Abstract
Ginkgolide B (GB), a terpene lactone and active ingredient of Ginkgo biloba, shows protective effects in neuronal cells subjected to hypoxia. We investigated whether GB might protect neurons from hypoxic injury through regulation of neuronal Ca2+ homeostasis. Primary hippocampal neurons subjected to chemical hypoxia (0.7 mM CoCl2) in vitro exhibited an increase in cytoplasmic Ca2+ (measured from the fluorescence of fluo-4), but this effect was significantly diminished by pre-treatment with 0.4 mM GB. Electrophysiological recordings from the brain slices of rats exposed to hypoxia in vivo revealed increases in spontaneous discharge frequency, action potential frequency and calcium current magnitude, and all these effects of hypoxia were suppressed by pre-treatment with 12 mg/kg GB. Western blot analysis demonstrated that hypoxia was associated with enhanced mRNA and protein expressions of Cav1.2 (a voltage-gated Ca2+ channel), STIM1 (a regulator of store-operated Ca2+ entry) and RyR2 (isoforms of Ryanodine Receptor which mediates sarcoplasmic reticulum Ca2+ release), and these actions of hypoxia were suppressed by GB. Taken together, our in vitro and in vivo data suggest that GB might protect neurons from hypoxia, in part, by regulating Ca2+ influx and intracellular Ca2+ release to maintain Ca2+ homeostasis.
Highlights
A hypoxic environment can severely damage organs, especially the brain
Ginkgolide B (GB) significantly increased the cellular metabolic activity of neurons exposed to chemical hypoxia (P < 0.05 vs. hypoxia group; Figure 1), indicating that it protected neurons against hypoxic injury
The administration of GB alone did not affect the Fluo-4 fluorescence intensity. These results suggest that hypoxia increases [Ca2+]i in neurons and that treatment with GB inhibits or reverses this effect through presently unclear mechanisms
Summary
Numerous investigations have provided evidence that a hypoxic environment can induce oxidative stress (Ramanathan et al, 2005; Niki, 2010; Yan et al, 2019), apoptosis (Li et al, 2007; Leszczynska et al, 2015), inflammation (Yang et al, 2013, 2015; Koh et al, 2015), autophagy (Xu and Zhang, 2011; Yang et al, 2015) and Ca2+ overload (Zhao et al, 1999) among other deleterious effects. Previous research has indicated that Ginkgo biloba leaf extracts or active components may be beneficial for the prevention of hypoxic injury, likely via anti-inflammatory, anti-apoptotic and antioxidant activity (Karcher et al, 1984; Jowers et al, 2004; Han and Li, 2013). The mechanisms underlying the beneficial effects of GB in the setting of cerebral hypoxia remain to be fully characterized
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