Decreased Akt Activity is Associated with Activation of Forkhead Transcription Factor after Transient Forebrain Ischemia in Gerbil Hippocampus

Kawano, Takayuki; Morioka, Motohiro; Yano, Shigetoshi; Hamada, Jun Ichiro; Ushio, Yukitaka; Miyamoto, Eishichi; Fukunaga, Kohji

doi:10.1097/00004647-200208000-00004

Cited by 58 publications

(48 citation statements)

References 59 publications

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“…Our findings extend work showing that brain injury activates FKHR/FKHRL-1 (27,46). The immediacy of FKHR/FKHRL-1 activation after seizures suggests that it could account for increased Bim levels and cell death.…”

Section: Discussionsupporting

confidence: 85%

“…It has previously been demonstrated that blocking of forkhead dephosphorylation with the nonspecific phosphatase inhibitor SOV reduces hippocampal neuronal death following ischemia (27). To gain insight into whether FKHR/FKHRL-1 activation, and, by inference, Bim, contribute significantly to seizure-induced neuronal death in vivo, we used a similar paradigm to block FKHR/FKHRL-1 dephosphorylation during seizures.…”

Section: Seizure-induced Neuronal Death Is Associated With Upregulatimentioning

confidence: 99%

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Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy

Shinoda¹,

Schindler²,

Meller³

et al. 2004

J. Clin. Invest.

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Programmed cell death pathways have been implicated in the mechanism by which neurons die following brief and prolonged seizures, but the significance of proapoptotic Bcl-2 family proteins in the process remains poorly defined. Expression of the death agonist Bcl-2-interacting mediator of cell death (Bim) is under the control of the forkhead in rhabdomyosarcoma (FKHR) transcription factors. This prompted us to examine the response of this pathway to experimental seizures and in hippocampi from patients with intractable temporal lobe epilepsy. A short period of status epilepticus in rats that damaged the hippocampus activated FKHR/FKHRL-1 and induced a significant increase in expression of Bim. Blocking of FKHR/FKHRL-1 dephosphorylation after seizures improved hippocampal neuronal survival in vivo, and Bim antisense oligonucleotides were neuroprotective against seizures in vitro. Inhibition of Akt increased the FKHR/Bim response and DNA fragmentation within the normally resistant cortex. Analysis of hippocampi from patients with intractable epilepsy revealed that Bim levels were significantly lower than in controls and FKHR was inhibited; we were able to reproduce these results experimentally in rats by evoking multiple brief, noninjurious electroshock seizures. We conclude that Bim expression may be a critical determinant of whether seizures damage the brain, and that its control may be neuroprotective in status epilepticus and epilepsy.Nonstandard abbreviations used: B cell lymphoma (Bcl); Bcl-2-associated death promoter (Bad); Bcl-2-associated X protein (Bax); Bcl-2-homologous antagonist/ killer (Bak); Bcl-2 homology domain 3 (BH3); Bcl-2-interacting mediator of cell death (Bim); BH3-interacting domain death agonist (Bid); cornu ammonis (CA); electroencephalogram (EEG); forkhead in rhabdomyosarcoma (FKHR); kainic acid (KA); 27-kDa Cdk-inhibitory protein 1 (p27 Kip1 ); lactate dehydrogenase (LDH); maximal electroshock seizure (MES); sodium orthovanadate (SOV).

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Section: Discussionsupporting

confidence: 85%

Section: Seizure-induced Neuronal Death Is Associated With Upregulatimentioning

confidence: 99%

Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy

Shinoda¹,

Schindler²,

Meller³

et al. 2004

J. Clin. Invest.

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“…Akt/GSK3b signaling and delayed neuronal cell death H Endo et al ischemia include Bad (Saito et al, 2003), prolinerich Akt substrate (Saito et al, 2004), Forkhead transcription factors (Kawano et al, 2002), and endothelial nitric oxide synthase (Hashiguchi et al, 2004). The current study shows that GSK3b is also one of the targets of Akt in the PI3-K signaling pathway after cerebral ischemia.…”

Section: Discussionmentioning

confidence: 50%

Activation of the Akt/GSK3β Signaling Pathway Mediates Survival of Vulnerable Hippocampal Neurons after Transient Global Cerebral Ischemia in Rats

