Lithium-induced activation of Akt and CaM kinase II contributes to its neuroprotective action in a rat microsphere embolism model.
Lithium used in bipolar mood disorder therapy protects neurons from brain ischemic cell death. Here, we documented that lithium administration under microsphere-embolism (ME)-induced brain ischemia restored decreased protein kinase B (Akt) and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activities 24 h after ischemia in rat brain. Akt activation was associated with increased phosphorylation of its potential targets forkhead transcription factor (FKHR) and glycogen synthase kinase-3beta (GSK-3beta). In parallel with decreased CaMKII autophosphorylation, we also found marked dephosphorylation of tau proteins 24-72 h after ME. Increased protein phosphatase 2A (PP2A) activity was found 24 h after ME. Inhibition of increased PP2A activity by lithium treatment apparently mediated restored tau phosphorylation. Taken together, activation of Akt and CaMKII by lithium was associated with neuroprotective activity in ME-induced neuronal injury.
Sasaki
Takuya
T
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
Han
Feng
F
Shioda
Norifumi
N
Moriguchi
Shigeki
S
Kasahara
Jiro
J
Ishiguro
Koichi
K
Fukunaga
Kohji
K
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology; D020520:Brain Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000187:drug effects / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D020766:Intracranial Embolism / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000187:drug effects / Q000378:metabolism; D054648:Protein Phosphatase 2; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D016875:tau Proteins / Q000187:drug effects / Q000378:metabolism; D000071161:Forkhead Box Protein O1
D018692:Antimanic Agents; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D051858:Forkhead Transcription Factors; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018021:Lithium Chloride; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D051057:Proto-Oncogene Proteins c-akt; D012694:Serine; D016875:tau Proteins; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C000605508:Gsk3b protein, rat