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Acidosis-Induced Zinc-Dependent Death of Cultured Cerebellar Granule Neurons

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Abstract

Severe acidosis caused death of cultured cerebellar granule neurons (CGNs). Acidosis was accompanied by a progressive increase of the intracellular zinc ions ([Zn2+]i) and decrease of [Ca2+]i. Zn2+ chelator, N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), prevented the increase of [Zn2+]i and acidosis-induced neuronal death. However, neuronal death was insensitive to blockade of ASIC1 channels with amiloride, as CGNs display considerably lower expression of ASIC1a than other neurons. The antioxidant trolox and menadione significantly protected neurons from acidotic death. Earlier, we demonstrated that menadione rescues neurons from the deleterious effect of inhibition of mitochondrial complex I (Isaev et al. Neuroreport 15:2227–2231, 2004). We speculate that excessive Zn2+-dependent production of reactive oxygen species by mitochondrial complex I may be a general motive for the induction of cell death in CGNs under acidotic conditions.

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Abbreviations

CGNs:

Cerebellar granule neurons

TPEN:

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

ASIC1a:

Acid sensitive ion channel 1a

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Acknowledgments

The authors would like to acknowledge Katharina Stohlmann and Ingo Przesdzing for excellent experimental support. This study was supported by RFBR grants 08-04-00762-a, 08-04-01667-a, 09-04-01096-a and the Deutsche Forschungsgemeinschaft (ME 3603/1-1 to PM).

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Authors and Affiliations

  1. A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, Russia, 119992

    Nikolay K. Isaev, Sergey V. Lukin & Dmitry B. Zorov

  2. Scientific Center of Neurology, Brain Research Department, Russian Academy of Medical Sciences, per. Obukha 5, Moscow, Russia, 105064

    Nikolay K. Isaev & Elena V. Stelmashook

  3. Department of Experimental Neurology, Center for Stroke Research, Charitè-Universitätsmedizin Berlin, 10117, Berlin, Germany

    Dorette Freyer & Philipp Mergenthaler

Authors
  1. Nikolay K. Isaev
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  2. Elena V. Stelmashook
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  3. Sergey V. Lukin
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  4. Dorette Freyer
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  5. Philipp Mergenthaler
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  6. Dmitry B. Zorov
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Correspondence to Nikolay K. Isaev.

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Isaev, N.K., Stelmashook, E.V., Lukin, S.V. et al. Acidosis-Induced Zinc-Dependent Death of Cultured Cerebellar Granule Neurons. Cell Mol Neurobiol 30, 877–883 (2010). https://doi.org/10.1007/s10571-010-9516-x

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  • DOI: https://doi.org/10.1007/s10571-010-9516-x

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