期刊
JOURNAL OF PHARMACY AND PHARMACOLOGY
卷 69, 期 7, 页码 896-906出版社
WILEY
DOI: 10.1111/jphp.12681
关键词
brain-derived neurotrophic factor; isoflurane; mitogen-activated protein kinases; PI3K; Akt signalling cascade; plumbagin
ObjectivesThis study was designed to assess the effects of plumbagin on isoflurane-induced neurotoxicity. MethodsNeonatal Sprague Dawley rat pups were treated with plumbagin (50, 100 or 150 mg/kg body weight, orally) from postnatal day 2. The pups on postnatal day 7 were subjected to isoflurane (0.75%) exposure for 6 h. Neuronal apoptosis in the hippocampal tissues was detected by TUNEL assay and FluroJade B staining following isoflurane exposure. Protein expressions were analysed by immunoblotting. RT-PCR was performed to assess mRNA levels of brain-derived neurotrophic factor (BDNF) and TrkB. Key findingsWe observed reduced apoptosis in hippocampal CA1, CA3 and dentate gyrus regions along with severely reduced pro-apoptotic factors (Bad, Bax and cleaved caspase-3) expression and raised levels of Bcl-2, Bcl-xL, survivin, xIAP and cIAPs (cell survival proteins) in plumbagin supplemented rats. Decrease in the levels of JNK, phospho-JNK, c-Jun and phospho-c-Jun with enhanced ERK1/2 levels was observed on plumbagin pretreatment. Down-regulated PI3K/Akt signalling following isoflurane was activated by plumbagin as evidenced by raised PI3K/Akt pathway proteins - mTORc1, Akt, phospho-Akt, GSK-3, phospho-GSK-3, PTEN and NF-Bp65 in the hippocampal tissues as detected by Western blotting. The mRNA levels were enhanced on plumbagin supplementation. ConclusionsPlumbagin exerted its neuroprotective effects by effectively suppressing isoflurane-induced neuronal apoptosis via regulating BDNF-TrkB-PI3/Akt and ERK/JNK signalling.
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