Abstract
Chronic cerebral hypoxia (CCH) is caused by a reduction in cerebral blood flow, and cognitive impairment has been the predominant feature that occurs after CCH. Recent reports have revealed that melatonin is proficient in neurodegenerative diseases. However, the molecular mechanism by which melatonin affects CCH remains uncertain. In this study, we aimed to explore the role and underlying mechanism of melatonin in inflammation and blood‒brain barrier conditions in rats with CCH. Male Wistar rats were subjected to permanent bilateral common carotid artery occlusion (BCCAO) to establish the VAD model. Rats were randomly divided into four groups: Sham, BCCAO, BCCAO treated with melatonin (10 mg/kg), and BCCAO treated with resveratrol (20 mg/kg). All drugs were administered once daily for 4 weeks. Our results showed that melatonin attenuated cognitive impairment, as demonstrated by the Morris water maze tests. Furthermore, melatonin reduced the activation of inflammation by attenuating the phosphorylated nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor alpha (pIκBα), causing the suppression of proteins related to inflammation and inflammasome formation. Moreover, immunohistochemistry revealed that melatonin reduced glial cell activation and proliferation, which were accompanied by Western blotting results. Additionally, melatonin also promoted the expression of sirtuin-1 (SIRT1), peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1α), and peroxisome proliferator-activated receptor-gamma (PPARγ), causing attenuated blood‒brain barrier (BBB) disruption by increasing tight junction proteins. Taken together, our results prove that melatonin treatment modulated inflammation and BBB disruption and improved cognitive function in VaD rats, partly by activating the SIRT1/PGC-1α/PPARγ signaling pathway.
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This work was supported by grants from Functional Food Research Center for Wellbeing, Chiang Mai University, Thailand Science Research and Innovation (TSRI) (grant number 64/004) and the Development and Promotion of Science and Technology Talents Project Royal Government of Thailand scholarship (grant number 572109).
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The authors declare that all data were generated in-house and that no paper mill was used. All authors were involved in the study design. PT performed writing–original draft, methodology, investigation, and formal analysis. PJ performed the investigation. PG performed resources. CT performed methodology, writing–review, and editing. JT performed writing–review and editing, conceptualization, supervision, project administration, and funding acquisition.
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All experimental procedures were approved by the Institutional Animal Care and Use Committee at the Faculty of Medicine, Chiang Mai University, (Permit number: 32/2563) and performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
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Thangwong, P., Jearjaroen, P., Tocharus, C. et al. Melatonin suppresses inflammation and blood‒brain barrier disruption in rats with vascular dementia possibly by activating the SIRT1/PGC-1α/PPARγ signaling pathway. Inflammopharmacol 31, 1481–1493 (2023). https://doi.org/10.1007/s10787-023-01181-5
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DOI: https://doi.org/10.1007/s10787-023-01181-5