LncRNA AC136007.2 alleviates cerebral ischemic-reperfusion injury by suppressing autophagy

Abstract

Differential expression and diagnostic significance of the long noncoding RNA (lncRNA) AC136007.2 has been reported in patients with acute ischemic stroke (AIS). However, its role on disease progression and outcome remains unclear. Here, we employed an oxygen-glucose deprivation/reperfusion (OGD/R) model in neuronal SH-SY5Y cells and performed middle cerebral artery occlusion (MCAO) surgery in rats to investigate the function of AC136007.2 in ischemia-reperfusion (I/R) injury. AC136007.2 expression was determined by RT-qPCR and cell viability was examined using CCK-8, Edu, LDH, and apoptosis assays. Pro-inflammatory cytokine expression was assessed using ELISA. OGD/R downregulated AC136007.2 expression in SH-SY5Y cells, decreased viability by inducing apoptosis, and stimulated secretion of TNF-α, IL-6, and IL-1β. In turn, lentivirus-mediated AC136007.2 overexpression significantly reversed these phenomena. LC3 immunofluorescence and western blotting analyses of LC3-I/II and Beclin-1 expression and AMPK/mTOR phosphorylation status showed that AC136007.2 suppressed autophagy in SH-SY5Y cells via inactivation of AMPK/mTOR signaling. Notably, incubation with the AMPK activator AICAR abolished the pro-survival effect of AC136007.2 upon OGD/R treatment. Importantly, intraventricular injection of AC136007.2 significantly reduced cerebral infarction and brain edema in MCAO rats, as shown by TTC staining and water content measurements. We conclude that AC136007.2 alleviates cerebral I/R injury by suppressing AMPK/mTOR-dependent autophagy.

EGCG protects the mouse brain against cerebral ischemia/reperfusion injury by suppressing autophagy via the AKT/AMPK/mTOR phosphorylation pathway

“…AMP-activated protein kinase (AMPK) plays an important role in keeping the balance of metabolic processes and is reported to be linked with the regulation of autophagy ( Heras-Sandoval et al, 2014 ). Some studies suggested that ischemia postcondition mitigated ischemic stroke by suppressing autophagy via promoting the phosphorylation of AKT and mTOR ( Yang et al, 2019 ; Wang H. et al, 2020 ; Wang M. M. et al, 2020 ; Meng et al, 2021 ), while others revealed that the poststroke treatment ameliorated CIRI through inhibiting autophagy via suppressing the phosphorylation of AKT, AMPK, and mTOR ( Wang J. F. et al, 2018 ; Zhang et al, 2020a ; Ma et al, 2020 ; Liu N. et al, 2021 ; Yang et al, 2021 ; Zhang et al, 2022 ). Therefore, the interaction between the phosphorylation of AKT, AMPK, and mTOR and poststroke treatment-induced autophagy suppression is complicated and remains to be further elucidated.…”

“…Basal autophagic activity exists in cells under physiological conditions, while the process turns more active induced by various stress events including CIRI and plays complex roles ( Wirawan et al, 2012 ). Some studies demonstrated that the activation of autophagy ameliorated CIRI ( Sun et al, 2020b ; Xu et al, 2020 ; Zhang B. et al, 2020 ; Chen et al, 2021 ; Jin et al, 2021 ; Yihao et al, 2021 ; Zha et al, 2021 ), while more research supported that the inhibition of autophagy activation exerted a neuroprotective effect in brain stroke ( Sun et al, 2020a ; Zhang et al, 2020b ; Li and Huang, 2020 ; Mei et al, 2020 ; Shi et al, 2020 ; Wang L. et al, 2020 ; Gu et al, 2021 ; Liu N. et al, 2021 ; Shao et al, 2021 ; Wang C. et al, 2021 ; Xu et al, 2021 ; Yao et al, 2021 ; Zhang et al, 2021 ; Zhao et al, 2021 ). Obviously, the controversial dual role of the induction of autophagy in the ischemic brain is still a hot topic in research and remains to be further investigated.…”

Neuronal Responses to Ischemia: Scoping Review of Insights from Human-Derived In Vitro Models

“…These cytokines can be divided in pro-inflammatory and anti-inflammatory cytokines. In undifferentiated SH-SY5Y (n = 12) and SK-N-SH (n = 1) cell models, expression of pro-inflammatory cytokines (interleukin-1β, interleukin-6, interleukin-18 and interferon γ) was increased after ischemia/hypoxia (Chai et al 2020 ; Dong et al 2021 ; Huang et al 2021 ; Li et al 2019a , b ; Li and Ma 2020 ; Liu et al 2021 ; Meng et al 2021 ; Shi et al 2020 , 2021 ; Yin et al 2021 ; Zhao and Wang 2020 ). Pro-inflammatory cytokines like IL-1β and IL-18 can be activated by NLR family pyrin domain containing 3 (NLRP3) inflammasomes, which comprises NLRP3, ASC, and pro-caspase-1.…”

Dysregulation of mTOR Signaling after Brain Ischemia

“…However, the role of autophagy in cerebral ischemia remains controversial, since current lines of evidence suggest that overactivation of autophagy induces cell death and aggravates ischemic brain injury [ 73 , 85 ]. Several data from in vivo models support the notion that autophagy suppression through the AMPK/mTORC1 pathway after ischemia–reperfusion (tMCAo models) reduces cerebral damage and brain edema, improving the neurological score [ 112 , 113 , 114 ]. This overactivation of autophagy is probably triggered by a dramatic decrease in mTORC1 activity through the upregulation of AMPK and downregulation of the PI3K/Akt pathway induced by the ischemic conditions.…”