Electroacupuncture improves hypoxic stress and energy metabolism to alleviate vascular cognitive impairment through activation of the HIF-1α/p53/NGB signaling pathway in rats

Articles in Press

Document Type : Original Article

Authors

1 The Second Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China

2 The First Clinical Medical School, Anhui University of Chinese Medicine, Hefei, China

10.22038/ijbms.2025.86988.18796

Abstract

Objective(s): We aimed to demonstrate that electroacupuncture (EA) alleviates vascular cognitive impairment (VCI) induced by cerebral ischemia in rats by modulating oxygen homeostasis and energy metabolism through the HIF-1α/p53/NGB signaling pathway.
Materials and Methods: Male Sprague‒Dawley rats underwent bilateral common carotid artery occlusion (BCCAO) to establish a VCI model. EA was administered once daily for 30 min over two weeks. Thirty minutes prior to EA, the hypoxia-inducible factor-1α (HIF-1α) inhibitor 2-methoxyestradiol (2ME2) was injected intraperitoneally. Cognitive function following BCCAO and EA was assessed using the Morris water maze test. Western blotting was performed to analyze the protein expression of HIF-1α, heme oxygenase-1 (HO-1), and neuroglobin (NGB). In addition, p53 mRNA expression was quantified by real-time PCR, and energy metabolite levels were determined using ELISA.
Results: EA significantly improved learning and memory in VCI model rats. Histopathological analysis revealed that EA attenuated neuronal apoptosis and ultrastructural damage in the cortex and hippocampus. EA upregulated HIF-1α, NGB, and HO-1 expression but downregulated p53 mRNA expression in these regions. Moreover, EA treatment reversed the expression of glucose, lactic acid, and acetone aldehyde. Notably, the beneficial effects of EA on cerebral energy metabolism were abolished by 2ME2 in VCI model rats.
Conclusion: EA alleviated BCCAO-induced neurological impairment and cognitive dysfunction in rats, possibly by reducing hypoxic stress and enhancing energy metabolism in the cortex and hippocampus, potentially through modulation of the HIF-1α/p53/NGB signaling pathway.

