Lithium-induced activation of Akt and CaM kinase II contributes to its neuroprotective action in a rat microsphere embolism model

Takuya Sasaki; Feng Han; Norifumi Shioda; Shigeki Moriguchi; Jiro Kasahara; Koichi Ishiguro; Kohji Fukunaga

doi:10.1016/j.brainres.2006.06.009

Lithium-induced activation of Akt and CaM kinase II contributes to its neuroprotective action in a rat microsphere embolism model

Brain Res. 2006 Sep 7;1108(1):98-106. doi: 10.1016/j.brainres.2006.06.009. Epub 2006 Jul 14.

Authors

Takuya Sasaki¹, Feng Han, Norifumi Shioda, Shigeki Moriguchi, Jiro Kasahara, Koichi Ishiguro, Kohji Fukunaga

Affiliation

¹ Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.

PMID: 16843447
DOI: 10.1016/j.brainres.2006.06.009

Abstract

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.

MeSH terms

Animals
Antimanic Agents / pharmacology
Brain Infarction / drug therapy*
Brain Infarction / metabolism
Brain Infarction / physiopathology
Brain Ischemia / drug therapy*
Brain Ischemia / metabolism
Brain Ischemia / physiopathology
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases / drug effects*
Calcium-Calmodulin-Dependent Protein Kinases / metabolism
Disease Models, Animal
Enzyme Activation / drug effects
Enzyme Activation / physiology
Forkhead Transcription Factors / drug effects
Forkhead Transcription Factors / metabolism
Glycogen Synthase Kinase 3 / drug effects
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
Intracranial Embolism / drug therapy
Intracranial Embolism / metabolism
Intracranial Embolism / physiopathology
Lithium Chloride / pharmacology*
Male
Nerve Tissue Proteins / drug effects
Nerve Tissue Proteins / metabolism
Neuroprotective Agents / pharmacology
Phosphoprotein Phosphatases / drug effects
Phosphoprotein Phosphatases / metabolism
Protein Phosphatase 2
Proto-Oncogene Proteins c-akt / drug effects*
Proto-Oncogene Proteins c-akt / metabolism
Rats
Rats, Wistar
Serine / metabolism
Up-Regulation / drug effects
Up-Regulation / physiology
tau Proteins / drug effects
tau Proteins / metabolism

Substances

Antimanic Agents
Forkhead Transcription Factors
Nerve Tissue Proteins
Neuroprotective Agents
tau Proteins
Foxo1 protein, rat
Serine
Glycogen Synthase Kinase 3 beta
Gsk3b protein, rat
Proto-Oncogene Proteins c-akt
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases
Glycogen Synthase Kinase 3
Phosphoprotein Phosphatases
Protein Phosphatase 2
Lithium Chloride