2025, Vol. 29 ›› Issue (36): 7797-7803

Gadd45b alleviates white matter damage in chronic ischemic rats by modulating astrocyte phenotype

Yu Hui1, Yang Yang2, Wei Ting2, Li Wenli2, Luo Wenqian2, Liu Bin2   

Abstract: BACKGROUND: Previous studies have found that growth arrest and DNA damage-inducible protein 45β (Gadd45b) is beneficial to the repair of acute cerebral ischemia, but the action mechanism is still unclear.
OBJECTIVE: To investigate the effect and mechanism of Gadd45b on white matter demyelinating lesions in rats with chronic cerebral ischemia.
METHODS: SD rats were randomly divided into four groups: sham operation group, model group, empty vector group, and Gadd45b overexpression group, with 15 rats in each group. Gadd45b-overexpressing lentivirus and no-load lentivirus were injected into the bilateral hippocampus and bilateral ventricles of rats. One week after lentivirus transfection, the rat model of chronic hypoperfusion cerebral ischemia was established by bilateral common carotid artery ligation. Three weeks after the bilateral common carotid artery ligation, the learning and cognitive functions of rats were evaluated by novel object recognition test. Luxol fast blue staining was used to observe the changes of myelin structure in the corpus callosum of rats. Hematoxylin-eosin staining and Nissl staining were used to observe the damage of the rat corpus callosum. Immunofluorescence staining was used to detect the expression of myelin basic protein and neurofilament protein 200 in the corpus callosum of rats. Immunofluorescence double staining was used to detect the expression of astrocyte markers GFAP/C3d and GFAP/S100A10 in rat brain tissue. ELISA was used to detect the levels of tumor necrosis factor-α and interleukin-6 in the supernatant of brain tissue.
RESULTS AND CONCLUSION: (1) Gadd45b overexpression could significantly improve the learning and cognitive function of rats with chronic cerebral ischemia, and improve demyelination and pathological damage in the rat corpus callosum. (2) The results of immunofluorescence showed that Gadd45b overexpression significantly increased the expression levels of myelin basic protein and neurofilament protein 200 in the brain tissue of rats with chronic cerebral ischemia. (3) Gadd45b overexpression reduced GFAP/C3d double positive cells and increased GFAP/S100A10 double positive cells in the brain tissue of rats with chronic cerebral ischemia. (4) Gadd45b overexpression reduced the levels of tumor necrosis factor-α and interleukin-6 in the brain tissue of rats with chronic cerebral ischemia. It is concluded that Gadd45b overexpression improves cognitive dysfunction by promoting the A2 phenotype transformation of astrocytes, alleviating white matter myelin structure damage and neuroinflammation in rats with chronic cerebral ischemia.

Key words: chronic cerebral ischemia, growth arrest and DNA damage inducible protein 45β, white matter, demyelination, astrocyte, nerve inflammation, engineered cell