Abstract
BackgroundThe neuroprotective role of propofol (PPF) in cerebral ischemia-reperfusion (I/R) has recently been highlighted. This study aimed to explore whether the neuroprotective mechanisms of PPF were linked to its regulation of Ca2+/CaMKKβ (calmodulin-dependent protein kinase kinase β)/AMPK (AMP-activated protein kinase)/mTOR (mammalian target of rapamycin)/autophagy pathway.MethodsCultured primary rat cerebral cortical neurons were treated with oxygen-glucose deprivation and re-oxygenation (OGD/R) to mimic cerebral I/R injury in vitro.ResultsCompared with the control neurons, OGD/R exposure successfully induced neuronal I/R injury. Furthermore, OGD/R exposure notably caused autophagy induction, reflected by augmented LC3-II/LC3-I ratio and Beclin 1 expression, decreased p62 expression, and increased LC3 puncta formation. Moreover, OGD/R exposure induced elevation of intracellular Ca2+ concentration ([Ca2+]i). However, PPF treatment significantly antagonized OGD/R-triggered cell injury, autophagy induction, and [Ca2+]i elevation. Further investigation revealed that both autophagy induction by rapamycin and [Ca2+]i elevation by the Ca2+ ionophore ionomycin significantly reversed the PPF-mediated amelioration of OGD/R-triggered cell injury. Importantly, ionomycin also significantly abrogated the PPF-mediated suppression of autophagy and CaMKKβ/AMPK/mTOR signaling in OGD/R-exposed neurons. Additionally, activation of CaMKKβ/AMPK/mTOR signaling abrogated the PPF-mediated autophagy suppression.ConclusionOur findings demonstrate that PPF antagonized OGD/R-triggered neuronal injury, which might be mediated, at least in part, via inhibition of autophagy through Ca2+/CaMKKβ/AMPK/mTOR pathway.
Highlights
The neuroprotective role of propofol (PPF) in cerebral ischemia-reperfusion (I/R) has recently been highlighted
Neuronal I/R injury model was successfully induced by Oxygen-glucose deprivation (OGD)/R After being cultured for 10 days, rat primary cortical neurons exhibited plump cell body, apparent halo, and complete neural network (Fig. 1a), with a high purity indicated by neuron-specific enolase (NSE) immunohistochemistry staining (Fig. 1b)
These results indicated that oxygen-glucose deprivation/ reperfusion (OGD/R) exposure successfully induced a model of neuronal I/R injury in cerebral cortical neurons
Summary
The neuroprotective role of propofol (PPF) in cerebral ischemia-reperfusion (I/R) has recently been highlighted. Cerebral ischemia-reperfusion (I/R) injury is characterized by an insufficient oxygen supply and restoration of blood flow and serves as the main cause for the aggravation of cerebral injury and functional impairment (He et al 2016). This injury involves complex and multi-factorial mechanisms, including intracellular Ca2+ overload and damage to oxidative stress (Chen et al 2017; Liu et al 2011). In addition to its sedative and hypnotic effects, the neuroprotective role of PPF in transient global and focal cerebral I/R has recently been highlighted in both animal and cell models (Wang et al 2016; Wang et al 2011). The mechanisms responsible for the neuroprotection of PPF involve the inhibition of apoptosis (Tao et al 2016), Ca2+ overload (Wang et al 2016), oxidative stress injury (Yu et al 2018), and so forth
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