Neuroprotective effect of GJ-4 against cognitive impairments in vascular dementia by improving white matter damage

GJ-4, a crocin-enriched extract isolated from the fruit of Gardenia jasminoides , could significantly attenuate cognitive impairments , cerebral blood flow and white matter damage of BCAS . • GJ-4 significantly decreased the apoptosis of oligodendrocytes in vitro and in vivo . • GJ-4 could mitigate oxidative stress damage by Keap 1/Nrf2-HO pathway in vitro and in vivo. • GJ-4 treatment significantly improved lipid metabolism disorder in the WM. White matter lesions (WMLs) are increasingly linked to the pathological process of chronic vascular dementia (VaD). An effective crocins fraction extracted from Gardenia Fructus , GJ-4, has been shown to improve cognitive function in several Alzheimer's disease models and VaD models. To explore the potential mechanisms of GJ-4 on WMLs in a chronic VaD mouse model. The chronic VaD mouse model was established, and WMLs were characterized by cerebral blood flow (CBF), behavioral tests, LFB staining, and immunohistochemistry. The anti-oxidative effect of GJ-4 was validated by examining biochemical parameters (SOD, MDA, and GSH) and the Keap1-Nrf2/HO-1 pathway. The impact of GJ-4 on lipid metabolism in WM was further investigated through lipidomic analysis. GJ-4 significantly attenuated cognitive impairments and improved the CBF of BCAS (bilateral common carotid artery stenosis)-induced mice. Mechanism research showed that GJ-4 could enhance cognition by promoting the repair of WMLs by inhibiting oxidative stress . Furthermore, GJ-4 treatment significantly reduced chronic cerebral hypoperfusion (CCH)-induced WMLs via improving lipid metabolism disorder in the WM. This research has provided valuable insights into the significance of WMLs in CCH-induced VaD and underscored the potential of GJ-4 as a therapeutic agent for improving cognitive function by targeting WMLs. These findings suggest that GJ-4 is a promising candidate for the treatment of VaD.