BDNF-TrkB pathway mediates neuroprotection of hydrogen sulfide against formaldehyde-induced toxicity to PC12 cells.
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.
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.
Jia-Mei
JM
Jiang
Department of Physiology & Institute of Neuroscience, Medical College, University of South China, Hengyang, 42100, Hunan, P. R. China.
Cheng-Fang
CF
Zhou
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.
Sheng-Lan
SL
Gao
Department of Biochemistry, Medical College, University of South China, Hengyang, 421001, Hunan, P.R. China.
Ying
Y
Tian
Department of Pathophysiology, Medical College, University of South China, Hengyang, 421001, Hunan, P.R. China.
Chun-Yan
CY
Wang
Department of Anthropotomy, Medical College, University of South China, Hengyang, 421001, Hunan, P.R. China.
Li
L
Wang
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.
Hong-Feng
HF
Gu
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.
Xiao-Qing
XQ
Tang
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology; D005557:Formaldehyde / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D026121:Indole Alkaloids / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D026121:Indole Alkaloids; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D005557:Formaldehyde; C049985:staurosporine aglycone; D020813:Receptor, trkB; D006862:Hydrogen Sulfide