Abstract
Age-related white matter lesions (WML) frequently present vascular problems by decreasing cerebral blood supply, resulting in the condition known as chronic cerebral hypoperfusion (CCH). This study aimed to investigate the effect of hexahydrocurcumin (HHC) on the processes of demyelination and remyelination induced by the model of the Bilateral Common Carotid Artery Occlusion (BCCAO) for 29 days to mimic the CCH condition. The pathological appearance of myelin integrity was significantly altered by CCH, as evidenced by Transmission Electron Microscopy (TEM) and Luxol Fast Blue (LFB) staining. In addition, CCH activated A1-astrocytes and reactive-microglia by increasing the expression of Glial fibrillary acidic protein (GFAP), complement 3 (C3d) and pro-inflammatory cytokines. However, S100a10 expression, a marker of neuroprotective astrocytes, was suppressed, as were regenerative factors including (IGF-1) and Transglutaminase 2 (TGM2). Therefore, the maturation step was obstructed as shown by decreases in the levels of myelin basic protein (MBP) and the proteins related with lipid synthesis. Cognitive function was therefore impaired in the CCH model, as evidenced by the Morris water maze test. By contrast, HHC treatment significantly improved myelin integrity, and inhibited A1-astrocytes and reactive-microglial activity. Consequently, pro-inflammatory cytokines and A1-astrocytes were attenuated, and regenerative factors increased assisting myelin maturation and hence improving cognitive performance. In conclusion, HHC improves cognitive function and also the integrity of white matter in CCH rats by reducing demyelination, and pro-inflammatory cytokine production and promoting the process of remyelination.
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Abbreviations
- 2VO:
-
2 Vessels occlusion
- AD:
-
Alzheimer’s disease
- APOE:
-
Apolipoprotein E
- BBB:
-
Blood–brain barrier
- BCCAO:
-
Bilateral common carotid artery occlusion
- C3d:
-
Complement 3
- CBF:
-
Cerebral blood flow
- CCA:
-
Common carotid artery occlusion
- CCH:
-
Chronic cerebral hypoperfusion
- CNS:
-
Central nervous system
- GFAP:
-
Glial fibrillary acidic protein
- HHC:
-
Hexahydrocurcumin
- Iba-1:
-
Ionized calcium-binding adaptor molecule 1
- IL-1β:
-
Interleukin 1 beta
- IGF-1:
-
Insulin-like growth factor 1
- MBP:
-
Myelin basic protein
- MMP-9:
-
Matrix metalloproteinase 9
- mTOR:
-
Mammalian target of rapamycin
- OPC:
-
Oligodendrocyte precursor cells
- SREBP:
-
Sterol regulatory element-binding protein
- TGM2:
-
Transglutaminase 2
- TNF-α:
-
Tumor necrosis factor alpha
- WML:
-
White matter lesion
- VaD:
-
Vascular dementia
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Funding
This work was supported by the Royal Golden Jubilee Ph.D. program (NRCT5-RGJ63004-076) and Thailand Science Research and Innovation (TSRI) (RUG6290031), Thailand. Partial support from Functional Food Research Center for Well-Being, Multidisciplinary Research Institute, Chiang Mai University and the Center of Excellence for Innovation in Chemistry (PERCH-CIC), Ministry of Higher Education, Science, Research and Innovation is gratefully acknowledged.
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PJ: conducted the experiments, performed data analysis, writing—original draft, review & editing. PT: conducted the experiments. CT: performed data analysis, and writing—review & editing. WC: preparation of hexahydrocurcumin. AS: preparation of hexahydrocurcumin, and writing—review & editing. JT: conceived and designed the experiments, performed data analysis, writing—original draft, review & editing, and project administration.
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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: 31/2563) and performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
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Jearjaroen, P., Thangwong, P., Tocharus, C. et al. Hexahydrocurcumin attenuated demyelination and improved cognitive impairment in chronic cerebral hypoperfusion rats. Inflammopharmacol 32, 1531–1544 (2024). https://doi.org/10.1007/s10787-023-01406-7
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DOI: https://doi.org/10.1007/s10787-023-01406-7