Bakkenolide-IIIa Protects Against Cerebral Damage Via Inhibiting NF-κB Activation.
OBJECTIVE
This study was designed to examine the neuroprotective effects of bakkenolide-IIIa, a major novel compound extracted from the rhizome of P. trichinous.


METHODS
Transient focal cerebral damage model in rats and oxygen-glucose deprivation (OGD) in cultured hippocampal neurons were performed. The amount of apoptotic neurons was determined using TUNEL assay. The expressions of Bcl-2, Bax, Akt, ERK1/2, IKKβ, IκBα were measured using Western blot. The nuclear translocation and activation of NF-κB was measured using a fluorescence microscope and electrophoretic mobility shift assay (EMSA).


RESULTS
Bakkenolide-IIIa (4, 8, 16 mg/kg; i.g.) was administered immediately after reperfusion could reduce the brain infarct volume, and the neurological deficit, as well as a high dose of bakkenolide-IIIa, increases the 72 h survival rate in cerebrally damaged rats. In vitro data demonstrated that bakkenolide-IIIa could increase cell viability and decrease the amount of apoptotic cells in cultured primary hippocampal neurons exposed to OGD. Bakkenolide-IIIa also dose-dependently increased the ratio of Bcl-2 to Bax. These results indicated that inhibition of apoptosis partly mediated the neuroprotection of bakkenolide-IIIa. Furthermore, bakkenolide-IIIa inhibited the phosphorylation of Akt, ERK1/2, IKKβ, IκBα, and p65 in cultured hippocampal neurons exposed to OGD. Bakkenolide-IIIa not only inhibited the nuclear translocation of NF-κB in cultured neurons exposed to OGD, but also inhibited the activation of NF-κB in peri-infarct area in cerebrally damaged rats.


CONCLUSIONS
Collectively, our findings indicated that bakkenolide-IIIa protects against cerebral damage by inhibiting AKT and ERK1/2 activation and inactivated NF-κB signaling.
Department of Pharmacognosy, College of Pharmacy, Second Military Medical University, Shanghai, China.
Qian
Q
Jiang
Department of Diving Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai, China.
Run-Ping
RP
Li
Department of Pharmacognosy, College of Pharmacy, Second Military Medical University, Shanghai, China.
Ying
Y
Tang
Department of Pharmacognosy, College of Pharmacy, Second Military Medical University, Shanghai, China.
Ye-Qing
YQ
Wang
Department of Pharmacology, College of Pharmacy, Second Military Medical University, Shanghai, China.
Chong
C
Liu
Department of Pharmacognosy, College of Pharmacy, Second Military Medical University, Shanghai, China.
Mei-Li
ML
Guo
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000172:deficiency*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*
D016328:NF-kappa B; D018696:Neuroprotective Agents; D012717:Sesquiterpenes; C000611606:bakkenolide-IIIa; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose
Bakkenolide-IIIa; Cerebral damage; NF-κB; Neuroprotection