Akt activation improves microregional oxygen supply/consumption balance after cerebral ischemia-reperfusion

Weiss, Harvey R.; Z., Oak; Kiss, Geza; Liu, Xia; Damito, Stacey; Jacinto, Estela

doi:10.1016/j.brainres.2018.01.019

Cited by 21 publications

(12 citation statements)

References 28 publications

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“…The inhibition of S6K1 is known to activate PI3K/Akt through a negative feedback loop (Kim et al, 2017), and the activation of PI3K/Akt may be needed for neuronal survival in cerebral ischemia-reperfusion as shown in our previous study (Weiss et al, 2018). mTORC1 is also involved in cell survival through the activation of S6K1-pS6 and antiapoptotic protein Bcl-2 (Shi et al, 2011;Kim et al, 2017;Murugan, 2019).…”

Section: Figure 3 | (A)mentioning

confidence: 56%

Rapalink-1 Increased Infarct Size in Early Cerebral Ischemia–Reperfusion With Increased Blood–Brain Barrier Disruption

Liu

Cofano

et al. 2021

Front. Physiol.

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It has been reported that the mechanistic target of rapamycin (mTOR) pathway is involved in cerebral ischemia–reperfusion injury. One of the important pathological changes during reperfusion after cerebral ischemia is disruption of blood–brain barrier (BBB). Rapamycin, a first-generation mTOR inhibitor, produces divergent effects on neuronal survival and alteration in BBB disruption. In this study, we investigated how Rapalink-1, a third-generation mTOR inhibitor, would affect neuronal survival and BBB disruption in the very early stage of cerebral ischemia–reperfusion that is within the time window of thrombolysis therapy. The middle cerebral artery occlusion (MCAO) was performed in rats under isoflurane anesthesia with controlled ventilation. Of note, 2 mg/kg of Rapalink-1 or vehicle was administered intraperitoneally 10 min after MCAO. After 1 h of MCAO and 2 h of reperfusion, the transfer coefficient (Ki) of 14C-α-aminoisobutyric acid (104 Da) and the volume of 3H-dextran (70,000 Da) distribution were determined to assess the degree of BBB disruption. At the same time points, phosphorylated S6 (Ser240/244) and Akt (Ser473) as well as matrix metalloproteinase-2 (MMP2) protein level were determined by Western blot along with the infarct size using tetrazolium stain. Rapalink-1 increased the Ki in the ischemic-reperfused cortex (IR-C, +23%, p < 0.05) without a significant change in the volume of dextran distribution. Rapalink-1 increased the percentage of cortical infarct out of the total cortical area (+41%, p < 0.005). Rapalink-1 significantly decreased phosphorylated S6 and Akt to half the level of the control rats in the IR-C, which suggests that both of the mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2) were inhibited. The MMP2 level was increased suggesting that BBB disruption could be aggravated by Rapalink-1. Taken together, our data suggest that inhibiting both mTORC1 and mTORC2 by Rapalink-1 could worsen the neuronal damage in the early stage of cerebral ischemia–reperfusion and that the aggravation of BBB disruption could be one of the contributing factors.

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Section: Figure 3 | (A)mentioning

confidence: 56%

Rapalink-1 Increased Infarct Size in Early Cerebral Ischemia–Reperfusion With Increased Blood–Brain Barrier Disruption

Liu

Cofano

et al. 2021

Front. Physiol.

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“…In addition, a previous study demonstrated that the JNK pathway, which is a MAPK signaling pathway, induces apoptosis following IR injury via the mitochondrial and death receptor pathways (94); as such, inhibiting the JNK pathway could protect neurons from injury. The PI3K/Akt signaling pathway is widely distributed in various cells and is a signal transduction pathway involved in cell survival, proliferation and differentiation regulation (95)(96)(97). Activation of the PI3K/Akt signaling pathway inhibits apoptosis via multiple pathways, reduces IR damage and exerts neuroprotective effects (98,99).…”

Section: Discussionmentioning

confidence: 99%

Advancement in research on the role of the transient receptor potential vanilloid channel in cerebral ischemic injury (Review)

