PMID- 21886605
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20111110
LR  - 20220408
IS  - 1662-5099 (Electronic)
IS  - 1662-5099 (Linking)
VI  - 4
DP  - 2011
TI  - GSK-3 as a Target for Lithium-Induced Neuroprotection Against Excitotoxicity in 
      Neuronal Cultures and Animal Models of Ischemic Stroke.
PG  - 15
LID - 10.3389/fnmol.2011.00015 [doi]
LID - 15
AB  - The mood stabilizer lithium inhibits glycogen synthase kinase-3 (GSK-3) directly 
      or indirectly by enhancing serine phosphorylation of both alpha and beta isoforms. 
      Lithium robustly protected primary brain neurons from glutamate-induced 
      excitotoxicity; these actions were mimicked by other GSK-3 inhibitors or 
      silencing/inhibiting GSK-3alpha and/or beta isoforms. Lithium rapidly activated Akt to 
      enhance GSK-3 serine phosphorylation and to block glutamate-induced Akt 
      inactivation. Lithium also up-regulated Bcl-2 and suppressed glutamate-induced 
      p53 and Bax. Induction of brain-derived neurotrophic factor (BDNF) was required 
      for lithium's neuroprotection to occur. BDNF promoter IV was activated by GSK-3 
      inhibition using lithium or other drugs, or through gene silencing/inactivation 
      of either isoform. Further, lithium's neuroprotective effects were associated 
      with inhibition of NMDA receptor-mediated calcium influx and down-stream 
      signaling. In rodent ischemic models, post-insult treatment with lithium 
      decreased infarct volume, ameliorated neurological deficits, and improved 
      functional recovery. Up-regulation of heat-shock protein 70 and Bcl-2 as well as 
      down-regulation of p53 likely contributed to lithium's protective effects. 
      Delayed treatment with lithium improved functional MRI responses, which was 
      accompanied by enhanced angiogenesis. Two GSK-3-regulated pro-angiogenic factors, 
      matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor were 
      induced by lithium. Finally, lithium promoted migration of mesenchymal stem cells 
      (MSCs) by up-regulation of MMP-9 through GSK-3beta inhibition. Notably, 
      transplantation of lithium-primed MSCs into ischemic rats enhanced MSC migration 
      to the injured brain regions and improved the neurological performance. Several 
      other GSK-3 inhibitors have also been reported to be beneficial in rodent 
      ischemic models. Together, GSK-3 inhibition is a rational strategy to combat 
      ischemic stroke and other excitotoxicity-related brain disorders.
FAU - Chuang, De-Maw
AU  - Chuang DM
AD  - Molecular Neurobiology Section, National Institute of Mental Health, National 
      Institutes of Health Bethesda, MD, USA.
FAU - Wang, Zhifei
AU  - Wang Z
FAU - Chiu, Chi-Tso
AU  - Chiu CT
LA  - eng
PT  - Journal Article
DEP - 20110809
PL  - Switzerland
TA  - Front Mol Neurosci
JT  - Frontiers in molecular neuroscience
JID - 101477914
PMC - PMC3152742
OTO - NOTNLM
OT  - cerebral ischemia
OT  - excitotoxicity
OT  - glycogen synthase kinase-3
OT  - lithium
OT  - mesenchymal stem cells
EDAT- 2011/09/03 06:00
MHDA- 2011/09/03 06:01
PMCR- 2011/01/01
CRDT- 2011/09/03 06:00
PHST- 2011/06/28 00:00 [received]
PHST- 2011/07/24 00:00 [accepted]
PHST- 2011/09/03 06:00 [entrez]
PHST- 2011/09/03 06:00 [pubmed]
PHST- 2011/09/03 06:01 [medline]
PHST- 2011/01/01 00:00 [pmc-release]
AID - 10.3389/fnmol.2011.00015 [doi]
PST - epublish
SO  - Front Mol Neurosci. 2011 Aug 9;4:15. doi: 10.3389/fnmol.2011.00015. eCollection 
      2011.