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Exercise Improves Cerebral Blood Flow and Functional Outcomes in an Experimental Mouse Model of Vascular Cognitive Impairment and Dementia (VCID)

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Abstract

Vascular cognitive impairment and dementia (VCID) are a growing threat to public health without any known treatment. The bilateral common carotid artery stenosis (BCAS) mouse model is valid for VCID. Previously, we have reported that remote ischemic postconditioning (RIPostC) during chronic cerebral hypoperfusion (CCH) induced by BCAS increases cerebral blood flow (CBF), improves cognitive function, and reduces white matter damage. We hypothesized that physical exercise (EXR) would augment CBF during CCH and prevent cognitive impairment in the BCAS model. BCAS was performed in C57/B6 mice of both sexes to establish CCH. One week after the BCAS surgery, mice were randomized to treadmill exercise once daily or no EXR for four weeks. CBF was monitored with an LSCI pre-, post, and 4 weeks post-BCAS. Cognitive testing was performed for post-BCAS after exercise training, and brain tissue was harvested for histopathology and biochemical test. BCAS led to chronic hypoperfusion resulting in impaired cognitive function and other functional outcomes. Histological examination revealed that BCAS caused changes in neuronal morphology and cell death in the cortex and hippocampus. Immunoblotting showed that BCAS was associated with a significant downregulate of AMPK and pAMPK and NOS3 and pNOS3. BCAS also decreased red blood cell (RBC) deformability. EXR therapy increased and sustained improved CBF and cognitive function, muscular strength, reduced cell death, and loss of white matter. EXR is effective in the BCAS model, improving CBF and cognitive function, reducing white matter damage, improving RBC deformability, and increasing RBC NOS3 and AMPK. The mechanisms by which EXR improves CBF and attenuates tissue damage need further investigation.

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Abbreviations

1MO :

One month

AMPK :

Adenosine monophosphate-activated protein kinase

BCAS :

Bilateral carotid artery stenosis

CBF:

Cerebral blood flow

CCAs :

Common carotid arteries

C-EXR :

Chronic exercise or regular exercise

CCH :

Chronic cerebral hypoperfusion

DTI:

Diffusion tensor imaging

EXR :

Exercise

FAIR:

Flow sensitive alternating inversion recovery

eNOS/NOS3 :

Endothelial nitric oxide synthase

pAMPK :

Phospho-AMPK

peNOS/pNOS3 :

Phospho-eNOS or Phospho-NOS3

LSCI :

Laser speckle contrast imager

LFB :

Luxol fast blue

NO :

Nitric oxide

RBC :

Red blood cells

VCID :

Vascular contributions to cognitive impairment and dementia or vascular cognitive impairment and dementia

WM :

White matter

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Acknowledgements

The authors want to thank Drs. Roxan Ara and Asamoah Bosomtwi of small animal imaging core at Georgia Cancer Center for their help acquiring MR images.

Funding

This work was supported by NIH Award R01 NS099455, 1U01Ns113356, and R01 NS112511 to David C. Hess.

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Author notes

  1. Haroon Alam and Shahneela Siddiqui contributed equally to this study.

Authors and Affiliations

  1. Department of Neurology, Medical College of Georgia, Augusta University, 1120 15thStreet, CA 1053, Augusta, GA, 30912, USA

    Mohammad Badruzzaman Khan, Haroon Alam, Shahneela Siddiqui, Muhammad Fasih Shaikh, Abhinav Sharma, Amna Rehman & David C. Hess

  2. Department of Oral Biology, Dental College of Georgia, Augusta University, Augusta, GA, 30912, USA

    Babak Baban

  3. Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA

    Ali S. Arbab

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Contributions

M.B.K., H.A., S.S. conceptualized, designed, performed experiments, analyzed data, and wrote the manuscript. H.A. performed exercise and behavioral experiments. S.S. performed exercise, western blot, and assisted with performing and analyzing behavioral tasks. M.F.S and A.S. performed behavioral analysis. B. B. performed flow cytometry experiments. A.S.A. analyses MRI data. D.C.H. and A.S.A assisted with the experimental design and editing of the manuscript with data interpretation.

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Correspondence to Mohammad Badruzzaman Khan.

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All applicable national and institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any authors.

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Khan, M.B., Alam, H., Siddiqui, S. et al. Exercise Improves Cerebral Blood Flow and Functional Outcomes in an Experimental Mouse Model of Vascular Cognitive Impairment and Dementia (VCID). Transl. Stroke Res. 15, 446–461 (2024). https://doi.org/10.1007/s12975-023-01124-w

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