Discovery of vinyl sulfones as a novel class of neuroprotective agents toward Parkinson's disease therapy.
Although the etiology of Parkinson's disease (PD) remains elusive, recent studies suggest that oxidative stress contributes to the cascade leading to dopaminergic (DAergic) neurodegeneration. The Nrf2 signaling is the main pathway responsible for cellular defense system against oxidative stress. Nrf2 is a transcription factor that regulates environmental stress response by inducing expression of antioxidant enzyme genes. We have synthesized novel vinyl sulfone derivatives. They exhibited a broad range of activities in inducing HO-1, whose gene expression is under the control of Nrf2. Among them, compound 12g was confirmed to activate Nrf2 and induce expression of the Nrf2-dependent antioxidant enzymes NQO1, GCLC, GLCM, and HO-1, at both mRNA and protein levels in DAergic neuronal cells. This was accompanied by protection of DAergic neurons in both in vitro and MPTP-induced in vivo models of PD. In addition, compound 12g effectively resulted in attenuation of the PD-associated behavioral deficits in the mouse model.
Center for Neuro-Medicine, Brain Science Institute, and ‡Doping Control Center, Korea Institute of Science and Technology , Seoul, 136-791, Republic of Korea.
Seo Yeon
SY
Woo
Ji Hyun
JH
Kim
Mi Kyeong
MK
Moon
Se-Hee
SH
Han
Seul Ki
SK
Yeon
Ji Won
JW
Choi
Bo Ko
BK
Jang
Hyo Jung
HJ
Song
Yong Gu
YG
Kang
Jin Woo
JW
Kim
Jaeick
J
Lee
Dong Jin
DJ
Kim
Onyou
O
Hwang
Ki Duk
KD
Park
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D021241:Spectrometry, Mass, Electrospray Ionization; D013450:Sulfones / Q000737:chemistry / Q000627:therapeutic use*
D017931:DNA Primers; D018696:Neuroprotective Agents; D013450:Sulfones; C009873:divinyl sulfone; D051547:Heme Oxygenase-1