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

  • Piyawadee Wicha
  • Jiraporn Tocharus
  • Adchara Janyou
  • Jinatta Jittiwat
  • Waraluck Chaichompoo
  • Apichart Suksamrarn
  • Chainarong TocharusEmail author



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.


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.


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.


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


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



Aquaporin 4


Astrocytic swelling


Blood–brain barrier


Basement membrane


Bovine serum albumin


Cerebral blood flow


Common carotid artery


Central nervous system




Evans blue


External carotid artery


Extracellular matrix




Hematoxylin and eosin




Horseradish peroxidase


Ischemia reperfusion


Internal carotid artery


Immunoglobulin G


Middle cerebral artery occlusion and reperfusion


Matrix metalloproteases




Nuclear factor kappa B


Polyvinylidene fluoride


Reactive oxygen species


Transmission electron microscope


Tight junction proteins


2,3,5-Triphenyltetrazolium chloride


Zona occludens-1



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.

Authors’ contribution

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


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Copyright information

© Maj Institute of Pharmacology Polish Academy of Sciences 2020

Authors and Affiliations

  • Piyawadee Wicha
    • 1
  • Jiraporn Tocharus
    • 2
  • Adchara Janyou
    • 1
  • Jinatta Jittiwat
    • 3
  • Waraluck Chaichompoo
    • 4
  • Apichart Suksamrarn
    • 4
  • Chainarong Tocharus
    • 1
    Email author
  1. 1.Department of Anatomy, Faculty of MedicineChiang Mai UniversityChiang MaiThailand
  2. 2.Department of Physiology, Faculty of MedicineChiang Mai UniversityChiang MaiThailand
  3. 3.Faculty of MedicineMaha Sarakham UniversityMaha SarakhamThailand
  4. 4.Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of ScienceRamkhamhaeng UniversityBangkokThailand

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