Abstract
Stroke is a long-term disability and one of the leading causes of death. However, no successful therapeutic intervention is available for the majority of stroke patients. In this study, we explored a traditional Chinese medicine Baifuzi (Typhonium giganteum Engl.). We show, at first, that the ethanol extract of Baifuzi exerts neuroprotective effects against brain damage induced by transient global or focal cerebral ischemia in rats and mice. Second, the extract activated large-conductance Ca2+-activated K+ channel (BKCa) channels, and BKCa channel blockade suppressed the neuroprotection of the extract, suggesting that the BKCa is the molecular target of Baifuzi. Third, Baifuzi cerebroside (Baifuzi-CB), purified from its ethanol extract, activated BKCa channels in a manner similar to that of the extract. Fourth, the stress axis hormone-regulated exon (STREX) domain of the BKCa channel directly interacted with Baifuzi-CB, and its deletion suppressed channel activation by Baifuzi-CB. These results indicate that Baifuzi-CB activated the BKCa channel through its direct interaction with the STREX domain of the channel and suggests that Baifuzi-CB merits exploration as a potential therapeutic agent for treating brain ischemia.
Highlights
Stroke is a devastating condition that annually affects 15 million people worldwide, and is the leading cause of adult disability in industrialized countries.[1]
We examined whether e-Baifuzi has neuroprotective roles in the CA1 region in the rat model of transient global ischemia, which was made by 20 min 4vessel occlusion (4VO)
These results suggested that e-Baifuzi could protect the brain from transient global cerebral ischemia and that its therapeutic time window may last up to 8 h after the onset of ischemia
Summary
Stroke is a devastating condition that annually affects 15 million people worldwide, and is the leading cause of adult disability in industrialized countries.[1]. Brain ischemia begins with energy depletion, followed by the disruption of ion homeostasis, membrane depolarization, excessive neurotransmitter (glutamate) release and elevation of intracellular calcium, all of which initiate a neurotoxic cascade that results in neurodegeneration and death of ischemic neurons.[8,9] The large-conductance Ca2 þ -activated K þ (BKCa) channels are widely expressed in the brain[10] and are preferentially located at glutamatergic synaptic terminals.[11,12] They react to either increases in intracellular Ca2 þ or membrane depolarization by increasing K þ efflux They function as an ‘emergency break’ to limit Ca2 þ influx for regulating synaptic transmission under conditions of enhanced neuronal excitability.[13] It has been shown that activation of BKCa channels in ischemic cells by BKCa channel openers could minimize neuronal depolarization, limit accumulation of potentially pathological levels of Ca2 þ from a number of potential sources, reduce neurotransmitter release and significantly attenuate infarct growth during ischemic stroke in animal models.[14,15] In addition, blockade of BKCa channels enhanced cell damage in organotypical slice cultures after oxygen and glucose deprivation.[16] In this study, we show that the ethanol extract of Baifuzi (e-Baifuzi) shows significant neuronal protective activity in the rat and mice model of ischemic stroke. We show that the stress axis hormone-regulated exon (STREX) domain of the BKCa channel, a 59-amino-acid splice insertion located in the cytoplasmic side of the channel, is required for the activation of the BKCa channel by Baifuzi-CB, probably due to direct interaction between Baifuzi-CB and the STREX domain
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