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Zinc Potentiates Lipopolysaccharide-induced Nitric Oxide Production in Cultured Primary Rat Astrocytes

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Abstract

Zn2+ plays a crucial role in the CNS where it accumulates in synaptic vesicles and is released during neurotransmission. Synaptically released Zn2+ is taken up by neurons and astrocytes. The majority of previous work has focused on neuronal damage caused by excess Zn2+. However, its effect on astrocyte function is not well understood. We examined the effect of extracellularly applied Zn2+ on nitric oxide (NO) production in primary cultured rat astrocytes, which were experimentally activated by lipopolysaccharide (LPS). Zn2+, at a concentration up to 125 μM, augmented LPS-induced NO production without affecting cell viability. LPS induced expression of both mRNA and protein of inducible NO synthase; this expression was enhanced by 125 µM Zn2+. Zn2+ also increased LPS-induced production of intracellular reactive oxygen species. Zn2+ enhanced the phosphorylation of p38-mitogen-activated protein kinase (MAPK) at 1–6 h after LPS treatment. The LPS-induced nuclear factor-kappaB (NFκB) activation was sustained for 6 h by Zn2+. Intracellular Zn2+ chelation with N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) or inhibition of p38-MAPK diminished the Zn2+ enhancement of LPS-induced NO production. These findings suggest that activation of MAPK and NFκB is important for mediating Zn2+enhancement of LPS-induced NO production in astrocytes. Such changes may exacerbate glial and neuronal damage during neuroinflammation.

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Abbreviations

AD:

Alzheimer’s disease

DAN:

2,3-Diaminonaphthalene

DCF:

Dichlorofluorescein

DMEM:

Dulbecco’s modified Eagle medium

ERK:

Extracellular signal-regulated kinase

FBS:

Fetal bovine serum

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GSH:

Glutathione

H2DCFDA:

2′,7′-dichlorodihydrofluorescein diacetate

HBS:

Hepes-buffered saline

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

JNK:

c-Jun N-terminal kinase

LPS:

Lipopolysaccharide

MAPK:

Mitogen-activated protein kinase

MTT:

3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-tetrazolium bromide

NFκB:

Nuclear factor-kappaB

NO:

Nitric oxide

PD:

Parkinson’s disease

ROS:

Reactive oxygen species

RT-PCR:

Reverse transcription-polymerase chain reaction

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TPEN:

N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine

ZIP:

Zn2+-importing protein

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Acknowledgements

This work was supported in part by JSPS KAKENHI Grant Numbers 23580408 and 17K08127 (to M. M.), 15K07768 (to Y. N.), and 26850209 and 17K15390 (to K. T.).

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  1. Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, 1-58 Rinku-Ourai Kita, Izumisano, Osaka, 598-8531, Japan

    Mitsuaki Moriyama, Shunsuke Fujitsuka, Kenji Kawabe, Katsura Takano & Yoichi Nakamura

  2. Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Kenji Kawabe

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  1. Mitsuaki Moriyama
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  2. Shunsuke Fujitsuka
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Moriyama, M., Fujitsuka, S., Kawabe, K. et al. Zinc Potentiates Lipopolysaccharide-induced Nitric Oxide Production in Cultured Primary Rat Astrocytes. Neurochem Res 43, 363–374 (2018). https://doi.org/10.1007/s11064-017-2431-5

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