Role of glycogen synthase kinase-3β in ketamine-induced developmental neuroapoptosis in rats

Liu, Jia-Ren; Baek, Chong Wha; Han, Xiao; Shoureshi, Poone; Soriano, Sulpicio G.

doi:10.1093/bja/aet057

Cited by 46 publications

(22 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, it has been reported that activation of PI3K/Akt/GSK-3β signaling had a protective effect on ketamine-induced neuroapoptosis [21,[43][44][45]. Moreover, Liu et al reported that lithium, an inhibitor of GSK-3β, could attenuate ketamine-induced neuroapoptosis [46]. Interestingly, lithium carbonate is an important therapeutic drug for psychosis while abuse of ketamine may induce psychosis [47].…”

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Protects Neural Stem Cells from Ketamine-Induced Injury

Lü

Shan

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Ketamine inhibits the proliferation of neural stem cells (NSCs) and disturbs normal neurogenesis. Dexmedetomidine provides neuroprotection against volatile anesthetic-induced neuroapoptosis and cognitive impairment in the developing brain. Whether it may protect NSCs from ketamine-induced injury remains unknown. In this study, we investigated the protective effects of dexmedetomidine on ketamine-exposed NSCs and explored the mechanisms potentially involved. Methods: Primary NSC cultures were characterized using immunofluorescence. Cell viability was determined using a Cell Counting Kit 8 assay. Proliferation and apoptosis were assessed with BrdU incorporation and TUNEL assays, respectively. Protein levels of cleaved caspase-3, phosphorylated protein kinase B (p-Akt), and glycogen synthase kinase-3β (p-GSK-3β) were quantified using western blotting. Results: Ket-amine significantly decreased NSC viability and proliferation and increased their apoptosis. Dexmedetomidine increased NSC proliferation and decreased their apoptosis in a dose-dependent manner. Furthermore, dexmedetomidine pretreatment notably augmented the viability and proliferation of ketamine-exposed NSCs and reduced their apoptosis. Moreover, dexmedetomidine lessened caspase-3 activation and increased p-Akt and p-GSK-3β levels in NSCs exposed to ketamine. The protective effects of dexmedetomidine on ketamine-exposed NSCs could be partly reversed by the PI3K inhibitor LY294002. Conclusions: Collectively, these findings indicate that dexmedetomidine may protect NSCs from ketamine-induced injury via the PI3K/Akt/GSK-3β signaling pathway.

show abstract

Section: Discussionmentioning

confidence: 99%

Dexmedetomidine Protects Neural Stem Cells from Ketamine-Induced Injury

Lü

Shan

et al. 2018

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Understanding the mechanism underlying astrocytes-induced paracrine effect can help develop potential therapeutic strategies to avoid propofol-induced neurotoxicity. PI3K/Akt and glycogen synthase kinase (GSK3β) have been shown to be involved in various cell survival pathways including developing human embryonic stem cell-derived neurons 23,24,53 . Blockage of Akt, a negative regulator of GSK3β or activation of GSK3β caused cells to undergo the apoptotic process 54,55 .…”

Section: Discussionmentioning

confidence: 99%

“…This toxic effect was associated with the decrease in Akt and GSK3β phosphorylation (p-GSK3β) and co-administration of lithium with ketamine attenuated the neuronal death through deactivation of GSK3β. 53 Recently, evidence linking propofol-induced neurotoxicity and defective STAT3/SPOUT2/Akt pathway was reported in human neurons 23 . Despite convincing evidence of involvement of Akt/ GSK3β pathway in developing neuronal death, whether astrocyte-derived BDNF regulates this pathway to increase neuronal survival in propofol-injured neurons is unknown.…”

Section: Discussionmentioning

confidence: 99%

Insufficient Astrocyte-Derived Brain-Derived Neurotrophic Factor Contributes to Propofol-Induced Neuron Death Through Akt/Glycogen Synthase Kinase 3β/Mitochondrial Fission Pathway

