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A Novel Hybrid of Telmisartan and Borneol Ameliorates Neuroinflammation and White Matter Injury in Ischemic Stroke Through ATF3/CH25H Axis

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Abstract

Cerebral ischemic stroke causes substantial white matter injury, which is further aggravated by neuroinflammation mediated by microglia/astrocytes. Given the anti-neuroinflammatory action of telmisartan and the enhancing blood-brain barrier (BBB) permeability potential of resuscitation-inducing aromatic herbs, 13 hybrids (3a-m) of telmisartan (or its simplified analogues) with resuscitation-inducing aromatic agents were designed, synthesized, and biologically evaluated. Among them, the optimal compound 3a (the ester hybrid of telmisartan and (+)-borneol) potently inhibited neuroinflammation mediated by microglia/astrocytes and ameliorated ischemic stroke. Particularly, 3a significantly conferred protection for white matter integrity after cerebral ischemic stroke via decreasing abnormally dephosphorylated neurofilament protein, upregulating myelin basic protein, and attenuating oligodendrocyte damage. Further RNA-sequencing data revealed that 3a upregulated expression of transcriptional regulator ATF3 to reduce the expression of CH25H, prevented proinflammatory state of lipid-droplet-accumulating microglia/astrocytes to limit excessive inflammation, and eventually protected neighboring oligodendrocytes to prevent white matter injury. Taken with the desirable pharmacokinetics behavior and improved brain distribution, 3a may be a feasible therapeutic agent for ischemic stroke and other neurological disorders with white matter injury.

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Abbreviations

ANOVA:

analysis of variance

ATCC:

American Type Culture Collection

AT1R:

angiotensin II type 1 receptor

ATF3:

activating transcription factor 3

AUC0-inf:

area under concentration-time curve from time zero to infinite

Bnl:

Borneol

BDNF:

brain-derived neurotrophic factor

BSA:

bovine serum albumin

CD206:

macrophage mannose receptor 1

CC:

corpus callosum

CH25H:

cholesterol 25-hydroxylase

CL:

clearance rates

Cmax:

maximum plasma concentration

CSPG:

hondroitin sulfate proteoglycans

DCC:

N,N'-dicyclohexylcarbodiimide

DIPEA:

N,N'-diisopropylethylamine

DMAP:

(dimethylamino) pyridine

DMEM:

Dulbecco’s modified Eagle’s medium

Eda:

edaravone

ELISA:

enzyme-linked immunosorbent assay

FBS:

fatal bovine serum

GM:

gray matter

GMI:

gray matter injury

GO:

Gene Ontology

HRMS:

high-resolution mass spectrometry

IC50:

half maximal inhibitory concentration

ICA:

internal carotid artery

IL-1β:

interleukin-1 beta

IL-10:

interleukin-10

iNOS:

inducible nitric oxide synthase

IGF-1:

insulin like growth factor 1

LAH:

lithium aluminum tetrahydride

KEGG:

Kyoto Encyclopedia of Genes and Genomes

LFB:

Luxol fast blue

LPS:

lipopolysaccharide

MBP:

myelin basic protein

MCA:

middle cerebral artery

mNSS:

modified Neurological Severity Scores

MS:

mass spectra

NGF:

nerve growth factor

OGD:

oxygen-glucose deprivation

OPC:

oligodendrocyte progenitor cell

PK:

pharmacokinetics

pMCAO:

permanent middle cerebral artery occlusion

PVDF:

polyvinylidene fluoride

PyBOP:

benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate

r-tPA:

recombinant tissue plasminogen activator

siRNA:

small interfering RNA

SD:

standard deviation

SMI32:

dephosphorylated neurofilament protein

t1/2 :

half-life

TBTU:

tetrafluoroborate

Telm:

telmisartan

TNF-α:

tumor necrosis factor-alpha

TGF-β:

transforming growth factor-β

tMCAO:

transient middle cerebral artery occlusion

TTC:

2, 3, 5-triphenyltetrazolium chloride

WB:

Western blot

WM:

white matter

WMI:

white matter injury

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Acknowledgements

We sincerely thank websites BioRender and SMART for providing some of drawing materials. We sincerely thank Ping Zhou (Public platform of State Key Laboratory of Natural Medicines) for her support with confocal microscopy. We sincerely thank Jie Zhao (Pharmaceutical Animal Experimental Center of China Pharmaceutical University) for her support with animal experiments.

Data Availability

The original contributions presented in the study are included in the article/supplementary material; further inquiries can be directed to the corresponding author.

Funding

This study was supported by the National Natural Science Foundation of China (81822041, 82174010, 81973512, 21977116, 81773573, 82173681, and 82104004); National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” (Number: 2018ZX09711002-006-013); the Open Project of State Key Laboratory of Natural Medicines (SKLNMZZCX201824, SKLNMZZ202029); the Open Fund of the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University (Grant No. KF-202206); State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia Fund (SKL-HIDCA-2018-1); the Natural Science Foundation of Zhejiang Province (LY18H310009); the Research project of Health Commission of Zhejiang Province (2018KY653); the Biomedical and Health Industry Development Support Science and Technology Project of Hangzhou (2022WJC139); and the project funded by China Postdoctoral Science Foundation (2021M693515).

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  1. Xin Guan and Jianbing Wu contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, New Drug Screening Center, Jiangsu Center for Pharmacodynamics Research and Evaluation, Institute of Pharmaceutical Sciences, China Pharmaceutical University, #24 Tong Jia Xiang Street, Nanjing, 210009, People’s Republic of China

    Xin Guan, Jianbing Wu, Jiahui Geng, Duorui Ji, Dasha Wei, Yihua Zhang, Tao Pang & Zhangjian Huang

  2. School of Pharmacy, Nantong University, Nantong, 226001, People’s Republic of China

    Yong Ling

  3. Department of Pharmacy, Zhejiang Xiaoshan Hospital, Hangzhou, 311201, People’s Republic of China

    Guojun Jiang

  4. State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, People’s Republic of China

    Tao Pang

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Contributions

XG and JW contributed equally to this work. YL, YZ, GJ, TP, and ZH conceived the project and designed the studies. XG, JW, TP, and ZH wrote the paper. JW, JG, and DJ conducted compound synthesis and analysis. XG and DW performed biological evaluation experiments and mechanism studies. All authors have given approval to the final version of the manuscript.

Corresponding authors

Correspondence to Tao Pang or Zhangjian Huang.

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All animal experiments were conducted in line with the Guideline for the Care and Use of Laboratory Animals of the National Institutes of Health (http://oacu.od.nih.gov/regs/index.htm). All experimental process was carried out with the approval of Animal Ethics Committee of China Pharmaceutical University.

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Guan, X., Wu, J., Geng, J. et al. A Novel Hybrid of Telmisartan and Borneol Ameliorates Neuroinflammation and White Matter Injury in Ischemic Stroke Through ATF3/CH25H Axis. Transl. Stroke Res. 15, 195–218 (2024). https://doi.org/10.1007/s12975-022-01121-5

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  • DOI: https://doi.org/10.1007/s12975-022-01121-5

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