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Involvement of heme oxygenase-1 expression in neuroprotection by piceatannol, a natural analog and a metabolite of resveratrol, against glutamate-mediated oxidative injury in HT22 neuronal cells

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Abstract

Neuronal cell death caused by oxidative stress is common in a variety of neural diseases and can be investigated in detail in cultured HT22 neuronal cells, where the amino acid glutamate at high concentrations causes glutathione depletion by inhibition of the glutamate/cystine antiporter system, intracellular accumulation of reactive oxygen species (ROS) and eventually oxidative stress-induced neuronal cell death. Using this paradigm, we have previously reported that resveratrol (3,5,4′-trans-trihydroxystilbene) protects HT22 neuronal cells from glutamate-induced oxidative stress by inducing heme oxygenase (HO)-1 expression. Piceatannol (3,5,4′,3′-trans-trihydroxystilbene), which is a hydroxylated resveratrol analog and one of the resveratrol metabolites, is estimated to exert neuroprotective effect similar to that of resveratrol. The aim of this study, thus, is to determine whether piceatannol, similarly to resveratrol, would protect HT22 neuronal cells from glutamate-induced oxidative stress. Glutamate at high concentrations induced neuronal cell death and ROS formation. Piceatannol reduced glutamate-induced cell death and ROS formation. The observed cytoprotective effect was much higher when HT22 neuronal cells were pretreated with piceatannol for 6 or 12 h prior to glutamate treatment than when pretreated for 0.5 h. Piceatannol also increased HO-1 expression and HO activity via its activation of nuclear factor-E2-related factor 2 (Nrf2). Interestingly, neuroprotective effect of piceatannol was partly (but not completely) abolished by either down-regulation of HO-1 expression or blockage of HO-1 activity. Taken together, our results suggest that piceatannol, similar to resveratrol, is capable of protecting HT22 neuronal cells against glutamate-induced cell death, at least in part, by inducing Nrf2-dependent HO-1 expression.

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Abbreviations

ARE:

Antioxidant responsive element

DCF-DA:

2′,7′-Dichlorofluorescein diacetate

DMEM:

Dulbecco’s modified Eagle’s medium

ELISA:

Enzyme-linked immunosorbent assay

Glu:

Glutamate

HO-1:

Heme oxygenase-1

MAPK:

Mitogen-activated protein kinase

MTT:

3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide

Nrf2:

Nuclear transcription factor-E2-related factor 2

OD:

Optical density

PBS:

Phosphate-buffered saline

Pic:

Piceatannol

PI3K:

Phosphoinositide 3-kinase

PKC:

Protein kinase C

ROS:

Reactive oxygen species

siRNA:

Small interfering RNA

SnPP:

Tin protoporphyrin IX (SnPP)

RuCO:

Tricarbonyldichlororuthenium-(II)-dimer

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Acknowledgments

This work was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea government (MEST) (No. 2011-0030717).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Anesthesiology and Pain Medicine, Wonkwang University School of Medicine, 460 Iksandae-ro, Iksan, 570-749, Republic of Korea

    Yong Son

  2. Department of Surgery, Wonkwang University School of Medicine, 460 Iksandae-ro, Iksan, 570-749, Republic of Korea

    Seung Jae Byun

  3. Department of Microbiology and Immunology, Wonkwang University School of Medicine, 460 Iksandae-ro, Iksan, 570-749, Republic of Korea

    Hyun-Ock Pae

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  1. Yong Son
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  2. Seung Jae Byun
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Correspondence to Hyun-Ock Pae.

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Son, Y., Byun, S.J. & Pae, HO. Involvement of heme oxygenase-1 expression in neuroprotection by piceatannol, a natural analog and a metabolite of resveratrol, against glutamate-mediated oxidative injury in HT22 neuronal cells. Amino Acids 45, 393–401 (2013). https://doi.org/10.1007/s00726-013-1518-9

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