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

doi:10.3892/mmr.2018.8660

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

Authors:
- Shih‑Huang Tai
- Wei‑Ting Lee
- Ai‑Chiang Lee
- Yu‑Wen Lin
- Hsin‑Yi Hung
- Sheng‑Yang Huang
- Tian‑Shung Wu
- E‑Jian Lee
View Affiliations

Affiliations: Neurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Medical Center and Medical School, Tainan 70428, Taiwan, R.O.C., Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C., School of Pharmacy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C., Institute of Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan, R.O.C.
Published online on: March 1, 2018 https://doi.org/10.3892/mmr.2018.8660
Pages: 6490-6496
Copyright: © Tai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	O'Bryant Z, Vann KT and Xiong ZG: Translational strategies for neuroprotection in ischemic stroke-focusing on acid-sensing ion channel 1a. Transl Stroke Res. 5:59–68. 2014. View Article : Google Scholar : PubMed/NCBI
2	Lee EJ, Chen HY, Hung YC, Chen TY, Lee MY, Yu SC, Chen YH, Chuang IC and Wu TS: Therapeutic window for cinnamophilin following oxygen-glucose deprivation and transient focal cerebral ischemia. Exp Neurol. 217:74–83. 2009. View Article : Google Scholar : PubMed/NCBI
3	Demaerschalk BM and Yip TR: Economic benefit of increasing utilization of intravenous tissue plasminogen activator for acute ischemic stroke in the United States. Stroke. 36:2500–2503. 2005. View Article : Google Scholar : PubMed/NCBI
4	Xiong ZG, Zhu XM, Chu XP, Minami M, Hey J, Wei WL, MacDonald JF, Wemmie JA, Price MP, Welsh MJ and Simon RP: Neuroprotection in ischemia: Blocking calcium-permeable acid-sensing ion channels. Cell. 118:687–698. 2004. View Article : Google Scholar : PubMed/NCBI
5	Li MH, Leng TD, Feng XC, Yang T, Simon RP and Xiong ZG: Modulation of acid-sensing ion channel 1a by intracellular pH and its role in ischemic stroke. J Biol Chem. 291:18370–18383. 2016. View Article : Google Scholar : PubMed/NCBI
6	Mutch WA and Hansen AJ: Extracellular pH changes during spreading depression and cerebral ischemia: Mechanisms of brain pH regulation. J Cereb Blood Flow Metab. 4:17–27. 1984. View Article : Google Scholar : PubMed/NCBI
7	von Hanwehr R, Smith ML and Siesjö BK: Extra- and intracellular pH during near-complete forebrain ischemia in the rat. J Neurochem. 46:331–339. 1986. View Article : Google Scholar : PubMed/NCBI
8	Mari Y, Katnik C and Cuevas J: ASIC1a channels are activated by endogenous protons during ischemia and contribute to synergistic potentiation of intracellular Ca(2+) overload during ischemia and acidosis. Cell Calcium. 48:70–82. 2010. View Article : Google Scholar : PubMed/NCBI
9	Szatkowski M and Attwell D: Triggering and execution of neuronal death in brain ischaemia: Two phases of glutamate release by different mechanisms. Trends Neurosci. 17:359–365. 1994. View Article : Google Scholar : PubMed/NCBI
10	Dubinsky JM: Intracellular calcium levels during the period of delayed excitotoxicity. J Neurosci. 13:623–631. 1993. View Article : Google Scholar : PubMed/NCBI
11	Lee WT, Lin MH, Lee EJ, Hung YC, Tai SH, Chen HY, Chen TY and Wu TS: Magnolol reduces glutamate-induced neuronal excitotoxicity and protects against permanent focal cerebral ischemia up to 4 hours. PLoS One. 7:e399522012. View Article : Google Scholar : PubMed/NCBI