Keywords

Main Subjects

References

1. Hainsworth AH, Markus HS, Schneider JA. Cerebral small vessel disease, hypertension, and vascular contributions to cognitive impairment and dementia. Hypertension 2024; 81: 75-86.
2. Hosoki S, Hansra GK, Jayasena T, Poljak A, Mather KA, Catts VS, et al. Molecular biomarkers for vascular cognitive impairment and dementia. Nat Rev Neurol 2023; 19: 737-753.
3. Kalimon OJ, Vekaria HJ, Gerhardt GA, Sullivan PG. Inhibition of monoamine oxidase-a increases respiration in isolated mouse cortical mitochondria. Exp Neurol 2023; 363: 114356-114378.
4. Zhang Z, Guo Z, Jin P, Yang H, Hu M, Zhang Y, et al. Transcriptome profiling of hippocampus after cerebral hypoperfusion in mice. J Mol Neurosci 2023; 73: 423-436.
5. Vatte S, Ugale R. HIF-1, an important regulator in potential new therapeutic approaches to ischemic stroke. Neurochem Int 2023; 170: 105605.
6. Chen X, Qian W, Zhang Y, Zhao P, Lin X, Yang S, et al. Ginsenoside CK cooperates with bone mesenchymal stem cells to enhance angiogenesis post-stroke via GLUT1 and HIF-1α/VEGF pathway. Phytother Res 2024; 38: 4321-4335.
7. Madan E, Parker TM, Pelham CJ, Palma AM, Peixoto ML, Nagane M, et al. HIF-transcribed p53 chaperones HIF-1α. Nucleic Acids Res 2019; 47: 10212-10234. 
8. Du X, Mawolo JB, Liu X, Mi X, Li Q, Wen Y. Expression and distribution of neuroglobin and hypoxia-inducible factor-1α in the adult yak telencephalon. Vet Med Sci 2021; 7: 1707-1717.
9. Huang XT, Chen CY, Zhang QF, Lu LH, She YL, Fang XY. Meta-analysis of the efficacy of acupuncture in the treatment of the vascular cognitive impairment associated with cerebral small vessel disease. Explore 2023; 19: 509-518.
10. Su XT, Sun N, Zhang N, Wang LQ, Zou X, Li JL, et al. Effectiveness and safety of acupuncture for vascular cognitive impairment: A systematic review and meta-analysis. Front Aging Neurosci 2021; 13: 692508-692529.
11. Dai Y, Zhang Y, Yang M, Lin H, Liu Y, Xu W, et al. Electroacupuncture increases the hippocampal synaptic transmission efficiency and long-term plasticity to improve vascular cognitive impairment. Mediators Inflamm 2022; 2022: 5985143-5985158.
12. Sa ZY, Xu JS, Pan XH, Zheng SX, Huang QR, Wan L, et al. Effects of electroacupuncture on rats with cognitive impairment: An iTRAQ-based proteomics analysis. J Integr Med 2023; 21: 89-98.
13. Pan P, Ma Z, Zhang Z, Ling Z, Wang Y, Liu Q, et al. Acupuncture can regulate the peripheral immune cell spectrum and inflammatory environment of the vascular dementia rat, and improve the cognitive dysfunction of the rats. Front Aging Neurosci 2021; 13: 706834.
14. Liu C, Yin H, Chen X, Ban W, Zhu G, Wang J. Electroacupuncture promotes oligodendrocyte differentiation and myelin repair in a rat model of vascular dementia: Investigation of the mechanism from NF-κB-mediated inflammation. Neuroscience 2025; 572: 21-34.
15. Janbandhu V, Tallapragada V, Patrick R, Li Y, Abeygunawardena D, Humphreys DT, et al. HIF-1a suppresses ros-induced proliferation of cardiac fibroblasts following myocardial infarction. Cell Stem Cell 2022; 29: 281-297.
16. Gao Y, Yin H, Zhang Y, Dong Y, Yang F, Wu X, Liu H. Dexmedetomidine protects hippocampal neurons against hypoxia/reoxygenation-induced apoptosis through activation HIF-1α/p53 signaling. Life Sci 2019; 232: 116611.
17. Niu Y, Wan C, Zhang J, Zhang S, Zhao Z, Zhu L, et al. Aerobic exercise improves VCI through circRIMS2/miR-186/BDNF-mediated neuronal apoptosis. Mol Med 2021; 27: 4-16.
18. Li HT, Zhou HJ, Zhong JH, Tang T, Cui HJ, Zhang QM, et al. 2-Methoxyestradiol inhibits intracerebral hemorrhage- induced angiogenesis in rats. Turk Neurosurg 2018; 28: 241-247.
19. Zhang J, Zhang Y, Zhang Y, Lu K, Zhang X, Wang X, et al. Farrerol alleviates cognitive impairments in chronic cerebral hypoperfusion via suppressing NLRP3 inflammasome-mediated pyroptosis. Int Immunopharmacol 2025; 153: 114442.
20. Yang JW, Wang XR, Zhang M, Xiao LY, Zhu W, Ji CS, et al. Acupuncture as a multifunctional neuroprotective therapy ameliorates cognitive impairment in a rat model of vascular dementia: A quantitative iTRAQ proteomics study. CNS Neurosci Ther 2018; 24: 1264-1274. 
21. Dai M, Qian K, Ye Q, Yang J, Gan L, Jia Z, et al. Specific mode electroacupuncture stimulation mediates the delivery of ngf across the hippocampus blood-brain barrier through p65-VEGFA-TJs to improve the cognitive function of MCAO/R convalescent rats. Mol Neurobiol 2025; 62: 1451-1466. 
