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MicroRNA Changes in Preconditioning-Induced Neuroprotection.

ABSTRACT: Preconditioning is a paradigm in which sublethal stress-prior to a more injurious insult-induces protection against injury. In the central nervous system (CNS), preconditioning against ischemic stroke is induced by short durations of ischemia, brief seizures, exposure to anesthetics, and other stresses. Increasing evidence supports the contribution of microRNAs (miRNAs) to the pathogenesis of cerebral ischemia and ischemic tolerance induced by preconditioning. Studies investigating miRNA changes induced by preconditioning have to date identified 562 miRNAs that change expression levels after preconditioning, and 15% of these changes were reproduced in at least one additional study. Of miRNAs assessed as changed by preconditioning in more than one study, about 40% changed in the same direction in more than one study. Most of the studies to assess the role of specific miRNAs in the neuroprotective mechanism of preconditioning were performed in vitro, with fewer studies manipulating individual miRNAs in vivo. Thus, while many miRNAs change in response to preconditioning stimuli, the mechanisms underlying their effects are not well understood. The data does suggest that miRNAs may play significant roles in preconditioning-induced neuroprotection. This review focuses on the current state of knowledge of the possible role of miRNAs in preconditioning-induced cerebral protection.

SUBMITTER: Bell JD

PROVIDER: S-EPMC5701644 | biostudies-other | 2017 Dec

REPOSITORIES: biostudies-other

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MicroRNA Changes in Preconditioning-Induced Neuroprotection.

Bell Josh D JD Cho Jang-Eun JE Giffard Rona G RG

Translational stroke research 20170623 6

Preconditioning is a paradigm in which sublethal stress-prior to a more injurious insult-induces protection against injury. In the central nervous system (CNS), preconditioning against ischemic stroke is induced by short durations of ischemia, brief seizures, exposure to anesthetics, and other stresses. Increasing evidence supports the contribution of microRNAs (miRNAs) to the pathogenesis of cerebral ischemia and ischemic tolerance induced by preconditioning. Studies investigating miRNA changes ...[more]

PMID: 28646450

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Project description:BackgroundIt has been reported that ischemia and ischemic preconditioning (IPC) have different effects on the expression of tuberous sclerosis complex 1 (TSC1), which may contribute to the tolerance to ischemia/hypoxia with the increase of autophagy. The mechanisms of TSC1 differential expression are still unclear under ischemia/IPC conditions in hippocampal Cornu Ammon 1 (CA1) and Cornu Ammon 3 (CA3) area neuronal cells. While we have shown that 5-Aza-CdR, a DNA methyltransferase inhibitor, can upregulate TSC1 and increase hypoxic tolerance by autophagy in vivo and in vitro, in this study, we examined whether DNA methylation was involved in the differential expression of TSC1 in the CA1 and CA3 regions induced by hypoxic preconditioning (HPC).MethodsLevel of rapamycin (mTOR) autophagy, a downstream molecular pathway of TSC1/TSC2 complex, was detected in HPC mouse hippocampal CA1 and CA3 areas as well as in the HPC model of mouse hippocampal HT22 cells. DNA methylation level of TSC1 promoter (-720 bp~ -360 bp) was determined in CA1 and CA3 areas by bisulfite-modified DNA sequencing (BMDS). At the same time, autophagy was detected in HT22 cells transfected with GFP-LC3 plasmid. The role of TSC1 in neuroprotection was measured by cell viability and apoptosis, and the role of TSC1 in metabolism was checked by ATP assay and ROS assay in HT22 cells that overexpressed/knocked down TSC1.ResultsHPC upregulated the expression of TSC1, downregulated the level of P-mTOR (Ser2448) and P-p70S6K (Thr389), and enhanced the activity of autophagy in both in vivo and in vitro. The increased expression of TSC1 in HPC may depend on its DNA hypomethylation in the promoter region in vivo. HPC also could reduce energy consumption in HT22 cells. Overexpression and knockdown of TSC1 can affect cell viability, cell apoptosis, and metabolism in HT22 cells exposed to hypoxia.ConclusionTSC1 expression induced by HPC may relate to the downregulation of its DNA methylation level with the increase of autophagy and the decrease of energy demand.

Project description:Background and purpose: A major gap in the field of ischemic preconditioning (IPC) is whether or not long-lasting neuroprotection can be achieved. Moreover, the specific mechanisms underlying IPC and how they can be translated into the clinic remain uncertain. To fill these gaps, we tested the hypothesis that IPC exerts long-lasting structural and functional neuroprotection against ischemic stroke through the master gatekeeper of antioxidant defenses, nuclear factor erythroid 2-related factor 2 (Nrf2). We also tested whether the brain could be pharmaceutically preconditioned with a potent and blood-brain barrier-permeable Nrf2 activator, 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-trifluoethyl amide (CDDO-TFEA).Methods: IPC was induced by transient middle cerebral artery occlusion (MCAO) for 12 min, and ischemic stroke was generated by MCAO for 60 min in wild-type (WT) or Nrf2 knockout (KO) mice. Sensorimotor function, learning/memory skills, and brain tissue loss were measured up to 35 days after stroke. Primary rodent cortical neurons from wildtype (WT) and Nrf2 KO mice were subjected to lethal oxygen-glucose deprivation (OGD) or a brief OGD episode as a preconditioning (PC) stimulus before OGD. Cell viability/death, lipid electrophile generation, and Nrf2 activation were measured. CDDO-TFEA or its vehicle was administered in vivo for three consecutive days before MCAO. Tissue loss and neurological tests were performed 35 days after stroke.Results: IPC significantly reduced sensorimotor deficits, post-stroke cognitive impairments, and brain tissue loss, 35 days after MCAO in WT mice. These enduring protective effects of IPC were inhibited in Nrf2 KO mice. In neuronal cultures, PC also endowed primary neurons with ischemic tolerance against OGD-induced cell death, an effect that was abolished by loss of Nrf2 expression in KO neurons. PC induced the generation of low levels of lipid electrophiles and led to activation of the Nrf2 pathway. The mechanism underlying IPC may be translatable, as exogenous administration of the Nrf2 activator CDDO-TFEA significantly reduced neurological dysfunction and ischemic brain damage after MCAO.Conclusions: IPC provides long-lasting neuroprotection against ischemic brain injury and post-stroke cognitive dysfunction. Nrf2 activation plays a key role in this beneficial outcome and is a promising therapeutic target for the attenuation of ischemic brain injury.

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MicroRNA Changes in Preconditioning-Induced Neuroprotection.

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MicroRNA Changes in Preconditioning-Induced Neuroprotection.

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