12	Hwang TL, Hung HW, Kao SH, Teng CM, Wu CC and Cheng SJ: Soluble guanylyl cyclase activator YC-1 inhibits human neutrophil functions through a cGMP-independent but cAMP-dependent pathway. Mol Pharmacol. 64:1419–1427. 2003. View Article : Google Scholar : PubMed/NCBI
13	DeNiro M, Al-Halafi A, Al-Mohanna FH, Alsmadi O and Al-Mohanna FA: Pleiotropic effects of YC-1 selectively inhibit pathological retinal neovascularization and promote physiological revascularization in a mouse model of oxygen-induced retinopathy. Mol Pharmacol. 77:348–367. 2010. View Article : Google Scholar : PubMed/NCBI
14	Yan J, Zhou B, Taheri S and Shi H: Differential effects of HIF-1 inhibition by YC-1 on the overall outcome and blood-brain barrier damage in a rat model of ischemic stroke. PLoS One. 6:e277982011. View Article : Google Scholar : PubMed/NCBI
15	Tai SH, Hung YC, Lee EJ, Lee AC, Chen TY, Shen CC, Chen HY, Lee MY, Huang SY and Wu TS: Melatonin protects against transient focal cerebral ischemia in both reproductively active and estrogen-deficient female rats: The impact of circulating estrogen on its hormetic dose-response. J Pineal Res. 50:292–303. 2011. View Article : Google Scholar : PubMed/NCBI
16	DeLorenzo RJ, Sun DA, Blair RE and Sombati S: An in vitro model of stroke-induced epilepsy: Elucidation of the roles of glutamate and calcium in the induction and maintenance of stroke-induced epileptogenesis. Int Rev Neurobiol. 81:59–84. 2007. View Article : Google Scholar : PubMed/NCBI
17	Trenholm S and Baldridge WH: The effect of aminosulfonate buffers on the light responses and intracellular pH of goldfish retinal horizontal cells. J Neurochem. 115:102–111. 2010. View Article : Google Scholar : PubMed/NCBI
18	Tai SH, Chen HY, Lee EJ, Chen TY, Lin HW, Hung YC, Huang SY, Chen YH, Lee WT and Wu TS: Melatonin inhibits postischemic matrix metalloproteinase-9 (MMP-9) activation via dual modulation of plasminogen/plasmin system and endogenous MMP inhibitor in mice subjected to transient focal cerebral ischemia. J Pineal Res. 49:332–341. 2010. View Article : Google Scholar : PubMed/NCBI
19	Papadia S, Soriano FX, Léveillé F, Martel MA, Dakin KA, Hansen HH, Kaindl A, Sifringer M, Fowler J, Stefovska V, et al: Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat Neurosci. 11:476–487. 2008. View Article : Google Scholar : PubMed/NCBI
20	Alzheimer C: Na+ channels and Ca2+ channels of the cell membrane as targets of neuroprotective substances. Adv Exp Med Biol. 513:161–181. 2002. View Article : Google Scholar : PubMed/NCBI
21	Yang X, Wang Y, Luo J, Liu S and Yang Z: Protective effects of YC-1 against glutamate induced PC12 cell apoptosis. Cell Mol Neurobiol. 31:303–311. 2011. View Article : Google Scholar : PubMed/NCBI
22	Wang WZ, Chu XP, Li MH, Seeds J, Simon RP and Xiong ZG: Modulation of acid-sensing ion channel currents, acid-induced increase of intracellular Ca2+, and acidosis-mediated neuronal injury by intracellular pH. J Biol Chem. 281:29369–29378. 2006. View Article : Google Scholar : PubMed/NCBI
23	Jiang N, Wu J, Leng T, Yang T, Zhou Y, Jiang Q, Wang B, Hu Y, Ji YH, Simon RP, et al: Region specific contribution of ASIC2 to acidosis-and ischemia-induced neuronal injury. J Cereb Blood Flow Metab. 37:528–540. 2017. View Article : Google Scholar : PubMed/NCBI