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Neuroprotective Effect of 3-(Naphthalen-2-Yl(Propoxy)Methyl)Azetidine Hydrochloride on Brain Ischaemia/Reperfusion Injury

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Abstract

Because ischaemic stroke is one of the most common brain disorders, diverse effective therapies are urgently required. Recent studies reported a variety of azetidine-based scaffolds for the development of central nervous system-focused lead-like libraries. However, their mechanisms of action and in vivo functions remain unclear. Here, we investigated the potential mechanism and beneficial effects of 3-(naphthalen-2-yl(propoxy)methyl)azetidine hydrochloride (KHG26792), a novel azetidine derivative, on ischaemia/reperfusion (I/R) brain injury. We adapted a mouse brain ischaemia model induced by 2 h of middle cerebral artery occlusion followed by 24 h of reperfusion. We measured apoptotic cell death, inflammatory mediators, free radical generation, and anti-oxidative enzymes activities. We also measured the mitochondrial ATP level and Na+, K+-ATPase and cytochrome c oxidase activities. Using western blotting, we analysed the protein levels of inducible NOS, hypoxia-upregulated protein 1, PTEN-induced putative kinase, uncoupling protein 2, p-Akt, MMP-3, and full-length receptor for advanced glycation end-products (RAGE). KHG26792 significantly improved neurological deficits and brain oedema and suppressed I/R-induced apoptosis. KHG26792 significantly attenuated I/R-induced inflammation and oxidative stress by upregulating SOD and catalase activity, GSH, p-Akt, mitochondrial ATP, Na+, K+-ATPase, cytochrome c oxidase, and soluble RAGE and downregulating iNOS, HYOUP1, and MMP-3, suggesting a potential anti-inflammatory and antioxidant role of KHG26792. This is the first study to show that KHG26792 can protect mouse brains against I/R injury by inhibiting apoptotic damage, modulating inflammation, scavenging free radicals, ameliorating oxidative stress, and improving the energy metabolism of the brain, although the clinical relevance of our findings remains unknown.

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Abbreviations

Bax:

Bcl-2-associated X protein

CAT:

catalase

CNS:

central nervous system

DCF-DA:

2′,7′-dichlorofluorescin diacetate

fl-RAGE:

full-length receptor for advanced glycation end-products

HNE:

4-hydroxy-2-nonenal

HYOU1:

hypoxia-upregulated protein 1

ICAM-1:

intercellular adhesion molecule-1

iNOS:

inducible nitric oxide synthase

I/R:

ischaemia/reperfusion

KC:

keratinocyte-derived chemokine

MCAO:

middle cerebral artery occlusion

MCP-1:

monocyte chemoattractant protein-1

MDA:

malondialdehyde

PINK1:

PTEN-induced putative kinase 1

sRAGE:

soluble receptor for advanced glycation end-products

UCP2:

uncoupling protein 2

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Acknowledgements

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1D1A1A09056947).

Author information

Authors and Affiliations

  1. Department of Biomedical Laboratory Science, Konyang University, Daejeon, 35365, South Korea

    Eun-A Kim

  2. Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, 88, Olympic-ro 43-Gil, Songpa-gu, Seoul, 05505, South Korea

    Jung-Min Na, Jiae Kim & Sung-Woo Cho

  3. Department of Biomedical Science and Research Institute for Bioscience and Biotechnology, Hallym University, Chunchon, 24252, South Korea

    Soo Young Choi

  4. Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, 16419, South Korea

    Jee-Yin Ahn

Authors
  1. Eun-A Kim
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  2. Jung-Min Na
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  3. Jiae Kim
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  4. Soo Young Choi
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  5. Jee-Yin Ahn
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  6. Sung-Woo Cho
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Corresponding author

Correspondence to Sung-Woo Cho.

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Kim, EA., Na, JM., Kim, J. et al. Neuroprotective Effect of 3-(Naphthalen-2-Yl(Propoxy)Methyl)Azetidine Hydrochloride on Brain Ischaemia/Reperfusion Injury. J Neuroimmune Pharmacol 12, 447–461 (2017). https://doi.org/10.1007/s11481-017-9733-x

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  • DOI: https://doi.org/10.1007/s11481-017-9733-x

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