2. Academic Validation
  3. Inhibition of Cathepsin B Ameliorates Murine Cognitive Dysfunction and Neuronal Damage in Ischemic Stroke by Inhibiting Mitochondrial Apoptosis and Drp1-Mediated Mitochondrial Fission

Inhibition of Cathepsin B Ameliorates Murine Cognitive Dysfunction and Neuronal Damage in Ischemic Stroke by Inhibiting Mitochondrial Apoptosis and Drp1-Mediated Mitochondrial Fission

  • Mol Neurobiol. 2025 May 30. doi: 10.1007/s12035-025-05094-y.
Hongyi Jia 1 2,  Bingge Zhang 2,  Xiao Han 3,  Pei Yu 1,  Bocheng Xiong 2,  Tiansu Liu 4,  Luchen Shan 5,  Xifei Yang 6,  Qinghua Hou 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Jinan University, 855 Xingye Rd, Guangzhou, Guangdong, 511400, China.
  • 2 Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong, China.
  • 3 Department of Toxicology, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi, 030001, China.
  • 4 School of Public Health, Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, 561113, China.
  • 5 State Key Laboratory of Bioactive Molecules and Druggability Assessment, College of Pharmacy, Jinan University, 855 Xingye Rd, Guangzhou, Guangdong, 511400, China. ytysxs@126.com.
  • 6 Shenzhen Key Laboratory of Modern Toxicology, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, Guangdong, China. xifeiyang@gmail.com.
  • 7 Department of Neurology, Clinical Neuroscience Center, the Seventh Affiliated Hospital, Sun Yat-Sen University, 628 Zhenyuan Rd, Shenzhen, Guangdong, 518017, China. houqinghua@sysush.com.
PMID: 40447852 DOI: 10.1007/s12035-025-05094-y
Abstract

The surviving brain tissue undergoes secondary degeneration long after an ischemic stroke. Cathepsin B plays dual roles as both a scavenger and an executor. Using a mouse model of ischemic stroke, we specifically investigated the mechanism by which inhibiting Cathepsin B with CA074 methyl ester (CA-074Me) during the chronic phase of stroke exerts a protective effect. In the intervention group, CA-074Me (20 μg CA-074Me/1 μl DMSO) was stereotaxically injected in the right ventricle, and, 30 min later, the Animals were subjected to develop transient middle cerebral artery occlusion and reperfusion (tMCAO/R) stroke model with modified Longa method. In the model group, 1 μl DMSO was given in the right ventricle instead and the sham-operated group received 1 μl DMSO in the right ventricle without arterial occlusion. We evaluated the effects of inhibition of Cathepsin B on the nervous system after tMCAO/R injury by combined use behavioral tests, neurological deficit scoring, Western blot and Other pharmacological methods and explored the underlying mechanism. After tMCAO/R, sustained upregulation and activation of Cathepsin B was noticed in the ipsilateral hippocampus CA1 zone and CA-074Me ameliorated the parallel lysosome-mitochondria damage, decreased Apoptosis, improved the cognitive dysfunction, but had no effects on levels of mouse anxiety or depression. Furthermore, CA-074Me reduced neuroinflammation, levels of oxidative stress and mitochondria fission. Inhibition of Cathepsin B alleviates mitochondrial abnormalities in the ipsilateral hippocampus CA1 zone 28 days after tMCAO/R by suppressing Drp-1mediated excessive mitochondrial fission. This, in turn, reduces neuronal Apoptosis, ameliorates neuroinflammation, and mitigates oxidative stress and neuronal damage, indicating Cathepsin B may serve as a potential therapeutic target for remote secondary degeneration following acute ischemic stroke.

Keywords

Apoptosis; CA-074Me; Cathepsin B; Ischemic stroke; Mitochondrial fission.

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