PDF《Lithium》

Current Drug Metabolism, 2009, 10, 000-000

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2009 Bentham Science Publishers Ltd. Calpains as a Target for Therapy of Neurodegenerative Diseases: Putative Role of Lithium Antoni Camins, Natalia Crespo-Biel, Félix Junyent, Ester Verdaguer, Anna M. Canudas and Mercè Pallàs* Unitat de Farmacologia i Farmacognòsia Facultat de Farmàcia, Institut de Biomedicina (IBUB), Centros de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Universitat de Barcelona. Nucli Universitari de Pedralbes,

08028 Barcelona, Spain Abstract: Lithium is a simple cation that has been used clinically since

1950 for the treatment of bipolar disorder. However in the last decade numerous studies either using animal models or human trials suggest that this cation may delay progression of neurodegenerative diseases. One of the main challenges facing researchers in the neurosciences is to identify key molecules in neuronal apoptosis. This would facili- tate the identification of targets in order to design drugs for the treatment of Alzheimer'

s disease, Parkinson'

s disease and other neuro- logical disorders. Although enormous effort has been made in the past few years and it has been demonstrated that the mitochondria comprise a key component of the neuronal apoptotic route, it seems that in addition to the mitochondria other intracellular components are implicated in this process. It has been proposed that DNA damage and re-entry into the cell cycle or the activation of different prote- ases, such as calpain, could constitute a common pathway in the apoptotic process and thus death processes in neurological diseases. The hypothesis about the implication of calpain in neuronal cell death is supported by existing data on neurodegenerative disorders in the brains of patients who show an increase in proteolytic activity of calpain compared with control brains. Indeed, studies performed in neu- ronal cell preparations suggest that activation of this protease is accompanied by other features such as structural modifications of the cy- toskeleton, cleavage of several receptors, activation of kinases, such as cdk5 or GSK3?, etc. Here, we summarize the potential routes in- volved in neurodegenerative disorders related to calpain activation, mainly those connected with changes in calcium homeostasis ma- chinery, activation of kinase pathways, transcription factors, and the cell cycle. Keywords: Neurodegeneration, calcium homeostasis, cytoskeleton, kinases, DNA damage, lithium, calpain, signal transduction, neurodegen- erative diseases, tau kinases, apoptosis, cell cycle control. 1. INTRODUCTION An increase in intracellular calcium concentration has been identified as one of the main elements in the cellular response to acute insults such as ischemia or excitotoxicity. In addition, distur- bances in calcium homeostasis have been found in tissues of older patients and in diseases linked to aging, such as Alzheimer'

s dis- ease. Thus, it is likely that some of the actions of calcium play a role in the progression of several neurodegenerative diseases. These calcium-dependent processes, which represent a point of conver- gence among a diverse group of degenerative mechanisms, are potential targets against which pharmacological action can be taken to halt degeneration. A common observation in this kind of pathol- ogy is the activation of the cysteine protease calpain, a non- lysosomal calcium-dependent enzyme. Calpain (EC 3.4.22.17), the prototypical cytosolic calcium-dependent cysteine proteinase, has been studied extensively, since its ubiquitous expression, at least in animal cells, suggests its indispensable physiological function as one of the cellular receptors of calcium ions [1,2]. Calpain is involved in an increasing number of pathological situations (Table 1). Different roles have been described for this enzyme, both direct and indirect, in intracellular processes, includ- ing mobility, cell apoptosis, cell differentiation and regulation of the cell cycle. Calpain is also involved in synaptic transmission, although prolonged abnormal activation may result in disruption through neural mechanisms of signalling and apoptosis. 2. THE CALPAIN FAMILY The first calpain was discovered