Liu

Yan²,

Inagaki³

et al. 2017

Anesthesia &Amp; Analgesia

View full text Add to dashboard Cite

BACKGROUND Growing animal evidence demonstrates that prolonged exposure to propofol during brain development induces widespread neuronal cell death, but there is little information on the role of astrocytes. Astrocytes can release neurotropic growth factors such as brain-derived neurotropic factor (BDNF), which can exert the protective effect on neurons in paracrine fashion. We hypothesize that during propofol anesthesia, BDNF released from developing astrocytes may not be sufficient to prevent propofol-induced neurotoxicity. METHODS Hippocampal astrocytes and neurons isolated from neonatal Sprague Dawley rats were exposed to propofol at a clinically relevant dose of 30 μM or dimethyl sulfoxide as control for 6 h. Propofol-induced cell death was determined by propidium iodide (PI) staining in astrocyte-alone cultures, neuron-alone cultures, or co-cultures containing either low or high density of astrocytes [1:9 or 1:1 ratio of astrocytes to neurons (ANR), respectively)]. The astrocyte-conditioned medium was collected 12 h following propofol exposure and measured by protein array assay. BDNF concentration in astrocyte-conditioned medium was quantified using ELISA. Neuron-alone cultures were treated with BDNF, tyrosine receptor kinase B (TrkB) inhibitor Cyclotraxin-B, glycogen synthase kinase 3β (GSK3β) inhibitor CHIR99021, or mitochondrial fission inhibitor Mdivi-1 prior to propofol exposure. Western blot was performed for quantification of the level of Akt and GSK3β. Mitochondrial shape was visualized through TOM20 staining. RESULTS Propofol increased cell death in neurons by 1.8 fold [% of PI-positive cells (PI%) =18.6, 95% CI=15.2–21.9, P<0.05], but did not influence astrocyte viability. The neuronal death was attenuated by a high ANR (1:1 co-cultures) [fold change (FC) =1.17, 95% CI=0.96–1.38, P<0.05), but not with a low ANR (1:9 co-cultures)] (FC=1.87, 95% CI=1.48–2.26, P>0.05). Astrocytes secreted BDNF in a cell density-dependent way and propofol decreased BDNF secretion from astrocytes. Administration of BDNF, CHIR99021, or Mdivi-1 significantly attenuated the propofol-induced neuronal death and aberrant mitochondria in neuron-alone cultures (FC=0.8, 95% CI=0.62–0.98; FC=1.22, 95% CI=1.11–1.32; FC=1.35, 95% CI=1.16–1.54 respectively, P<0.05) and the co-cultures with a low ANR (1:9) (FC=0.85, 95% CI=0.74–0.97; FC=1.08, 95% CI=0.84–1.32; FC=1.25, 95% CI=1.1–1.39 respectively, P<0.05) Blocking BDNF receptor or Akt activity abolished astrocyte-induced neuroprotection in the co-cultures with a high ANR (1:1). CONCLUSIONS Astrocytes attenuate propofol-induced neurotoxicity through BDNF-mediated cell survival pathway suggesting multiple neuroprotective strategies such as administration of BDNF, astrocyte-conditioned medium, decreasing mitochondrial fission, or inhibition of GSK3β.

show abstract

“…The Akt pathways are important intracellular signaling systems that act downstream of the neurotrophin receptors (Mullen et al, 2012). Previous studies indicated that ketamine induces neuroapoptosis by blocking the NMDA receptor activity and decreasing the pAkt levels (Shang et al, 2007;Straiko et al, 2009;Liu et al, 2013b;Li et al, 2013) and that the Akt pathway prevents ketamineinduced neuroapoptosis (Shang et al, 2007;Liu et al, 2013b;Li et al, 2013). Moreover, the NMDAR antagonist MK-801 triggers neuroapoptosis in the neonatal cortex by depressing BDNFAkt signaling (Dzietko et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

17β-estradiol attenuates ketamine-induced neuroapoptosis and persistent cognitive deficits in the developing brain

Wang

et al. 2014

Brain Research

View full text Add to dashboard Cite

Role of glycogen synthase kinase-3β in ketamine-induced developmental neuroapoptosis in rats

Abstract: Ketamine-induced neuroapoptosis is associated with a temporal decrease in GSK-3β phosphorylation, and simultaneous administration of lithium mitigated this response. These findings suggest that GSK-3β is activated during this ketamine-induced neuroapoptosis.

Cited by 46 publications

References 37 publications

Dexmedetomidine Protects Neural Stem Cells from Ketamine-Induced Injury

Dexmedetomidine Protects Neural Stem Cells from Ketamine-Induced Injury

Insufficient Astrocyte-Derived Brain-Derived Neurotrophic Factor Contributes to Propofol-Induced Neuron Death Through Akt/Glycogen Synthase Kinase 3β/Mitochondrial Fission Pathway

17β-estradiol attenuates ketamine-induced neuroapoptosis and persistent cognitive deficits in the developing brain

Contact Info

Product

Resources

About