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

• Main Authors: Bei Sun (Author), Hao Ou (Author), Fei Ren (Author), Ye Huan (Author), Tao Zhong (Author), Min Gao (Author), Hongwei Cai (Author)
• Format: Book
• Published: BMC, 2018-11-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.1186/s10020-018-0054-1; 1076-1551; 1528-3658
• Keywords: Propofol; Oxygen-glucose deprivation and re-oxygenation; Autophagy; Ca2+/CaMKKβ/AMPK/mTOR; Therapeutics. Pharmacology; RM1-950; Biochemistry; QD415-436
• Source: Molecular Medicine, Vol 24, Iss 1, Pp 1-11 (2018)

Abstract Background The 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. Methods Cultured primary rat cerebral cortical neurons were treated with oxygen-glucose deprivation and re-oxygenation (OGD/R) to mimic cerebral I/R injury in vitro. Results Compared 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. Conclusion Our 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.