BDNF-TrkB Pathway Mediates Neuroprotection of Hydrogen Sulfide against Formaldehyde-Induced Toxicity to PC12 Cells

Jia-Mei Jiang,Ying Tian,Li Wang,Xiao-Qing Tang,Cheng-Fang Zhou,Hong-Feng Gu,Sheng-Lan Gao,Chun-Yan Wang,Aditya Bhushan Pant

doi:10.1371/journal.pone.0119478

Abstract

Formaldehyde (FA) is a common environmental contaminant that has toxic effects on the central nervous system (CNS). Our previous data demonstrated that hydrogen sulfide (H2S), the third endogenous gaseous mediator, has protective effects against FA-induced neurotoxicity. As is known to all, Brain-derived neurotropic factor (BDNF), a member of the neurotrophin gene family, mediates its neuroprotective properties via various intracellular signaling pathways triggered by activating the tyrosine kinase receptor B (TrkB). Intriguingly, our previous data have illustrated the upregulatory role of H2S on BDNF protein expression in the hippocampus of rats. Therefore, in this study, we hypothesized that H2S provides neuroprotection against FA toxicity by regulating BDNF-TrkB pathway. In the present study, we found that NaHS, a donor of H2S, upregulated the level of BDNF protein in PC12 cells, and significantly rescued FA-induced downregulation of BDNF levels. Furthermore, we found that pretreatment of PC12 cells with K252a, an inhibitor of the BDNF receptor TrkB, markedly reversed the inhibition of NaHS on FA-induced cytotoxicity and ablated the protective effects of NaHS on FA-induced oxidative stress, including the accumulation of intracellular reactive oxygen species (ROS), 4-hydroxy-2-trans-nonenal (4-HNE), and malondialdehyde (MDA). We also showed that K252a abolished the inhibition of NaHS on FA-induced apoptosis, as well as the activation of caspase-3 in PC12 cells. In addition, K252a reversed the protection of H2S against FA-induced downregulation of Bcl-2 protein expression and upregulation of Bax protein expression in PC12 cells. These data indicate that the BDNF-TrkB pathway mediates the neuroprotection of H2S against FA-induced cytotoxicity, oxidative stress and apoptosis in PC12 cells. These findings provide a novel mechanism underlying the protection of H2S against FA-induced neurotoxicity.

Highlights

Formaldehyde (FA), a common environmental contaminant, is widely found in domestic air, tobacco smoke, garments, paint, and industrial and medical products [1,2]
We demonstrated that NaHS, a donor of H2S, significantly rescues FA-induced the downregulation of Brain-derived neurotrophic factor (BDNF) expression in PC12 cells and that K252a, a BDNF-tyrosine kinase receptor B (TrkB) pathway inhibitor, abolished the protective effects of H2S against FA-induced cytotoxicity, oxidative stress, and apoptosis
To illustrate whether BDNF is involved in the protective effect of H2S against FA-elicited neurotoxicity, we first investigated the effects of H2S on the level of BDNF protein in PC12 cells

Summary

Introduction

Formaldehyde (FA), a common environmental contaminant, is widely found in domestic air, tobacco smoke, garments, paint, and industrial and medical products [1,2]. Increasing evidence indicated that FA is toxic to mammals [3,4,5,6], especially inducing impairment in learning and memory as well as neurotoxicity in the central nervous system (CNS) [7,8,9,10]. Epidemiological data showed that long-term exposure to FA causes neurocognitive and neurobehavioral impairment in histology technicians and workers [11]. It has been shown that FA exposure induces the apoptosis and neurotoxicity in the cultured cortical neurons and PC12 cells [12,13], and elicits behavioral and learning and memory disorders in rats and mice[8,9]. It is important to explore novel therapeutic targets for the neurotoxicity of FA

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Conclusion