Activation of Akt by lithium: pro-survival pathways in aging.
The effects of lithium on senescence were investigated using the senescence-accelerated mouse prone 8 (SAMP8) mice and cultures of aging cerebellar granule cells. Our in vitro findings, using cerebellar granule neurons, demonstrate that lithium (1-10mM) exerts neuroprotective effects in young cultures (7-8 days) against LY294002-induced Akt inhibition. Furthermore, lithium (10mM) inhibits GSK-3beta activity by upregulating p-GSK-3beta (ser-9) and increases p-FOXO1 (Ser256) suggesting an effective anti-apoptotic effect. Our data also showed that lithium in aged cultures exerts anti-apoptotic effects via Akt activation and consequent inhibition of downstream targets regulated by this enzyme. Finally, the administration of lithium to senescence-accelerated mice (SAMP8) and senescence-accelerated resistant mice (SAMR1) at 3 months of age also caused increased Akt activity and p-FoxO-1. These results demonstrate the effectiveness of lithium in preventing age-related neural loss and the potential therapeutic applications of lithium in treatment/prevention of neurological disease.
Tajes
Marta
M
Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina, Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.
Yeste-Velasco
Marc
M
Zhu
Xiongwei
X
Chou
Steven P
SP
Smith
Mark A
MA
Pallàs
Mercè
M
Camins
Antoni
A
Casadesús
Gemma
G
D000375:Aging / Q000187:drug effects* / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D008094:Lithium / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D046509:Tissue Culture Techniques
D047428:Protein Kinase Inhibitors; D008094:Lithium; D051057:Proto-Oncogene Proteins c-akt