Int J Biol Sci 2022; 18(16):6052-6067. doi:10.7150/ijbs.75188 This issue Cite

Research Paper

Intermittent Fasting Attenuates Hallmark Vascular and Neuronal Pathologies in a Mouse Model of Vascular Cognitive Impairment

Vismitha Rajeev1, David Y. Fann2,3,4✉, Quynh Nhu Dinh5, Hyun Ah Kim5, T. Michael De Silva5, Dong-Gyu Jo6, Grant R. Drummond5, Christopher G. Sobey5, Mitchell K.P. Lai1, Christopher Li-Hsian Chen1, Thiruma V. Arumugam5,6✉

1. Memory Aging and Cognition Centre, Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
2. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
3. Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
4. Centre for Healthy Longevity, National University Health System (NUHS), Singapore
5. Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia
6. School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea

Citation:
Rajeev V, Fann DY, Dinh QN, Kim HA, De Silva TM, Jo DG, Drummond GR, Sobey CG, Lai MKP, Chen CLH, Arumugam TV. Intermittent Fasting Attenuates Hallmark Vascular and Neuronal Pathologies in a Mouse Model of Vascular Cognitive Impairment. Int J Biol Sci 2022; 18(16):6052-6067. doi:10.7150/ijbs.75188. https://www.ijbs.com/v18p6052.htm
Other styles

File import instruction

Abstract

Graphic abstract

Background - Chronic cerebral hypoperfusion (CCH) is an important pathophysiological mechanism of vascular cognitive impairment (VCI). The heterogeneous effects of CCH complicate establishing single target therapies against VCI and its more severe form, vascular dementia (VaD). Intermittent fasting (IF) has multiple targets and is neuroprotective across a range of disease conditions including stroke, but its effects against CCH-induced neurovascular pathologies remain to be elucidated. We therefore assessed the effect of IF against CCH-associated neurovascular pathologies and investigated its underlying mechanisms.

Methods - Male C57BL/6NTac mice were subjected to either ad libitum feeding (AL) or IF (16 hours of fasting per day) for 4 months. In both groups, CCH was experimentally induced by the bilateral common carotid artery stenosis (BCAS) method. Sham operated groups were used as controls. Measures of leaky microvessels, blood-brain barrier (BBB) permeability, protein expression of tight junctions, extracellular matrix components and white matter changes were determined to investigate the effect of IF against CCH-induced neurovascular pathologies.

Results - IF alleviated CCH-induced neurovascular pathologies by reducing the number of leaky microvessels, BBB breakdown and loss of tight junctional proteins. In addition, IF mitigated the severity of white matter lesions, and maintained myelin basic protein levels, while concurrently reducing hippocampal neuronal cell death. Furthermore, IF reduced the CCH-induced increase in levels of matrix metalloproteinase (MMP)-2 and its upstream activator MT1-MMP, which are involved in the breakdown of the extracellular matrix that is a core component of the BBB. Additionally, we observed that IF reduced CCH-induced increase in the oxidative stress marker malondialdehyde, and increased antioxidant markers glutathione and superoxide dismutase. Overall, our data suggest that IF attenuates neurovascular damage, metalloproteinase and oxidative stress-associated pathways, and cell death in the brain following CCH in a mouse model of VCI.

Conclusion - Although IF has yet to be assessed in human patients with VaD, our data suggest that IF may be an effective means of preventing the onset or suppressing the development of neurovascular pathologies in VCI and VaD.

Keywords: Vascular dementia, Vascular cognitive impairment, Intermittent fasting, Neuronal death, White matter lesions, Blood brain barrier breakdown, Chronic cerebral hypoperfusion


Citation styles

APA
Rajeev, V., Fann, D.Y., Dinh, Q.N., Kim, H.A., De Silva, T.M., Jo, D.G., Drummond, G.R., Sobey, C.G., Lai, M.K.P., Chen, C.L.H., Arumugam, T.V. (2022). Intermittent Fasting Attenuates Hallmark Vascular and Neuronal Pathologies in a Mouse Model of Vascular Cognitive Impairment. International Journal of Biological Sciences, 18(16), 6052-6067. https://doi.org/10.7150/ijbs.75188.

ACS
Rajeev, V.; Fann, D.Y.; Dinh, Q.N.; Kim, H.A.; De Silva, T.M.; Jo, D.G.; Drummond, G.R.; Sobey, C.G.; Lai, M.K.P.; Chen, C.L.H.; Arumugam, T.V. Intermittent Fasting Attenuates Hallmark Vascular and Neuronal Pathologies in a Mouse Model of Vascular Cognitive Impairment. Int. J. Biol. Sci. 2022, 18 (16), 6052-6067. DOI: 10.7150/ijbs.75188.

NLM
Rajeev V, Fann DY, Dinh QN, Kim HA, De Silva TM, Jo DG, Drummond GR, Sobey CG, Lai MKP, Chen CLH, Arumugam TV. Intermittent Fasting Attenuates Hallmark Vascular and Neuronal Pathologies in a Mouse Model of Vascular Cognitive Impairment. Int J Biol Sci 2022; 18(16):6052-6067. doi:10.7150/ijbs.75188. https://www.ijbs.com/v18p6052.htm

CSE
Rajeev V, Fann DY, Dinh QN, Kim HA, De Silva TM, Jo DG, Drummond GR, Sobey CG, Lai MKP, Chen CLH, Arumugam TV. 2022. Intermittent Fasting Attenuates Hallmark Vascular and Neuronal Pathologies in a Mouse Model of Vascular Cognitive Impairment. Int J Biol Sci. 18(16):6052-6067.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.