Kainate-induced toxicity in the hippocampus: potential role of lithium.
OBJECTIVE
We investigated the neuroprotective effects of lithium in an experimental neurodegeneration model gated to kainate (KA) receptor activation.


METHODS
The hippocampus from KA-treated mice and hippocampal cell cultures were used to evaluate the pathways regulated by chronic lithium pretreatment in both in vivo and in vitro models.


RESULTS
Treatment with KA, as measured by fragmentation of alpha-spectrin and biochemically, induced the activation of calpain resulting in p35 cleavage to p25, indicating activation of cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase-3ss (GSK-3ss) and an increase in tau protein phosphorylation. Treatment with lithium reduced calpain activation and reduced the effects of cdk5 and GSK-3ss on tau. KA treatment of cultures resulted in neuronal demise. According to nuclear condensed cell counts, the addition of lithium to neuronal cell cultures (0.5-1 mM) a few days before KA treatment had neuroprotective and also antiapoptotic effects. The action of lithium on calpain/cdk5 and GSK-3ss pathways produced similar results in vivo. As calpain is activated by an increase in intracellular calcium, we showed that lithium reduced calcium concentrations in basal and KA-treated hippocampal cells, which was accompanied by an increase in NCX3, a Na+/Ca2+ exchanger pump.


CONCLUSIONS
A robust neuroprotective effect of lithium in the excitotoxic process induced by KA in mouse hippocampus was demonstrated via modulation of calcium entry and the subsequent inhibition of the calpain pathway. These mechanisms may act in an additive way with other mechanisms previously described for lithium, suggesting that it may be useful as a possible therapeutic strategy for Alzheimer's disease.
Crespo-Biel
Natalia
N
Unitat de Farmacologia i Farmacognòsia i Institut de Biomedicina (IBUB) i Centro de Investigación de Biomedicina en Red de Enfermedades Neurodegenerativas (CIBERNED), Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, Barcelona, Spain.
Camins
Antoni
A
Canudas
Anna M
AM
Pallàs
Mercè
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004195:Disease Models, Animal; D038341:Glycogen Synthase Kinases / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007608:Kainic Acid / Q000633:toxicity; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism
D018696:Neuroprotective Agents; D016875:tau Proteins; D038341:Glycogen Synthase Kinases; D051360:Cyclin-Dependent Kinase 5; D002154:Calpain; D018021:Lithium Chloride; D007608:Kainic Acid; D002118:Calcium