Neuroprotective effects of amlodipine besylate and benidipine hydrochloride on oxidative stress-injured neural stem cells.
Hypertension is associated with oxidative stress. Amlodipine besylate (AB) and benidipine hydrochloride (BH), which are Ca(2+) antagonists, have been reported to reduce oxidative stress. In this study, we examined the neuroprotective effects of AB and BH on oxidative stress-injured neural stem cells (NSCs), with a focus on the phosphatidylinositol 3-kinase (PI3K) pathway and the extracellular signal-regulated kinase (ERK) pathway. After treatment with H2O2, the viability of NSCs decreased in a concentration-dependent manner; however, co-treatment with AB or BH restored the viability of H2O2-injured NSCs. H2O2 increased free radical production and apoptosis in NSCs, whereas co-treatment with AB or BH attenuated these effects. To evaluate the effects of AB or BH on the H2O2-inhibited proliferation of NSCs, we performed BrdU labeling and colony formation assays and found that NSC proliferation decreased upon H2O2 treatment but that combined treatment with AB or BH restored this proliferation. Western blot analysis showed that AB and BH increased the expression of cell survival-related proteins that were linked with the PI3K and ERK pathways but decreased the expression of cell death-related proteins. To investigate whether the PI3K and ERK pathways were directly involved in the neuroprotective effects of AB and BH on H2O2-treated NSCs, NSCs were pretreated with the PI3K inhibitor, LY294002, or the ERK inhibitor, FR180204, which significantly blocked the effects of AB and BH. Together, our results suggest that AB and BH restore the H2O2-inhibited viability and proliferation of NSCs by inhibiting oxidative stress and by activating the PI3K and ERK pathways.
Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Republic of Korea.
Na-Young
NY
Choi
Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea.
Hojin
H
Choi
Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea.
Hyun-Hee
HH
Park
Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Republic of Korea.
Eun-Hye
EH
Lee
Department of Neurology, Bundang Jesaeng Hospital, Gyeonggi Province, Republic of Korea.
Hyun-Jeung
HJ
Yu
Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea.
Kyu-Yong
KY
Lee
Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea.
Young
Y
Joo Lee
Department of Neurology, Hanyang University College of Medicine, Seoul, Republic of Korea; Department of Translational Medicine, Hanyang University Graduate School of Biomedical Science & Engineering, Seoul, Republic of Korea. Electronic address: ksh213@hanyang.ac.kr.
Seong-Ho
SH
Koh
D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; C050883:benidipine hydrochloride; D017311:Amlodipine; D058539:Phosphatidylinositol 3-Kinase; D048052:Mitogen-Activated Protein Kinase 3; D009543:Nifedipine
Amlodipine besylate; Benidipine hydrochloride; Neural Stem Cell; Phosphatidylinositol 3-kinase