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A large number of the disease states dealt with by neurologists and neurosurgeons (and against which neurotherapeutics will be directed) involve the dysfunction and ultimately the death of neural cells. Examples of such diseases include stroke, Alzheimer disease and other neurodegenerative diseases, and neurotrauma. In addition, central nervous system neoplasms also display abnormalities of cell death, but in contrast to the preceding examples, they feature a decrease rather than an increase in cell death.
It has become increasingly clear that cells may take more than one pathway to death, and that, in contrast to previous beliefs, cells may play an active role in their own demise. Until recently, a major focus of research was on extrinsic factors that contribute to cell loss (eg, hypoxia, ischemia, and glucose deprivation). However, it has become clear that intrinsic factors also play crucial roles in the outcomes of neural insults, and that cells can effectively set their own probabilities of death across a relatively wide range. Therefore, it is of interest to examine the biochemical pathways of neural cell death and the modulation thereof.
Broadly speaking, cells may die passively or actively. When the cell's role is passive, this is referred to as necrosis. When the cell undergoes active, "suicidal" death, this is referred to as programmed cell death (PCD). To date, more than 50 000 research papers have been published on one form of PCD, apoptosis, which is characterized by the activation of a set of cell death cysteine proteases dubbed caspases. These cleave specific substrates (more than 100 have been identified, and the total number may turn out to be closer to 1000) at specific aspartate residues, leading to the apoptotic phenotype, including nuclear fragmentation, chromatin condensation, internucleosomal DNA fragmentation, membrane blebbing, the budding of cellular fragments (apoptotic bodies), and phagocytosis of the apoptotic cell. However, recent work has reinforced the notion that alternative, nonapoptotic forms of PCD also occur, and may play important roles in disease states. Much less is known about these alternative forms, which include autophagic cell death, paraptosis, and oncosis, among others. In some cases, blocking one form of cell death has been shown to push the cell toward an alternative pathway, and therefore it will be important to develop both markers and modulators for these alternative programmatic cell deaths.
Bredesen D. Which Way Did They Go? Neural Cell Death Pathways. Arch Neurol. 2003;60(2):296. doi:10.1001/archneur.60.2.296-a
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