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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 K252a on H2S-induced protection against formaldehyde-exerted cytotoxicity in PC12 cells.PC12 cells were preincubated with K252a (10 nM) for 30 min before pretreatment with NaHS (200 μM) for 30 min, and then cotreated with formaldehyde (FA, 120 μM) for 24 h. Cell viability was determined by the CCK-8 assay. Results were expressed as the mean ± S.E.M. of three independent experiments. **P < 0.01, versus control group; ##P < 0.01, versus FA-treated alone group; &&P < 0.01, versus cotreatment with NaHS and FA group.
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pone.0119478.g003: Effect of K252a on H2S-induced protection against formaldehyde-exerted cytotoxicity in PC12 cells.PC12 cells were preincubated with K252a (10 nM) for 30 min before pretreatment with NaHS (200 μM) for 30 min, and then cotreated with formaldehyde (FA, 120 μM) for 24 h. Cell viability was determined by the CCK-8 assay. Results were expressed as the mean ± S.E.M. of three independent experiments. **P < 0.01, versus control group; ##P < 0.01, versus FA-treated alone group; &&P < 0.01, versus cotreatment with NaHS and FA group.

Mentions: To confirm the hypothesis that BDNF-TrkB pathway mediates the protection of H2S against FA-induced neurotoxicity, we next explored whether K252a, a specific BDNF-TrkB pathway inhibitor, reverses the protective role of H2S against FA-indcued cytotoxicity. Pretreatment of PC12 cells with K252a (10 nM) for 30 min before the administration of NaHS (200 mM) significantly attenuated NaHS-suppressed the loss of cell viability induced by treatment with FA (120 μM) (Fig. 3). K252a (10 nM) or NaHS (200 mM) alone did not affect the viability of PC12 cells. These data suggested that H2S protects PC12 cells against FA-induced cytotoxicity via BDNF-TrkB pathway.


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 K252a on H2S-induced protection against formaldehyde-exerted cytotoxicity in PC12 cells.PC12 cells were preincubated with K252a (10 nM) for 30 min before pretreatment with NaHS (200 μM) for 30 min, and then cotreated with formaldehyde (FA, 120 μM) for 24 h. Cell viability was determined by the CCK-8 assay. Results were expressed as the mean ± S.E.M. of three independent experiments. **P < 0.01, versus control group; ##P < 0.01, versus FA-treated alone group; &&P < 0.01, versus cotreatment with NaHS and FA group.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0119478.g003: Effect of K252a on H2S-induced protection against formaldehyde-exerted cytotoxicity in PC12 cells.PC12 cells were preincubated with K252a (10 nM) for 30 min before pretreatment with NaHS (200 μM) for 30 min, and then cotreated with formaldehyde (FA, 120 μM) for 24 h. Cell viability was determined by the CCK-8 assay. Results were expressed as the mean ± S.E.M. of three independent experiments. **P < 0.01, versus control group; ##P < 0.01, versus FA-treated alone group; &&P < 0.01, versus cotreatment with NaHS and FA group.
Mentions: To confirm the hypothesis that BDNF-TrkB pathway mediates the protection of H2S against FA-induced neurotoxicity, we next explored whether K252a, a specific BDNF-TrkB pathway inhibitor, reverses the protective role of H2S against FA-indcued cytotoxicity. Pretreatment of PC12 cells with K252a (10 nM) for 30 min before the administration of NaHS (200 mM) significantly attenuated NaHS-suppressed the loss of cell viability induced by treatment with FA (120 μM) (Fig. 3). K252a (10 nM) or NaHS (200 mM) alone did not affect the viability of PC12 cells. These data suggested that H2S protects PC12 cells against FA-induced cytotoxicity via BDNF-TrkB pathway.

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