Activation of the AKT/GSK-3β/β-catenin pathway via photobiomodulation therapy promotes neural stem cell proliferation in neonatal rat models of hypoxic-ischemic brain damage

Zhaoying Liao; Xuanzi Zhou; Siyu Li; Wei Jiang; Tingsong Li; Nanqing Wang; Nong Xiao

doi:10.21037/atm-21-5619

Activation of the AKT/GSK-3β/β-catenin pathway via photobiomodulation therapy promotes neural stem cell proliferation in neonatal rat models of hypoxic-ischemic brain damage

Ann Transl Med. 2022 Jan;10(2):55. doi: 10.21037/atm-21-5619.

Authors

Zhaoying Liao¹, Xuanzi Zhou¹, Siyu Li¹, Wei Jiang¹, Tingsong Li¹, Nanqing Wang¹, Nong Xiao¹

Affiliation

¹ Department of Rehabilitation, Children's Hospital of Chongqing Medical University, National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing Engineering Research Center of Stem Cell Therapy, Chongqing Key Laboratory of Child Health and Nutrition, Chongqing, China.

Abstract

Background: Hypoxic-ischemic brain damage (HIBD) significantly affects neurodevelopment in infants and is a leading cause of severe neurological morbidity and mortality in neonates. Our previous study found that photobiomodulation therapy (PBMT) improves the impaired spatial learning and memory of HIBD rat models. However, the neuroprotective mechanism conferred by PBMT in HIBD is unclear.

Methods: In the present study, HIBD model rats were treated with PBMT at 5 mW/cm² per day in the dark for 14 days (10 min each day), and primary neural stem cells (NSCs) after oxygen-glucose deprivation (OGD) were treated with PBMT for 10 min at 1, 5, 10, and 20 mW/cm² in the dark. PBMT promoted hippocampal neural stem cell (NSC) proliferation in vivo and in vitro.

Results: Mechanistically, PBMT upregulated phosphatidylinositol 3 kinase (PI3K), phosphorylated protein kinase B (p-AKT), phosphorylated glycogen synthase kinase 3 beta (p-GSK-3β), β-catenin, and cyclin D1 expression in vivo and in vitro, promoting NSC proliferation. Furthermore, both LY294002 (a PI3K inhibitor) and IWR-1 (a Wnt/β-catenin inhibitor) inhibited the PBMT promotion of NSC proliferation after OGD and suppressed β-catenin and cyclin D1 expression in vitro.

Conclusions: PBMT improved the spatial learning and memory of HIBD rats and promoted hippocampal NSC proliferation through the AKT/GSK-3β/β-catenin pathway.

Keywords: Hypoxic-ischemic brain damage (HIBD); neural stem cell (NSC); photobiomodulation therapy (PBMT); proliferation; spatial learning and memory.