Mild mitochondrial depolarization is involved in a neuroprotective mechanism of Citrus sunki peel extract.
Mitochondrial membrane potential (∆Ψm ) contributes to determining a driving force for calcium to enter the mitochondria. It has been demonstrated that even a small mitochondrial depolarization is sufficient to prevent mitochondrial calcium overload and the subsequent apoptosis. Therefore, mild mitochondrial depolarization has been recently evaluated as a novel mechanism of neuroprotection via inhibiting neurotoxic mitochondrial calcium overload during neuronal insults. In the present study, using both real-time recording and flow cytometric analyses of ∆Ψm , we demonstrated that ethanolic peel extract of Citrus sunki Hort. ex Tanaka (CPE) and its active compounds are capable of inducing a mild mitochondrial depolarization. Polymethoxylated flavones such as nobiletin and tangeretin were found as the active compounds responsible for CPE effects on ∆Ψm . Neuronal viability was significantly increased in a dose-dependent manner by CPE treatment in H2 O2 -stimulated HT-22 cells as an in vitro neuronal insult model. CPE treatment significantly inhibited H2 O2 -induced apoptotic processes such as chromatin condensation, caspase 3 activation and anti-poly (ADP-ribose) polymerase (PARP) cleavage. CPE treatment significantly blocked mitochondrial calcium overload in H2 O2 -stimulated HT-22 neurons as indicated by rhod-2 acetoxymethyl ester. Taken together, our findings suggest that CPE and its active compounds may be considered as promising neuroprotective agents via inducing a mild mitochondrial depolarization.
Department of Physiology, Jeju National University School of Medicine, 66 Jejudaehakno, Jeju-si, Jeju-do, Republic of Korea.
Jin-Ji
JJ
Wu
Yanji
Y
Cui
Yoon-Sil
YS
Yang
Sung-Cherl
SC
Jung
Jin Won
JW
Hyun
Young-Hee
YH
Maeng
Deok-Bae
DB
Park
Sun-Ryung
SR
Lee
Se-Jae
SJ
Kim
Su-Yong
SY
Eun
D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002957:Citrus / Q000737:chemistry*; D047309:Flavones / Q000494:pharmacology; D005434:Flow Cytometry; D005638:Fruit / Q000737:chemistry; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*
D047309:Flavones; D018696:Neuroprotective Agents; D010936:Plant Extracts; D006861:Hydrogen Peroxide; C008661:nobiletin; C059006:tangeretin; D002118:Calcium