Neuroprotective effects of an herbal medicine, Yi-Gan San on MPP+/MPTP-induced cytotoxicity in vitro and in vivo.
BACKGROUND
A traditional herb, Yi-Gan San, has been widely used for the management of neurodegenerative disorders in traditional East Asian Medicine.


OBJECTIVE
The present study investigated the neuroprotective effects of Yi-Gan San in 1-methyl-4-phenylpyridine/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced cytotoxicity in vitro and in vivo and sought to clarify its underlying mechanisms.


METHODS
The effect of Yi-Gan San on 1-methyl-4-phenylpyridine was measured in terms of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays, caspase-3 activity, and western blot analysis of phosphorylated Akt, one of the survival-related signaling proteins in SH-SY5Y cells. The effects of Yi-Gan San were also confirmed in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonian mouse model using a rotarod test and tyrosine hydroxylase-immunohistochemistry.


RESULTS
Pretreatment of Yi-Gan San with 1-methyl-4-phenylpyridine showed a significant protective effect on SH-SY5Y cells and significantly decreased the level of caspase-3 activity compared to the values for the 1-methyl-4-phenylpyridine-treated cells. This process increased the protein expressions of phosphorylated Akt, and an inhibitor of phosphatidylinositol 3-kinase (PI3K)/Akt, LY294002, significantly decreased this protective effect of Yi-Gan San. In the mouse Parkinson's disease model, treatment with Yi-Gan San also significantly improved motor functioning and prevented dopaminergic loss related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine challenge.


CONCLUSIONS
Using both in vitro and in vivo methods, this study revealed that Yi-Gan San has neuroprotective effects and rescues dopaminergic neurons from 1-methyl-4-phenylpyridine/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity, possibly via the PI3K/Akt pathway.
Doo
Ah-Reum
AR
Studies of Translational Acupuncture Research (STAR), Acupuncture & Meridian Science Research Center (AMSRC), Kyung Hee University, Seoul, Republic of Korea.
Kim
Seung-Nam
SN
Park
Ji-Yeon
JY
Cho
Ki Ho
KH
Hong
Jongki
J
Eun-Kyung
Kim
K
Moon
Sang Kwan
SK
Jung
Woo Sang
WS
Lee
Hyejung
H
Jung
Jae Han
JH
Park
Hi-Joon
HJ
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives; D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D003603:Cytotoxins; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D019684:Magnoliopsida; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation; D008517:Phytotherapy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
D002867:Chromones; D003603:Cytotoxins; D004365:Drugs, Chinese Herbal; D004791:Enzyme Inhibitors; D009025:Morpholines; D018696:Neuroprotective Agents; C524644:Yi-Gan San; C040846:4-phenyl-1,2,3,6-tetrahydropyridine; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine