Physiological Concentration of H2O2 Supports Dopamine Neuronal Survival via Activation of Nrf2 Signaling in Glial Cells


Traditionally, hydrogen peroxide (H2O2) was formed from cellular oxidative metabolism and often viewed as toxic waste. In fact, H2O2 was a benefit messenger for neuron-glia signaling and synaptic transmission. Thus, H2O2 was a double-edged sword and neuroprotection vs. neurotoxicity produced by H2O2 was difficult to define. Nuclear factor erythroid 2-related factor 2 (Nrf2) has been implicated as an intracellular regulator of neuronal growth. Inactivation of Nrf2 participated in the development of Parkinson's disease (PD). Thus, suitable activation of Nrf2 was essential for the prevention and treatment of PD. This study aimed to explore whether H2O2-conferred neuroprotective effects to support neuronal survival. H2O2 were added into primary neuron-glia, neuron-astroglia and neuron-microglia co-cultures in concentration- and time-dependent manners. H2O2 increased dopamine (DA) neuronal survival in concentration- and time-dependent manners. In addition, glial cells Nrf2 activation involved in H2O2-supported DA neuronal survival with the following phenomenons. First, H2O2 activated Nrf2 signaling pathway. Second, H2O2 generated beneficial neuroprotection in neuron-glia, neuron-astroglia and neuron-microglia co-cultures but not in neuron-enriched cultures. Third, silence of Nrf2 in glial cells abolished H2O2-conferred DA neuronal survival. This study demonstrated that physiological concentration of H2O2-supported DA neuronal survival via activation of Nrf2 signaling in glial cells. Our data permit to re-evaluate the role of H2O2 in the pathogenesis and therapeutic strategies for PD.

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Cytosine β-D-arabinofuranoside


Central nervous system






Glial cell-derived neurotrophic factor


Heme oxygenase-1

H2O2 :

Hydrogen peroxide


Kelch-like ECH-associated protein 1


Leu-leu methyl ester


Nerve growth factor


Nuclear factor erythroid 2-related factor 2


NADPH quinone oxidoreductase 1


Parkinson's disease


Substantia nigra pars compacta


Tyrosine hydroxylase


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All experiments were supported by National Natural Science Foundation of China (No. 81760658), High-level Innovative Talents of Guizhou Province (No. 20164027), Governor Talent Foundation of Guizhou Province (No. 201288), Innovation Research Group Project of Education Department of Guizhou Province (no. 2016038), and Excellent Young Talents of Zunyi Medical University.

Author information




FZ designed all the experiments. GQW performed the experiments and wrote the manuscript. QYY, CQZ, DDL, and JJL participated in the data analysis and approved the submitted manuscript.

Corresponding author

Correspondence to Feng Zhang.

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The authors declared no conflicts of interest.

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All animal experiments were performed in accordance with National Institute of Health Guideline for the Animal Care and Use of Laboratory Animal and approved protocol by the institutional Animal Care and Use Committee at Zunyi Medical University (Zunyi, China).

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Wang, G., Yang, Q., Zheng, C. et al. Physiological Concentration of H2O2 Supports Dopamine Neuronal Survival via Activation of Nrf2 Signaling in Glial Cells. Cell Mol Neurobiol 41, 163–171 (2021).

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  • H2O2
  • Dopamine neurons
  • Glial cells
  • Nrf2