22.  Lang J, Luo J, Lang J, Wang L, Xu W, Jia J, et al. Electroacupuncture alleviated post-stroke cognitive impairment via the mTOR/NLRP3-mediated autophagy-inflammatory pathway. Eur J Med Res 2024; 29: 532-542. 
23. Wang J, Lyu H, Chen J, Lin S, Zheng H, Li J, et al. Cortical alterations are associated with depression in subcortical vascular mild cognitive impairment revealed by surface-based morphometry. J Alzheimers Dis 2020; 78: 673-681.
24.Wang J, Niu Y, Tao H, Xue M, Wan C. Knockdown of LncRNA TUG1 inhibits hippocampal neuronal apoptosis and participates in aerobic exercise-alleviated vascular cognitive impairment. Biol Res 2020; 53: 53-63.
25. Yan N, Xu Z, Qu C, Zhang J. Dimethyl fumarate improves cognitive deficits in chronic cerebral hypoperfusion rats by alleviating inflammation, oxidative stress, and ferroptosis via NRF2/ARE/NF-κB signal pathway. Int Immunopharmacol 2021; 98: 107844.
26. Zhao L, Song Y, Zhang Y, Liu H, Shen Y, Fan Y, et al. HIF-1a/BNIP 3l induced cognitive deficits in a mouse model of sepsis-associated encephalopathy. Front Immunol 2022; 13: 1095427-1095438.
27. Wu YF, Jin KY, Wang DP, Lin Q, Sun J, Su SH, et al. VEGF loaded nanofiber membranes inhibit chronic cerebral hypoperfusion-induced cognitive dysfunction by promoting HIF-1a/VEGF mediated angiogenesis. Nanomedicine 2023; 48: 102639.
28. Qiang J, Zhu XW, He J, Tao YF, Bao JW, Zhu JH, et al. mir-34a regulates the activity of HIF-1a and p53 signaling pathways by promoting glut1 in genetically improved farmed tilapia (gift, oreochromis niloticus) under hypoxia stress. Front Physiol 2020; 11: 670-682.
29. Shang L, Mao D, Li Z, Gao X, Deng J. Neuroglobin is involved in the hypoxic stress response in the brain. Biomed Res Int 2022; 2022: 8263373.
30.Hu JH, Fan P, Zhang LR, Chen CY, Xu J, Huang J, et al. Neuroglobin expression and function in the temporal cortex of bilirubin encephalopathy rats. Anat Rec (Hoboken) 2022; 305: 254-264.
31. Liu X, Gao Y, Liu Y, Zhang W, Yang Y, Fu X, et al. Neuroglobin alleviates arsenic-induced neuronal damage. Environ Toxicol Pharmacol 2021; 84: 103604.
32. Xiao P, Huang H, Zhao H, Liu R, Sun Z, Liu Y, et al. Edaravone dexborneol protects against cerebral ischemia/reperfusion-induced blood-brain barrier damage by inhibiting ferroptosis via activation of nrf-2/HO-1/GPX4 signaling. Free Radic Biol Med 2024; 217: 116-125.
33. Lal R, Dharavath RN, Chopra K. Alpha-lipoic acid ameliorates doxorubicin-induced cognitive impairments by modulating neuroinflammation and oxidative stress via NRF-2/HO-1 signaling pathway in the rat hippocampus. Neurochem Res 2023; 48: 2476-2489.
34. Shi J, Yu T, Song K, Du S, He S, Hu X, et al. Dexmedetomidine ameliorates endotoxin-induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the HIF-1a/HO-1 signaling pathway. Redox Biol 2021; 41: 101954-101968.
35. Jin W, Zhao J, Yang E, Wang Y, Wang Q, Wu Y, et al. Neuronal STAT3/HIF-1α/PTRF axis-mediated bioenergetic disturbance exacerbates cerebral ischemia-reperfusion injury via PLA2G4A. Theranostics 2022; 12: 3196-3216. 
36. Guan L, Lee H, Geng X, Li F, Shen J, Ji Y, et al. Neuroprotective effects of pharmacological hypothermia on hyperglycolysis and gluconeogenesis in rats after ischemic stroke. Biomolecules 2022; 12: 851-868.
37. Wu X, Wang C, Wang J, Zhu M, Yao Y, Liu J. Hypoxia preconditioning protects neuronal cells against traumatic brain injury through stimulation of glucose transport mediated by HIF-1α/GLUTs signaling pathway in rat. Neurosurg Rev 2021; 44: 411-422. 
38. Zhang Y, Zhang S, Yang L, Zhang Y, Cheng Y, Jia P, et al. Lactate modulates microglial inflammatory responses through HIF-1α-mediated CCL7 signaling after cerebral ischemia in mice. Int Immunopharmacol 2025; 146: 113801.
39.Li F, Geng X, Ilagan R, Bai S, Chen Y, Ding Y. Exercise postconditioning reduces ischemic injury via suppression of cerebral gluconeogenesis in rats. Brain Behav 2023; 13: e2805-2819.
40. Baranovicova E, Grendar M, Kalenska D, Tomascova A, Cierny D, Lehotsky J. NMR metabolomic study of blood plasma in ischemic and ischemically preconditioned rats: An increased level of ketone bodies and decreased content of glycolytic products 24 h after global cerebral ischemia. J Physiol Biochem 2018; 74: 417-429.
Iranian Journal of Basic Medical Sciences

Articles in Press, Accepted Manuscript
Available Online from 29 October 2025

Files

Share

How to cite

Statistics