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BDNF-TrkB pathway mediates neuroprotection of hydrogen sulfide against formaldehyde-induced toxicity to PC12 cells.

Jiang JM, Zhou CF, Gao SL, Tian Y, Wang CY, Wang L, Gu HF, Tang XQ - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology & Institute of Neuroscience, Medical College, University of South China, Hengyang, 42100, Hunan, P. R. China; Key Laboratory for Cognitive Disorders and Neurodegenerative Diseases, University of South China, Hengyang, 421001, Hunan, P. R. China.

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.

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Effect of H2S on the expression of BDNF protein in formaldehyde-treated PC12 cells.(A) PC12 cells were treated with formaldehyde (FA, 60, 120, or 240 μM) for 24 h. (B)After pretreatment of PC12 cells with NaHS (200 μM) for 30 min, FA (120 μM) was added to culture medium and coincubated for 24 h. The expression of BDNF protein was determined by Western blot using anti-BDNF antibody, and β-actin was used as a loading control. The ratio of BDNF to β-actin is normalized by the value in control group. Values were expressed as the mean ± S.E.M. of three independent experiments. **P < 0.01, versus control group; ##P < 0.01, versus FA-treated along group.
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pone.0119478.g002: Effect of H2S on the expression of BDNF protein in formaldehyde-treated PC12 cells.(A) PC12 cells were treated with formaldehyde (FA, 60, 120, or 240 μM) for 24 h. (B)After pretreatment of PC12 cells with NaHS (200 μM) for 30 min, FA (120 μM) was added to culture medium and coincubated for 24 h. The expression of BDNF protein was determined by Western blot using anti-BDNF antibody, and β-actin was used as a loading control. The ratio of BDNF to β-actin is normalized by the value in control group. Values were expressed as the mean ± S.E.M. of three independent experiments. **P < 0.01, versus control group; ##P < 0.01, versus FA-treated along group.

Mentions: Next, we explored the effect of H2S on the expression of BDNF protein in formaldehyde (FA)-exposed PC12 cells. We found that treatment with different concentrations of FA (60, 120, or 240 μM, for 24 h) markedly downregulated the levels of BDNF in PC12 cells (Fig. 2A). Interestingly, pretreatment with NaHS (200 μM) for 30 min significantly rescued FA-induced the downregulation of BDNF protein in PC12 cells (Fig. 2B). In addition, treatment of PC12 cells with NaHS alone also upregulated the levels of BDNF protein. These data indicated that BDNF may be involved in the protection of H2S against FA-induced neurotoxicity.


BDNF-TrkB pathway mediates neuroprotection of hydrogen sulfide against formaldehyde-induced toxicity to PC12 cells.

Jiang JM, Zhou CF, Gao SL, Tian Y, Wang CY, Wang L, Gu HF, Tang XQ - PLoS ONE (2015)

Effect of H2S on the expression of BDNF protein in formaldehyde-treated PC12 cells.(A) PC12 cells were treated with formaldehyde (FA, 60, 120, or 240 μM) for 24 h. (B)After pretreatment of PC12 cells with NaHS (200 μM) for 30 min, FA (120 μM) was added to culture medium and coincubated for 24 h. The expression of BDNF protein was determined by Western blot using anti-BDNF antibody, and β-actin was used as a loading control. The ratio of BDNF to β-actin is normalized by the value in control group. Values were expressed as the mean ± S.E.M. of three independent experiments. **P < 0.01, versus control group; ##P < 0.01, versus FA-treated along group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352058&req=5

pone.0119478.g002: Effect of H2S on the expression of BDNF protein in formaldehyde-treated PC12 cells.(A) PC12 cells were treated with formaldehyde (FA, 60, 120, or 240 μM) for 24 h. (B)After pretreatment of PC12 cells with NaHS (200 μM) for 30 min, FA (120 μM) was added to culture medium and coincubated for 24 h. The expression of BDNF protein was determined by Western blot using anti-BDNF antibody, and β-actin was used as a loading control. The ratio of BDNF to β-actin is normalized by the value in control group. Values were expressed as the mean ± S.E.M. of three independent experiments. **P < 0.01, versus control group; ##P < 0.01, versus FA-treated along group.
Mentions: Next, we explored the effect of H2S on the expression of BDNF protein in formaldehyde (FA)-exposed PC12 cells. We found that treatment with different concentrations of FA (60, 120, or 240 μM, for 24 h) markedly downregulated the levels of BDNF in PC12 cells (Fig. 2A). Interestingly, pretreatment with NaHS (200 μM) for 30 min significantly rescued FA-induced the downregulation of BDNF protein in PC12 cells (Fig. 2B). In addition, treatment of PC12 cells with NaHS alone also upregulated the levels of BDNF protein. These data indicated that BDNF may be involved in the protection of H2S against FA-induced neurotoxicity.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiology & Institute of Neuroscience, Medical College, University of South China, Hengyang, 42100, Hunan, P. R. China; Key Laboratory for Cognitive Disorders and Neurodegenerative Diseases, University of South China, Hengyang, 421001, Hunan, P. R. China.

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.

Show MeSH
Related in: MedlinePlus