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Astaxanthin ameliorates spinal cord edema and astrocyte activation via suppression of HMGB1/TLR4/NF-κB signaling pathway in a rat model of spinal cord injury

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Abstract

Spinal cord edema is a quick-onset phenomenon with long-term effects. This complication is associated with inflammatory responses, as well as poor motor function. No effective treatment has been developed against spinal edema, which urges the need to provide novel therapies. Astaxanthin (AST) is a fat-soluble carotenoid with anti-inflammatory effects and a promising candidate for treating neurological disorders. This study aimed to investigate the underlying mechanism of AST on the inhibition of spinal cord edema, astrocyte activation, and reduction of inflammatory responsesin a rat compression spinal cord injury (SCI) model. Male rats underwent laminectomy at thoracic 8–9, and the SCI model was induced using an aneurysm clip. After SCI, rats received dimethyl sulfoxide or AST via intrathecal injection. The effects of AST were examined on the motor function, spinal cord edema, integrity of blood-spinal cord barrier (BSCB), and expression of high mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), glial fibrillary acidic protein (GFAP), and aquaporin-4 (AQP4), and matrix metallopeptidase- 9 (MMP-9) post-SCI. We showed that AST potentially improved the recovery of motor function and inhibited the spinal cord edema via maintaining the integrity of BSCB, reducing the expression of HMGB1, TLR4, and NF-κB, MMP-9 as well as downregulation of astrocyte activation (GFAP) and AQP4 expression. AST improves motor function and reduces edema and inflammatory responses in the spinal tissue. These effects are mediated by suppression of the HMGB1/TLR4/NF-κB signaling pathway, suppressing post-SCI astrocyte activation, and decreasing AQP4 and MMP-9 expression.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AQP4:

Aquapurin-4

AST:

Astaxanthin

BBB:

Basso, Beattie and Bresnahan

BSA:

Bovine serum albumin

BSCB:

Blood-spinal cord barrier

CAM:

Calmodulin

DMSO:

Dimethyl sulfoxide

EB:

Evans blue

FSA:

Foot-stepping angle

GFAP:

Glial fibrillary acidic protein

HMGB1:

High mobility group box-1

MMP-9:

Matrix metalloproteinase-9

MRI:

Magnetic Resonance Imaging

NF-Κb:

Nuclear factor-kappa B

PBS:

Phosphate-buffered saline

PKA:

Protein kinase A

PVDF:

Polyvinylidene difluoride

RAGE:

Receptor of advanced glycation end product

RHI:

Rump height index

RI:

Recovery index

SAH:

Subarachnoid hemorrhage

SCI:

Spinal cord injury

TBI:

Traumatic brain injury

TLR4:

Toll-like receptor-4

TRPV4:

Transient receptor potential vanilloid-type 4

TNF:

Tumor necrosis factor

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Funding

This study was performed as a part of the Ph.D. thesis of Fatemeh Abbaszadeh. It was supported by a grant from the Department of Neuroscience of Iran University of Medical Science (Grant No. 18555) and the Neuroscience Research Center of Shahid Beheshti University of Medical Sciences (Grant No. 31278).

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Authors and Affiliations

  1. Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Science, Tehran, Iran

    Fatemeh Abbaszadeh, Mohammad taghi Joghataei & Soraya Mehrabi

  2. Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Fatemeh Abbaszadeh & Masoumeh Jorjani

  3. Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Masoumeh Jorjani

  4. Department of Innovation in Medical Education, Faculty of Medicine, Ottawa University, Ottawa, Canada

    Mohammad taghi Joghataei

  5. Neuroimaging and Analysis Group, Research Center for Molecular and Cellular Imaging, Advanced Medical Technologies and Equipment Institue, Tehran University of Medical Sciences, Tehran, Iran

    Samira Raminfard

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  1. Fatemeh Abbaszadeh
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Contributions

F.A. was involved in the literature search, the data analysis, the conceptualization and design of the study, the graphic design and the drafting of the manuscript. S. R. was involved in performing MRI procedures and analyzing MRI data. M. J. (principal investigator), MT. J. and S. M. were involved in the conceptualization and design of the study, the critical revision of the manuscript for important intellectual content and the supervision of the study. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Masoumeh Jorjani or Mohammad taghi Joghataei.

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The authors declare no competing interests.

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All protocols for animal experiments were approved by the institutional animal Ethical Committee, the Iran University of Medical Sciences (IR.IUMS.REC.1399.1007).

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The authors declared that they have no conflict of interest.

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Abbaszadeh, F., Jorjani, M., Joghataei, M.t. et al. Astaxanthin ameliorates spinal cord edema and astrocyte activation via suppression of HMGB1/TLR4/NF-κB signaling pathway in a rat model of spinal cord injury. Naunyn-Schmiedeberg's Arch Pharmacol 396, 3075–3086 (2023). https://doi.org/10.1007/s00210-023-02512-7

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