Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (3): 845-857.doi: 10.4103/1673-5374.392889

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Maintaining moderate levels of hypochlorous acid promotes neural stem cell proliferation and differentiation in the recovery phase of stroke

Lin-Yan Huang1, #, Yi-De Zhang1, #, Jie Chen1, #, Hai-Di Fan2, 3, #, Wan Wang1 , Bin Wang4 , Ju-Yun Ma2 , Peng-Peng Li4 , Hai-Wei Pu4 , Xin-Yian Guo1 , Jian-Gang Shen5, *, Su-Hua Qi1, 2, *   

  1. 1 School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, Jiangsu Province, China; 2 School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, China; 3 Department of Laboratory Medicine, Branch Hospital of Huai’an First People’s Hospital, Huai’an, Jiangsu Province, China; 4 Department of Laboratory Medicine, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China; 5 School of Chinese Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China
  • Online:2025-03-15 Published:2024-06-26
  • Contact: Su-Hua Qi, PhD, suhuaqi@xzhmu.edu.cn; Jian-Gang Shen, MD, PhD, shenjg@hkucc.hku.hk.
  • Supported by:
    This study was supported by the Natural Science Foundation of Jiangsu Province of China, No. BK20211348 (to SHQ); Xuzhou Basic Research Program, No. KC21030 (to LYH); Leadership Program of Xuzhou Medical University, No. JBGS202203 (to SHQ); and Research Grant Council GRF of Hong Kong Special Administrative Region of China, No. 17105220 (to JGS).

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Abstract: It has been shown clinically that continuous removal of ischemia/reperfusion-induced reactive oxygen species is not conducive to the recovery of late stroke. Indeed, previous studies have shown that excessive increases in hypochlorous acid after stroke can cause severe damage to brain tissue. Our previous studies have found that a small amount of hypochlorous acid still exists in the later stage of stroke, but its specific role and mechanism are currently unclear. To simulate stroke in vivo, a middle cerebral artery occlusion rat model was established, with an oxygen-glucose deprivation/reoxygenation model established in vitro to mimic stroke. We found that in the early stage (within 24 hours) of ischemic stroke, neutrophils produced a large amount of hypochlorous acid, while in the recovery phase (10 days after stroke), microglia were activated and produced a small amount of hypochlorous acid. Further, in acute stroke in rats, hypochlorous acid production was prevented using a hypochlorous acid scavenger, taurine, or myeloperoxidase inhibitor, 4-aminobenzoic acid hydrazide. Our results showed that high levels of hypochlorous acid (200 μM) induced neuronal apoptosis after oxygen/glucose deprivation/reoxygenation. However, in the recovery phase of the middle cerebral artery occlusion model, a moderate level of hypochlorous acid promoted the proliferation and differentiation of neural stem cells into neurons and astrocytes. This suggests that hypochlorous acid plays different roles at different phases of cerebral ischemia/reperfusion injury. Lower levels of hypochlorous acid (5 and 100 μM) promoted nuclear translocation of β-catenin. By transfection of single-site mutation plasmids, we found that hypochlorous acid induced chlorination of the β-catenin tyrosine 30 residue, which promoted nuclear translocation. Altogether, our study indicates that maintaining low levels of hypochlorous acid plays a key role in the recovery of neurological function.

Key words: cell differentiation, cerebral ischemia/reperfusion injury, chlorination, hypochlorous acid, microglia, neural stem cell, neurogenesis, nuclear translocation, stroke, β-catenin