Calpains as a Target for Therapy of Neurodegenerative Diseases: Putative Role of Lithium

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 facilitate the identification of targets in order to design drugs for the treatment of Alzheimer's disease, Parkinson's disease and other neurological 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 proteases, 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 neuronal cell preparations suggest that activation of this protease is accompanied by other features such as structural modifications of the cytoskeleton, cleavage of several receptors, activation of kinases, such as cdk5 or GSK3 beta, etc. Here, we summarize the potential routes involved in neurodegenerative disorders related to calpain activation, mainly those connected with changes in calcium homeostasis machinery, activation of kinase pathways, transcription factors, and the cell cycle.