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Hexahydrocurcumin alleviated blood–brain barrier dysfunction in cerebral ischemia/reperfusion rats

Abstract

Background

Hexahydrocurcumin (HHC), a major metabolite of curcumin, has been reported to have protective effects against ischemic and reperfusion damage. The goal of the present research was to examine whether HHC could alleviate brain damage and ameliorate functional outcomes by diminishing the blood–brain barrier (BBB) damage that follows cerebral ischemia/reperfusion.

Methods

Middle cerebral artery occlusion was induced for 2 h in rats followed by reperfusion. The rats were divided into three groups: sham-operated, vehicle-treated, and HHC-treated groups. At the onset of reperfusion, the rats were immediately intraperitoneally injected with 40 mg/kg HHC. At 48 h after reperfusion, the rats were evaluated for neurological deficits and TTC staining. At 24 h and 48 h after reperfusion, animals were sacrificed, and their brains were extracted.

Results

Treatment with HHC reduced neurological scores, infarct volume, morphological changes, Evans blue leakage and immunoglobulin G extravasation. Moreover, HHC treatment reduced BBB damage and neutrophil infiltration, downregulated myeloperoxidase, ICAM-1, and VCAM-1, upregulated tight junction proteins (TJPs), and reduced aquaporin 4 expression and brain water content.

Conclusion

These results revealed that HHC treatment preserved the BBB from cerebral ischemia/reperfusion injury by regulating TJPs, attenuating neutrophil infiltration, and reducing brain edema formation.

Graphic abstract

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Abbreviations

AQP4:

Aquaporin 4

AS:

Astrocytic swelling

BBB:

Blood–brain barrier

BM:

Basement membrane

BSA:

Bovine serum albumin

CBF:

Cerebral blood flow

CCA:

Common carotid artery

CNS:

Central nervous system

COX-2:

Cyclooxygenase-2

EB:

Evans blue

ECA:

External carotid artery

ECM:

Extracellular matrix

GI:

Gastrointestinal

H&E:

Hematoxylin and eosin

HHC:

Hexahydrocurcumin

HRP:

Horseradish peroxidase

I/R:

Ischemia reperfusion

ICA:

Internal carotid artery

IgG:

Immunoglobulin G

MCAO/R:

Middle cerebral artery occlusion and reperfusion

MMPs:

Matrix metalloproteases

MPO:

Myeloperoxidase

NF-κB:

Nuclear factor kappa B

PVDF:

Polyvinylidene fluoride

ROS:

Reactive oxygen species

TEM:

Transmission electron microscope

TJPs:

Tight junction proteins

TTC:

2,3,5-Triphenyltetrazolium chloride

ZO-1:

Zona occludens-1

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Acknowledgements

This study was supported by Functional Food Research Center for Well-being, Chiang Mai University and Faculty of Medicine Chiang Mai University. We also gratefully acknowledge support from the Thailand Research Fund (DBG6180030) and the Center of Excellence for Innovation in Chemistry, Office of the Higher Education Commission. PW acknowledges the financial support of the Royal Golden Jubilee (RGJ) PhD program (Grant No. PHD/0008/2558). We thank the staff of the Medical Science Research Equipment Center, Faculty of Medicine, Chiang Mai University for their help in the preparation of the tissue to be analyzed by Transmission Electron Microscopy.

Author information

Conception: CT. Data curation: PW, JT, and CT. Funding acquisition: AS, CT. Methodology: PW, JT, AJ, JJ, and WC. Project administration: CT. Resources: AS. Supervision: CT. Writing—original draft: PW. Writing—review and editing: AS and CT.

Correspondence to Chainarong Tocharus.

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Wicha, P., Tocharus, J., Janyou, A. et al. Hexahydrocurcumin alleviated blood–brain barrier dysfunction in cerebral ischemia/reperfusion rats. Pharmacol. Rep (2020). https://doi.org/10.1007/s43440-019-00050-9

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Keywords

  • Blood–brain barrier
  • Cerebral edema
  • Cerebral ischemia/reperfusion
  • Neutrophil infiltration
  • Tight junction proteins