Baicalein ameliorates cognitive decline induced by chronic cerebral hypoperfusion through the SIRT1-mediated Notch1 pathway to improve angiogenesis and suppress neuroinflammation

Meixi Li; Jiaxi Song; Xiaoli Niu; Feng Mo; Xiaohua Xie; Xiuqin Li; Yu Yin; Tianjun Wang; Xiujuan Song; Jingze Liu; Peiyuan Lv

doi:10.3389/fnagi.2025.1521353

Baicalein ameliorates cognitive decline induced by chronic cerebral hypoperfusion through the SIRT1-mediated Notch1 pathway to improve angiogenesis and suppress neuroinflammation

Front Aging Neurosci. 2025 Apr 11:17:1521353. doi: 10.3389/fnagi.2025.1521353. eCollection 2025.

Authors

Meixi Li^{1

2

3

4

5}, Jiaxi Song^{3

4}, Xiaoli Niu^{3

4}, Feng Mo⁶, Xiaohua Xie^{3

4}, Xiuqin Li⁷, Yu Yin⁵, Tianjun Wang^{3

4}, Xiujuan Song⁸, Jingze Liu^{2

9}, Peiyuan Lv^{1

3

4}

Affiliations

¹ Postdoctoral Innovation Practice Base of Hebei General Hospital, Shijiazhuang, Hebei, China.
² Postdoctoral Research Station of Biology, Hebei Normal University, Shijiazhuang, Hebei, China.
³ Department of Neurology, Hebei General Hospital, Shijiazhuang, Hebei, China.
⁴ Hebei Key Laboratory of Cerebral Networks and Cognitive Disorders, Hebei General Hospital, Shijiazhuang, Hebei, China.
⁵ Department of Rehabilitation, Hebei General Hospital, Shijiazhuang, Hebei, China.
⁶ Department of Neurosurgery, Hebei General Hospital, Shijiazhuang, Hebei, China.
⁷ Department of Geriatrics, Hebei General Hospital, Shijiazhuang, Hebei, China.
⁸ Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
⁹ Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Shijiazhuang, Hebei, China.

Abstract

Introduction: The potential for therapeutic strategies that promote angiogenesis and suppress neuroinflammation to ameliorate cognitive decline induced by chronic cerebral hypoperfusion (CCH) has led to their recognition as promising therapeutic targets for vascular dementia (VD). The SIRT1-mediated Notch1 signaling pathway is important in regulating angiogenesis and neuroinflammation. Previous studies have demonstrated that baicalein alleviates cognitive decline in rats with CCH. Nevertheless, it remains unclear whether baicalein can stimulate angiogenesis in the context of VD and whether this cognitive protective effect is achieved by regulating the SIRT1-mediated Notch1 pathway. The aim of this study was to investigate the impact and the underlying mechanism of baicalein on angiogenesis and neuroinflammation in rats with CCH.

Methods: Adult Sprague-Dawley (SD) rats were administered baicalein or a SIRT1 inhibitor. Cognitive function was assessed by the Morris water maze (MWM) test, and angiogenesis was assessed by immunohistochemical analysis of microvascular density (MVD) and the number of CD31+/5-bromo-2'-deoxyuridine (BrdU)+ cells. Neuroinflammation and apoptosis were assessed by immunohistochemistry for GFAP, Iba-1, NEUN/cleaved caspase-3, and ELISA analysis for TNF-α and IL-1β. Additionally, Western blotting was employed to evaluate the expression of the SIRT1-mediated Notch1 pathway.

Results: The results demonstrated that baicalein ameliorated memory and learning deficits in rats following CCH by promoting angiogenesis and suppressing neuroinflammation. However, this protective effect could be reversed by inhibiting SIRT1. Baicalein was observed to up-regulate the expression of SIRT1 and down-regulate the Notch1-related molecules.

Discussion: The SIRT1-related pathway plays a crucial role in regulating angiogenesis and neuroinflammation. Moreover, baicalein exerts a neuroprotective effect against cognitive decline through the SIRT1-mediated Notch1 pathway, which in turn improves angiogenesis and suppresses neuroinflammation.

Keywords: SIRT1-mediated Notch1 pathway; angiogenesis; baicalein; neuroinflammation; vascular dementia (VD).