A dibenzoylmethane derivative protects dopaminergic neurons against both oxidative stress and endoplasmic reticulum stress.
The enhancement of intracellular stresses such as oxidative stress and endoplasmic reticulum (ER) stress has been implicated in several neurodegenerative disorders including Parkinson's disease (PD). During a search for compounds that regulate ER stress, a dibenzoylmethane (DBM) derivative 14-26 (2,2'-dimethoxydibenzoylmethane) was identified as a novel neuroprotective agent. Analysis in SH-SY5Y cells and in PC12 cells revealed that the regulation of ER stress by 14-26 was associated with its anti-oxidative property. 14-26 prevented the production of reactive oxygen species (ROS) when the cells were exposed to oxidants such as hydrogen peroxide and 6-hydroxydopamine (6-OHDA) or an ER stressor brefeldin A (BFA). 14-26 also prevented ROS-induced damage in both the ER and the mitochondria, including the protein carbonylation in the microsome and the reduction of the mitochondrial membrane potential. Further examination disclosed the presence of the iron-chelating activity in 14-26. In vivo, 14-26 suppressed both oxidative stress and ER stress and prevented neuronal death in the substantia nigra pars compacta (SNpc) after injection of 6-OHDA in mice. These results suggest that 14-26 is an antioxidant that protects dopaminergic neurons against both oxidative stress and ER stress and could be a therapeutic candidate for the treatment of PD.
Takano
Katsura
K
Department of Neuroanatomy, Kanazawa University Graduate School of Medical Science, Kanazawa City, Ishikawa, Japan.
Kitao
Yasuko
Y
Tabata
Yoshiyuki
Y
Miura
Hikari
H
Sato
Kosuke
K
Takuma
Kazuhiro
K
Yamada
Kiyofumi
K
Hibino
Satoshi
S
Choshi
Tominari
T
Iinuma
Munekazu
M
Suzuki
Hiroto
H
Murakami
Rika
R
Yamada
Masashi
M
Ogawa
Satoshi
S
Hori
Osamu
O
D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D047188:Chalcones / Q000494:pharmacology* / Q000627:therapeutic use; D004298:Dopamine / Q000378:metabolism; D054278:Embryonal Carcinoma Stem Cells; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018384:Oxidative Stress / Q000187:drug effects*; D016627:Oxidopamine / Q000494:pharmacology; D016716:PC12 Cells; D010300:Parkinson Disease / Q000188:drug therapy; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects; D013565:Sympatholytics / Q000494:pharmacology
C526906:2,2'-dimethoxydibenzoylmethane; D047188:Chalcones; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D013565:Sympatholytics; D016627:Oxidopamine; D004298:Dopamine