Kainate-induced toxicity in the hippocampus: potential role of lithium

Authors

  • Natalia Crespo-Biel,

    1. 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
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  • Antoni Camins,

    1. 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
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  • Anna M Canudas,

    1. 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
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  • Mercè Pallàs

    1. 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
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  • The authors of this paper do not have any commercial associations that might pose a conflict of interest in connection with this manuscript.

Corresponding author:
Mercè Pallàs, Ph.D.
Institut de Biomedicina (IBUB)
Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)
Unitat de Farmacologia i Farmacognòsia
Facultat de Farmàcia
Universitat de Barcelona
Nucli Universitari de Pedralbes
08028, Barcelona, Spain
Fax: 3434035982
E-mail: pallas@ub.edu

Abstract

Crespo-Biel N, Camins A, Canudas AM, Pallàs M. Kainate-induced toxicity in the hippocampus: potential role of lithium.
Bipolar Disord 2010: 12: 425–436. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S.

Objectives:  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 α-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.

Conclusion:  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.

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