Endo

Nito

Kamada

et al. 2006

J Cereb Blood Flow Metab

173

113

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Recent studies have revealed that the phosphatidylinositol 3-kinase (PI3-K) pathway is involved in apoptotic cell death after experimental cerebral ischemia. The serine-threonine kinase, Akt, functions in the PI3-K pathway and prevents apoptosis by phosphorylation at Ser473 after a variety of cell death stimuli. After phosphorylation, activated Akt inactivates other apoptogenic factors, including glycogen synthase kinase-3b (GSK3b), thereby inhibiting cell death. However, the role of Akt/GSK3b signaling in the delayed death of hippocampal neurons in the CA1 subregion after transient global cerebral ischemia (tGCI) has not been clarified. Transient global cerebral ischemia for 5 mins was induced by bilateral common carotid artery occlusion combined with hypotension. Western blot analysis showed a significant increase in phospho-Akt (Ser473) and phospho-GSK3b (Ser9) in the hippocampal CA1 subregion after tGCI. Immunohistochemistry showed that expression of phospho-Akt (Ser473) and phospho-GSK3b (Ser9) was markedly increased in the vulnerable CA1 subregion, but not in the ischemic-tolerant CA3 subregion. Double staining with phospho-GSK3b (Ser9) and terminal deoxynucleotidyl transferase-mediated uridine 5 0 -triphosphate-biotin nick end labeling showed different cellular distributions in the CA1 subregion 3 days after tGCI. Phosphorylation of Akt and GSK3b was prevented by LY294002, a PI3-K inhibitor, which facilitated subsequent DNA fragmentation 3 days after tGCI. Moreover, transgenic rats that overexpress copper/zinc-superoxide dismutase, which is known to be neuroprotective against delayed hippocampal CA1 injury after tGCI, had enhanced and persistent phosphorylation of both Akt and GSK3b after tGCI. These findings suggest that activation of the Akt/GSK3b signaling pathway may mediate survival of vulnerable hippocampal CA1 neurons after tGCI.

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“…Indeed, both Fas ligand and Bim are induced in the ventricular cardiomyocyte after myocardial ischemia/reperfusion-induced injury (18,30). Moreover, we previously documented the FOXOs-mediated increased expression of Fas ligand and Bim in ischemic brain injury in a mouse bilateral common carotid artery occlusion model (61,62,66,67). VO(OPT) treatments prevented ischemia/reperfusion injury-induced expression of Fas ligand and Bim in rat heart (18,19) and brain (51).…”

Section: +mentioning

confidence: 92%

“…We documented that Bad dephosphorylation in the myocardium is associated with decreased Akt activity following myocardial ischemia/reperfusion injury, and VO(OPT)-induced rescue of Akt activity promoted Bad phosphorylation (18). Akt phosphorylates forkhead transcription factors (FOXOs) such as FKHR and FKHRL1 as downstream targets in cell survival signaling (61,62). Phosphorylation of FOXOs reduces their DNA-binding activities, interferes with interactions with other transcription factors, and promotes nuclear export and tethering in the cytoplasm by binding to 14-3-3 proteins (63).…”

Section: +mentioning

confidence: 99%

Cardioprotection by Vanadium Compounds Targeting Akt-Mediated Signaling

Bhuiyan

Fukunaga

2009

J Pharmacol Sci

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Abstract. Treatment with inorganic and organic compounds of vanadium has been shown to exert a wide range of cardioprotective effects in myocardial ischemia/reperfusion-induced injury, myocardial hypertrophy, hypertension, and vascular diseases. Furthermore, administration of vanadium compounds improves cardiac performance and smooth muscle cell contractility and modulates blood pressure in various models of hypertension. Like other vanadium compounds, we documented bis(1-oxy-2-pyridinethiolato) oxovanadium (IV) [VO(OPT)] as a potent cardioprotective agent to elicit cardiac functional recovery in myocardial infarction and pressure overload-induced hypertrophy. Vanadium compounds activate Akt signaling through inhibition of protein tyrosine phosphatases, thereby eliciting cardioprotection in myocardial ischemia / reperfusion-induced injury and myocardial hypertrophy. Vanadium compounds also promote cardiac functional recovery by stimulation of glucose transport in diabetic heart. We here discuss the current understanding of mechanisms underlying vanadium compound-induced cardioprotection and propose a novel therapeutic strategy targeting for Akt signaling to rescue cardiomyocytes from heart failure.

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Decreased Akt Activity is Associated with Activation of Forkhead Transcription Factor after Transient Forebrain Ischemia in Gerbil Hippocampus

Cited by 58 publications

References 59 publications

Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy

Bim regulation may determine hippocampal vulnerability after injurious seizures and in temporal lobe epilepsy

Activation of the Akt/GSK3β Signaling Pathway Mediates Survival of Vulnerable Hippocampal Neurons after Transient Global Cerebral Ischemia in Rats

Cardioprotection by Vanadium Compounds Targeting Akt-Mediated Signaling

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