Minocycline attenuates both OGD-induced HMGB1 release and HMGB1-induced cell death in ischemic neuronal injury in PC12 cells.
High mobility group box-1 (HMGB1), a non-histone DNA-binding protein, is massively released into the extracellular space from neuronal cells after ischemic insult and exacerbates brain tissue damage in rats. Minocycline is a semisynthetic second-generation tetracycline antibiotic which has recently been shown to be a promising neuroprotective agent. In this study, we found that minocycline inhibited HMGB1 release in oxygen-glucose deprivation (OGD)-treated PC12 cells and triggered the activation of p38mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK1/2). The ERK kinase (MEK)1/2 inhibitor U-0126 and p38MAPK inhibitor SB203580 blocked HMGB1 release in response to OGD. Furthermore, HMGB1 triggered cell death in a dose-dependent fashion. Minocycline significantly rescued HMGB1-induced cell death in a dose-dependent manner. In light of recent observations as well as the good safety profile of minocycline in humans, we propose that minocycline might play a potent neuroprotective role through the inhibition of HMGB1-induced neuronal cell death in cerebral infarction.
Kikuchi
Kiyoshi
K
Department of Advanced Therapeutics, Division of Laboratory and Vascular Medicine, Field of Cardiovascular and Respiratory Disorders, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Kawahara
Ko-ichi
K
Biswas
Kamal Krishna
KK
Ito
Takashi
T
Tancharoen
Salunya
S
Morimoto
Yoko
Y
Matsuda
Fumiyo
F
Oyama
Yoko
Y
Takenouchi
Kazunori
K
Miura
Naoki
N
Arimura
Noboru
N
Nawa
Yuko
Y
Meng
Xiaojie
X
Shrestha
Binita
B
Arimura
Shinichiro
S
Iwata
Masahiro
M
Mera
Kentaro
K
Sameshima
Hisayo
H
Ohno
Yoshiko
Y
Maenosono
Ryuichi
R
Yoshida
Yoshihiro
Y
Tajima
Yutaka
Y
Uchikado
Hisaaki
H
Kuramoto
Terukazu
T
Nakayama
Kenji
K
Shigemori
Minoru
M
Hashiguchi
Teruto
T
Maruyama
Ikuro
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002070:Butadienes / Q000494:pharmacology; D002417:Cattle; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007511:Ischemia / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008911:Minocycline / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D002070:Butadienes; D004791:Enzyme Inhibitors; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D009570:Nitriles; C113580:U 0126; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D008911:Minocycline; D005947:Glucose; D010100:Oxygen