LLDT-67 attenuates MPTP-induced neurotoxicity in mice by up-regulating NGF expression

doi:10.1038/aps.2012.88

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第二研究室

	LLDT-67 attenuates MPTP-induced neurotoxicity in mice by up-regulating NGF expression
	Wu, Dong-dong 1; Huang, Li 1; Zhang, Lei 1; Wu, Le-yu 1; Li, Yuan-chao 2; Feng, Linyin1
刊名	ACTA PHARMACOLOGICA SINICA
	2012-09
卷号	33 期号:9 页码:1187-1194
关键词	LLDT-67 triptolide Parkinson's disease MPTP neuroprotection dopaminergic neurons substantia nigra striatum NGF TrkA
ISSN号	1671-4083
DOI	10.1038/aps.2012.88
文献子类	Article
英文摘要	Aim: To investigate the neuroprotective effects of LLDT-67, a novel derivative of triptolide, in MPTP-induced mouse Parkinson's disease (PD) models and in primary cultured astrocytes, and to elucidate the mechanisms of the action. Methods: In order to induce PD, C57BL/6 mice were injected MPTP (30 mg/kg, ip) daily from d 2 to d 6. MPTP-induced behavioral changes in the mice were examined using pole test, swimming test and open field test. The mice were administered LLDT-67 (1, 2, or 4 mg/kg, po) daily from d 1 to d 11. On d 12, the mice were decapitated and brains were collected for immunohistochemistry study and measuring monoamine levels in the striatum. Primary cultured astrocytes from the cortices of neonatal C57BL/6 mouse pups were prepared for in vitro study. Results: In MPTP-treated mice, administration of LLDT-67 significantly reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra, and ameliorated the behavioral changes. LLDT-67 (4 mg/kg) significantly increased the expression of NGF in astrocytes in the substantia nigra and striatum of the mice. Furthermore, administration of LLDT-67 caused approximately 2-fold increases in the phosphorylation of TrkA at tyrosine 751, and marked increases in the phosphorylation of AKT at serine 473 as compared with the mice model group. In the cultured astrocytes, LLDT-67 (1 and 10 nmol/L) increased the NGF levels in the culture medium by 179% and 160%, respectively. Conclusion: The neuroprotective effect of LLDT-67 can be mostly attributed to its ability to enhance NGF synthesis in astrocytes in the midbrain and to rescue dopaminergic neurons indirectly through TrkA activation.
资助项目	National Natural Science Foundation of China[81123004] ; National Natural Science Foundation of China[30570565] ; National Natural Science Foundation of China[C03020706] ; National Laboratory of Biomacromolecules[00000000]
WOS关键词	FACTOR GENE-THERAPY ; PARKINSONS-DISEASE ; DOPAMINERGIC-NEURONS ; NEUROTROPHIC FACTORS ; SIGNAL-TRANSDUCTION ; NERVOUS-SYSTEM ; ANIMAL-MODELS ; CELL-DEATH ; IN-VITRO ; GROWTH
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:4635870
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000308391000011
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277967]
专题	药理学第二研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Feng, Linyin
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Wu, Dong-dong,Huang, Li,Zhang, Lei,et al. LLDT-67 attenuates MPTP-induced neurotoxicity in mice by up-regulating NGF expression[J]. ACTA PHARMACOLOGICA SINICA,2012,33(9):1187-1194.
APA	Wu, Dong-dong,Huang, Li,Zhang, Lei,Wu, Le-yu,Li, Yuan-chao,&Feng, Linyin.(2012).LLDT-67 attenuates MPTP-induced neurotoxicity in mice by up-regulating NGF expression.ACTA PHARMACOLOGICA SINICA,33(9),1187-1194.
MLA	Wu, Dong-dong,et al."LLDT-67 attenuates MPTP-induced neurotoxicity in mice by up-regulating NGF expression".ACTA PHARMACOLOGICA SINICA 33.9(2012):1187-1194.