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Hydrogen sulfide inhibits homocysteine-induced endoplasmic reticulum stress and neuronal apoptosis in rat hippocampus via upregulation of the BDNF-TrkB pathway

   
@article{APS5938,
	author = {Hai-jun Wei and Jin-hua Xu and Man-hong Li and Ji-ping Tang and Wei Zou and Ping Zhang and Li Wang and Chun-yan Wang and Xiao-qing Tang},
	title = {Hydrogen sulfide inhibits homocysteine-induced endoplasmic reticulum stress and neuronal apoptosis in rat hippocampus via upregulation of the BDNF-TrkB pathway},
	journal = {Acta Pharmacologica Sinica},
	volume = {35},
	number = {6},
	year = {2016},
	keywords = {},
	abstract = {Hai-jun WEI1, #, Jin-hua XU2, #, Man-hong LI1, 3, Ji-ping TANG1, 3, Wei ZOU3, Ping ZHANG3, *, Li WANG4, Chun-yan WANG5, Xiao-qing TANG1, *
1Institute of Neuroscience, Medical College, University of South China, Hengyang 421001, China; 2Laboratory Center of Biochemistry and Molecular Biology, University of South China, Hengyang 421001, China; 3Department of Neurology, Nanhua Affiliated Hospital, University of South China, Hengyang 421001, China; 4Department of Anthropotomy, Medical College, University of South China, Hengyang 421001, China; 5Department of Pathophysiology, Medical College, University of South China, Hengyang 421001, China
 
Aim: Homocysteine (Hcy) can elicit neuronal cell death, and hyperhomocysteinemia is a strong independent risk factor for Alzheimer’s disease.  The aim of this study was to examine the effects of hydrogen sulfide (H2S) on Hcy-induced endoplasmic reticulum (ER) stress and neuronal apoptosis in rat hippocampus. 
Methods: Adult male SD rats were intracerebroventricularly (icv) injected with Hcy (0.6 μmol/d) for 7 d.  Before Hcy injection, the rats were treated with NaHS (30 or 100 μmol·kg-1·d-1, ip) and/or k252a (1 μg/d, icv) for 2 d.  The apoptotic neurons were detected in hippocampal coronal slices with TUNEL staining.  The expression of glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), cleaved caspase-12, and BDNF in the hippocampus were examined using Western blotting assays.  The generation of H2S in the hippocampus was measured with the NNDPD method.

Results: Hcy markedly inhibited the production of endogenous H2S and increased apoptotic neurons in the hippocampus.  Further­more, Hcy induced ER stress responses in the hippocampus, as indicated by the upregulation of GRP78, CHOP, and cleaved caspase-12.  Treatment with the H2S donor NaHS increased the endogenous H2S production and BDNF expression in a dose-dependent manner, and significantly reduced Hcy-induced neuronal apoptosis and ER stress responses in the hippocampus.  Treatment with k252a, a specific inhibitor of TrkB (the receptor of BDNF), abolished the protective effects of NaHS against Hcy-induced ER stress in the hippocampus. 

Conclusion: H2S attenuates ER stress and neuronal apoptosis in the hippocampus of Hcy-treated rats via upregulating the BDNF-TrkB pathway.

 
Keywords: hydrogen sulfide; homocysteine; neurotoxicity; hippocampus; apoptosis; ER stress; BDNF; tyrosine protein kinase B; Alzheimer’s disease
 
This study was supported by the National Natural Science Foundation of China (No 81202518, 81200985, and 81071005), the Natural Science Foundation of Hunan Province, China (No 11JJ3117, 12JJ9032), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education of the People’s Republic of China ([2011]508) and the Construct Program of the Key Discipline in the Hunan province.
# These authors contributed equally to this work.
* To whom correspondence should be addressed. 
E-mail tangxq01001@foxmail.com (Xiao-qing TANG); zhangp-usc@foxmail.com (Ping ZHANG)
Received 2013-09-17    Accepted 2013-12-08},
	issn = {1745-7254},	url = {http://www.chinaphar.com/article/view/5938}
}