhengzhou, China.
  • 2 Institute of Clinical Pharmacology, School of Basic Medicine, Zhengzhou University, Zhengzhou, China.
  • 3 Department of Neurosurgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 4 Department of Cerebrovascular Disease, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, China.
  • 5 Department of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, China.
PMID: 40841277 DOI: 10.1080/14756366.2025.2547259
Abstract

Brozopine (BZP), a novel inhibitor of 12/15-lipoxygenase (12/15-LOX), has previously demonstrated efficacy in mitigating inflammatory and oxidative stress-related injury in cerebral ischaemia models. This study aimed to evaluate the therapeutic potential and underlying mechanisms of BZP in a mouse model of vascular dementia induced by chronic cerebral hypoperfusion. BZP was administered for 28 days following right unilateral common carotid artery occlusion (rUCCAO) in mice. BZP significantly alleviated cognitive impairment, behavioural deficits, and fine motor function. Mechanistically, BZP inhibited 12/15-LOX, cPLA2, p-p38 MAPK/p38 MAPK ratio, tumour necrosis factor-α, interlukin-1β, Aβ1-42 deposition, and Tau hyperphosphorylation in the brain and serum of rUCCAO mice. Similar protective effects were observed in both 12/15-LOX-overexpressed and H2O2-induced HT22 cell models. These findings suggest that BZP exerts its neuroprotective effects by targeting the 12/15-LOX/cPLA2/p38 MAPK pathway, offering a promising therapeutic strategy for mitigating the progression of cognitive impairment.

Keywords

12/15-LOX; BZP; CCH; cognitive decline; inflammation.

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