Propofol inhibited autophagy through Ca2+/CaMKKβ/AMPK/mTOR pathway in OGD/R-induced neuron injury

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.Electronic supplementary materialThe online version of this article (10.1186/s10020-018-0054-1) contains supplementary material, which is available to authorized users.

Hypoxic Adaptation of Mitochondrial Metabolism in Rat Cerebellum Decreases in Pregnancy

“…Autophagy is also coupled to pro-survival function of mitochondrial fission under energy stress [44][45][46][47]. However, the homeostatic and pro-survival functions of mTOR, autophagy and mitochondrial fission are highly conditional, with overactivation of these processes also mediating the brain damage by hypoxia [48][49][50].…”

Petatewalide B alleviates oxygen‑glucose deprivation/reoxygenation‑induced neuronal injury via activation of the AMPK/Nrf2 signaling pathway

“…neuronal apoptosis frequently occurs in neurodegenerative diseases, resulting in long-term alterations in brain function. evidence suggests that excessive oxidative stress occurring in damaged neighboring neuronal cells could activate multiple cellular signaling pathways that lead to apoptosis, including dna fragmentation, as well as genes related to pro-apoptosis and anti-apoptosis (18,19). Here, we also demonstrated that petatewalide B could alleviate oGd/r-induced apoptosis, inhibit pro-apoptosis (cleaved ParP, cleaved caspase-9, cleaved caspase-3, p53, Bax, and p21), and increase the anti-apoptotic protein Bcl-2, demonstrating that this active constituent may exert its inhibitory effects on oGd/r-induced apoptosis by suppressing apoptosis-related genes.…”

Roles of CaMKIIβ in the neurotoxicity induced by ropivacaine hydrochloride in dorsal root ganglion

“…CaMKIIb, a subtype of CaMK II, is widely distributed in the central nervous system. Studies have shown that CaMKIIb is related to cerebral ischemiareperfusion injury and the formation of learning and memory [21,22]. CaMKIIb is one important factor for the neurons physiological activity.…”