Chapter 2. Neuronal Cell Death and Strategies for Neuroprotection

Abstract

Publisher Summary Necrotic cell death, prominent in acute neurological conditions, such as stroke, is characterized by swelling of the cell and disruption of the internal and external membranes and cell lysis. Acute neuronal death is easily modeled in primary neuronal cell culture and brain slices. In apoptosis, cells undergo nuclear condensation, fragmentation, and nuclear fragments, along with intracellular organelles. The apoptotic process is energy dependent, and in some instances requires ongoing RNA and protein synthesis. High levels of intracellular calcium [Ca 2+ ] i is thought to be the primary causative event in mediating necrotic neuronal death. Calcium enters the neuron, through a variety of mechanisms, including ligand-gated ion channels, such as the N-methyl-D-aspartate (NMDA) glutamate receptor, voltage-gated calcium channels, leak channels, and reversal of the Na + -Ca 2+ anti-porter. Neurons also have inositol trisphosphate receptors (IPS) on intracellular organelles that can liberate calcium from intracellular stores. Alterations in the mosaic of phosphorylated products, with concomitants, increase and decrease in the activity of cellular enzymes, and ion channels, influence the expression of immediate early genes (IEGs) that is involved in programmed cell death. Sporadic energy supplies disrupt ion homeostasis as in focal ischemia, where depolarization in the penumbra is initially moderate and/or intermittent although adenosine triphosphate (ATP) is produced. Important clues, regarding apoptotic cell death, have come from genetic studies in the nematode, caenorhabditis elegans.