Xie

et al. 2021

Exp Ther Med

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Stroke is a common critical disease occurring in middle-aged and elderly individuals, and is characterized by high morbidity, lethality and mortality. As such, it is of great concern to medical professionals. The aim of the present review was to investigate the effects of transient receptor potential vanilloid (TRPV) subtypes during cerebral ischemia in ischemia-reperfusion animal models, oxygen glucose deprivation and in other administration cell models in vitro to explore new avenues for stroke research and clinical treatments. TRPV1, TRPV2 and TRPV4 employ different methodologies by which they confer protection against cerebral ischemic injury. TRPV1 and TRPV4 are likely related to the inhibition of inflammatory reactions, neurotoxicity and cell apoptosis, thus promoting nerve growth and regulation of intracellular calcium ions (Ca 2+ ). The mechanisms of neuroprotection of TRPV1 are the JNK pathway, N-methyl-D-aspartate (NMDA) receptor and therapeutic hypothermia. The mechanisms of neuroprotection of TRPV4 are the PI3K/Akt pathways, NMDA receptor and p38 MAPK pathway, amongst others. The mechanisms by which TRPV2 confers its protective effects are predominantly connected with the regulation of nerve growth factor, MAPK and JNK pathways, as well as JNK-dependent pathways. Thus, TRPVs have the potential for improving outcomes associated with cerebral ischemic or reperfusion injuries. The protection conferred by TRPV1 and TRPV4 is closely related to cellular Ca 2+ influx, while TRPV2 has a different target and mode of action, possibly due to its expression sites. However, in light of certain contradictory research conclusions, further experimentation is required to clarify the mechanisms and specific pathways by which TRPVs act to alleviate nerve injuries.

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“…The analysis of Cyt c phosphorylation state post-treatment resulted in complete dephosphorylation of Cyt c in the presence of wortmannin, suggesting a potential role for Akt in mediating this pathway. Interestingly, several studies have shown that Akt activator SC79 is an effective treatment for cerebral ischemia/reperfusion injury in animal models [ 54 , 55 , 56 ]. We and others have shown that activated, phosphorylated Akt translocates to the mitochondrial IMS where Cyt c resides [ 34 , 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Brain-Specific Serine-47 Modification of Cytochrome c Regulates Cytochrome c Oxidase Activity Attenuating ROS Production and Cell Death: Implications for Ischemia/Reperfusion Injury and Akt Signaling

Kalpage

Wan

Morse

et al. 2020

Cells

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We previously reported that serine-47 (S47) phosphorylation of cytochrome c (Cytc) in the brain results in lower cytochrome c oxidase (COX) activity and caspase-3 activity in vitro. We here analyze the effect of S47 modification in fibroblast cell lines stably expressing S47E phosphomimetic Cytc, unphosphorylated WT, or S47A Cytc. Our results show that S47E Cytc results in partial inhibition of mitochondrial respiration corresponding with lower mitochondrial membrane potentials (ΔΨm) and reduced reactive oxygen species (ROS) production. When exposed to an oxygen-glucose deprivation/reoxygenation (OGD/R) model simulating ischemia/reperfusion injury, the Cytc S47E phosphomimetic cell line showed minimal ROS generation compared to the unphosphorylated WT Cytc cell line that generated high levels of ROS upon reoxygenation. Consequently, the S47E Cytc cell line also resulted in significantly lower cell death upon exposure to OGD/R, confirming the cytoprotective role of S47 phosphorylation of Cytc. S47E Cytc also resulted in lower cell death upon H2O2 treatment. Finally, we propose that pro-survival kinase Akt (protein kinase B) is a likely mediator of the S47 phosphorylation of Cytc in the brain. Akt inhibitor wortmannin abolished S47 phosphorylation of Cytc, while the Akt activator SC79 maintained S47 phosphorylation of Cytc. Overall, our results suggest that loss of S47 phosphorylation of Cytc during brain ischemia drives reperfusion injury through maximal electron transport chain flux, ΔΨm hyperpolarization, and ROS-triggered cell death.

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Akt activation improves microregional oxygen supply/consumption balance after cerebral ischemia-reperfusion

Cited by 21 publications

References 28 publications

Rapalink-1 Increased Infarct Size in Early Cerebral Ischemia–Reperfusion With Increased Blood–Brain Barrier Disruption

Rapalink-1 Increased Infarct Size in Early Cerebral Ischemia–Reperfusion With Increased Blood–Brain Barrier Disruption

Advancement in research on the role of the transient receptor potential vanilloid channel in cerebral ischemic injury (Review)

Brain-Specific Serine-47 Modification of Cytochrome c Regulates Cytochrome c Oxidase Activity Attenuating ROS Production and Cell Death: Implications for Ischemia/Reperfusion Injury and Akt Signaling

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