Therapeutic window for YC-1 following glutamate-induced neuronal damage and transient focal cerebral ischemia

Shih-Huang Tai, Wei Ting Lee, Ai Chiang Lee, Yu Wen Lin, Hsin-Yi Hung, Sheng Yang Huang, Tian-Shung Wu, E-Jian Lee

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Abstract

3-(5'-Hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), has been demonstrated to inhibit platelet aggregation, vascular contraction and hypoxia-inducible factor 1 activity in vitro and in vivo. The present study investigated the neuroprotective efficacy of YC-1 in cultured neurons exposed to glutamate-induced excitotoxicity and in an animal model of stroke. In a cortical neuronal culture model, YC-1 demonstrated neurotoxicity at a concentration >100 μM, and YC-1 (10-30 μM) achieved potent cytoprotection against glutamate-induced neuronal damage. Additionally, YC-1 (30 μM) effectively attenuated the increase in intracellular Ca2+ levels. Delayed treatment of YC-1 (30 μM) also protected against glutamate-induced neuronal damage and cell swelling in cultured neurons, though only at 4 h post-treatment. In addition, immediate treatment of YC-1 (30 μM) following the exposure of cortical neurons to glutamate (300 μM) produced a marked reduction in intracellular pH. Delayed treatment of YC-1 (25 mg/kg) protected against ischemic brain damage in vivo, though only when administered at 3 h post-insult. Thus, YC-1 exhibited neuroprotection against glutamate-induced neuronal damage and in mice subjected to transient focal cerebral ischemia. This neuroprotection may be mediated via its ability to limit the glutamate-induced excitotoxicity. However, the neuroprotective therapeutic window of YC-1 is only at 3 h in vivo and 4 h in vitro, which may, at least in part, be attributed to its ability to reduce the intracellular pH in the early phase of ischemic stroke. Although YC-1 provided the potential for clinical therapy, the treatment time point must be carefully evaluated following ischemia.

Original languageEnglish
Pages (from-to)6490-6496
Number of pages7
JournalMolecular Medicine Reports
Volume17
Issue number5
DOIs
Publication statusPublished - 2018 May 1

Fingerprint

Transient Ischemic Attack
Glutamic Acid
Neurons
Therapeutics
Stroke
Hypoxia-Inducible Factor 1
Cytoprotection
Platelets
Platelet Aggregation
Blood Vessels
Swelling
Brain
Animals
Ischemia
Agglomeration
Animal Models

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Oncology
  • Cancer Research

Cite this

Tai, Shih-Huang ; Lee, Wei Ting ; Lee, Ai Chiang ; Lin, Yu Wen ; Hung, Hsin-Yi ; Huang, Sheng Yang ; Wu, Tian-Shung ; Lee, E-Jian. / Therapeutic window for YC-1 following glutamate-induced neuronal damage and transient focal cerebral ischemia. In: Molecular Medicine Reports. 2018 ; Vol. 17, No. 5. pp. 6490-6496.
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Therapeutic window for YC-1 following glutamate-induced neuronal damage and transient focal cerebral ischemia. / Tai, Shih-Huang; Lee, Wei Ting; Lee, Ai Chiang; Lin, Yu Wen; Hung, Hsin-Yi; Huang, Sheng Yang; Wu, Tian-Shung; Lee, E-Jian.

In: Molecular Medicine Reports, Vol. 17, No. 5, 01.05.2018, p. 6490-6496.

Research output: Contribution to journalArticle

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