Analysis of neuroprotection by taurine and taurine combinations in primary neuronal cultures and in neuronal cell lines exposed to glutamate excitotoxicity and to hypoxia/re-oxygenation

Howard Prentice, Chunliu Pan, Payam Mohammadgharibani, Zhiyuan Ma, Allison L. Price, Grace S. Giraldo, Howard M. Retz, Amit Gupta, Po Chih Chen, Hongyuan Chiu, Jigar Modi, Janet Menzie, Rui Tao, Jang Yen Wu

Research output: Contribution to journalArticle

Abstract

Ischemic stroke is one of the greatest contributors to death and long term disability in developed countries. Ischemia induced brain injury arises due to excessive release of glutamate and involves cell death due to apoptosis and endoplasmic reticulum (ER) stress responses. Despite major research efforts there are currently no effective treatments for stroke. Taurine, a free amino acid found in high concentrations in many invertebrate and vertebrate systems can provide protection against a range of neurological disorders. Here we demonstrate that taurine can combat ER stress responses induced by glutamate or by hypoxia/re-oxygenation in neuronal cell lines and primary neuronal cultures. Taurine decreased expression of ER stress markers GRP78, CHOP, Bim and caspase 12 in primary neuronal cultures exposed to hypoxia/re-oxygenation. In analyzing individual ER stress pathways we demonstrated that taurine treatment can result in reduced levels of cleaved ATF6 and decreased p-IRE1 levels. We hypothesized that because of the complex nature of stroke a combination therapy approach may be optimal. For this reason we proceeded to test combination therapies using taurine plus low dose administration of an additional drug: either granulocyte colony stimulating factor (G-CSF) or sulindac a non-steroidal anti-inflammatory drug with potent protective functions through signaling via ischemic preconditioning pathways. When primary neurons were pretreated with 25 mM taurine and 25 ng/mL G-CSF for I hour and then exposed to high levels of glutamate, the taurine/G-CSF combination increased the protective effect against glutamate toxicity to 88% cell survival compared to 75% cell survival from an individual treatment with taurine or G-CSF alone. Pre-exposure of PC12 cells to 5 mM taurine or 25 μM sulindac did not protect the cells from hypoxia/re-oxygenation stress whereas at these concentrations the combination of taurine plus sulindac provided significant protection. In summary we have demonstrated the protective effect of taurine in primary neuronal cultures against hypoxia with re-oxygenation through inhibition of ATF6 or p-IRE-1 pathway but not the PERK pathway of ER stress. Furthermore the combinations of taurine plus an additional drug (either G-CSF or sulindac) can show enhanced potency for protecting PC 12 cells from glutamate toxicity or hypoxia/re-oxygenation through inhibition of ER stress responses.

Original languageEnglish (US)
Pages (from-to)207-216
Number of pages10
JournalAdvances in experimental medicine and biology
Volume975
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Fingerprint

Oxygenation
Taurine
Cell culture
Glutamic Acid
Cells
Cell Line
Endoplasmic Reticulum Stress
Sulindac
Granulocyte Colony-Stimulating Factor
Stroke
Toxicity
Neuroprotection
Hypoxia
Cell Survival
Caspase 12
Pharmaceutical Preparations
Therapeutics
Cell Hypoxia
Ischemic Preconditioning
PC12 Cells

Keywords

  • Endoplasmic reticulum stress
  • Glutamate excitotoxicity
  • Hypoxia
  • Neuroprotection
  • Taurine

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Analysis of neuroprotection by taurine and taurine combinations in primary neuronal cultures and in neuronal cell lines exposed to glutamate excitotoxicity and to hypoxia/re-oxygenation. / Prentice, Howard; Pan, Chunliu; Mohammadgharibani, Payam; Ma, Zhiyuan; Price, Allison L.; Giraldo, Grace S.; Retz, Howard M.; Gupta, Amit; Chen, Po Chih; Chiu, Hongyuan; Modi, Jigar; Menzie, Janet; Tao, Rui; Wu, Jang Yen.

In: Advances in experimental medicine and biology, Vol. 975, 01.01.2017, p. 207-216.

Research output: Contribution to journalArticle

Prentice, Howard ; Pan, Chunliu ; Mohammadgharibani, Payam ; Ma, Zhiyuan ; Price, Allison L. ; Giraldo, Grace S. ; Retz, Howard M. ; Gupta, Amit ; Chen, Po Chih ; Chiu, Hongyuan ; Modi, Jigar ; Menzie, Janet ; Tao, Rui ; Wu, Jang Yen. / Analysis of neuroprotection by taurine and taurine combinations in primary neuronal cultures and in neuronal cell lines exposed to glutamate excitotoxicity and to hypoxia/re-oxygenation. In: Advances in experimental medicine and biology. 2017 ; Vol. 975. pp. 207-216.
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AU - Menzie, Janet

AU - Tao, Rui

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N2 - Ischemic stroke is one of the greatest contributors to death and long term disability in developed countries. Ischemia induced brain injury arises due to excessive release of glutamate and involves cell death due to apoptosis and endoplasmic reticulum (ER) stress responses. Despite major research efforts there are currently no effective treatments for stroke. Taurine, a free amino acid found in high concentrations in many invertebrate and vertebrate systems can provide protection against a range of neurological disorders. Here we demonstrate that taurine can combat ER stress responses induced by glutamate or by hypoxia/re-oxygenation in neuronal cell lines and primary neuronal cultures. Taurine decreased expression of ER stress markers GRP78, CHOP, Bim and caspase 12 in primary neuronal cultures exposed to hypoxia/re-oxygenation. In analyzing individual ER stress pathways we demonstrated that taurine treatment can result in reduced levels of cleaved ATF6 and decreased p-IRE1 levels. We hypothesized that because of the complex nature of stroke a combination therapy approach may be optimal. For this reason we proceeded to test combination therapies using taurine plus low dose administration of an additional drug: either granulocyte colony stimulating factor (G-CSF) or sulindac a non-steroidal anti-inflammatory drug with potent protective functions through signaling via ischemic preconditioning pathways. When primary neurons were pretreated with 25 mM taurine and 25 ng/mL G-CSF for I hour and then exposed to high levels of glutamate, the taurine/G-CSF combination increased the protective effect against glutamate toxicity to 88% cell survival compared to 75% cell survival from an individual treatment with taurine or G-CSF alone. Pre-exposure of PC12 cells to 5 mM taurine or 25 μM sulindac did not protect the cells from hypoxia/re-oxygenation stress whereas at these concentrations the combination of taurine plus sulindac provided significant protection. In summary we have demonstrated the protective effect of taurine in primary neuronal cultures against hypoxia with re-oxygenation through inhibition of ATF6 or p-IRE-1 pathway but not the PERK pathway of ER stress. Furthermore the combinations of taurine plus an additional drug (either G-CSF or sulindac) can show enhanced potency for protecting PC 12 cells from glutamate toxicity or hypoxia/re-oxygenation through inhibition of ER stress responses.

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