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Neuroprotectants: Cell-Death Based


Introduction

Research in the 1990s provided fundamental discoveries of the molecular mechanisms of apoptosis, one type of cell death. In the nematode Caenorhabditis elegans , the genetic control of the programmed cell death during development was elucidated . Cloning of the cell death–related genes was completed. Among them, ced-3 and ced-4 are death-promoting genes and ced-9 is death inhibiting. The identification of their mammalian homologues suggested that the cell death mechanism might be conserved from nematode to humans. In addition, there was the speculation that the death mechanism might be shared by various types of cells and by various types of death stimuli. A great deal of interest was generated in translating the knowledge to human disease conditions, including cerebrovascular diseases, with a hope to identify new therapeutic targets. Moreover, the recognition of apoptosis, in turn, promoted mechanistic studies concerning necrosis, the predominant form of ischemic cell death. Necrosis had been thought to be merely an unregulated cellular crisis. A group of proteases called caspase are homologous to the ced-3 gene product. Apaf-1 family and Bcl-2 family members are mammalian homologues of the ced-4 and ced-9 gene products, respectively. In this chapter, the molecular mechanisms of cell death will be summarized ( Fig. 38.1 ). Experimental studies reporting neuroprotection by targeting these death mechanisms will also be described.

Figure 38.1, Schematic representation of cell death pathways. Caspase-dependent cleavage of apoptotic substrates is induced by the mitochondrial pathway in which cytochrome c release from the mitochondria plays a pivotal role in initiation. In some cell types, the death receptor-caspase-8 axis also activates caspase-3 and -7. Caspase-independent pathways, either by the tumor necrosis factor (TNF) receptor (TNFR)-receptor interacting protein (RIP) axis or the poly-ADP-ribose polymerase (PARP)-1-apoptosis-inducing factor (AIF) axis, lead to energy crisis and DNA break, resulting in programmed-type necrosis. Arrows indicate activation of the targets, whereas lines with blunt ends indicate inactivation. IAP , inhibitors of apoptosis protein; PTP , permeability transition pore.

Caspase

Caspase is the family of cysteine proteases that are Ced-3 homologues. In mammals, more than 10 caspases have been identified. Caspases are made as inactive proform. After being cleaved, they become active. Among the caspases, caspase-3 has the highest homology to Ced-3. It cleaves multiple apoptosis substrates, being considered as the main effector in apoptosis. Pro-caspase-3 is activated by being cleaved by initiator caspases, caspase-9 and caspase-8, which are, respectively, activated by the mitochondrial pathway and the extrinsic pathway, as described later. There is evidence suggesting that caspases are activated in the neuronal injury caused by brain ischemia . In addition, intracerebroventricular injection of caspase inhibitors, such as z-VAD-fmk and z-DEVD-fmk, has been shown to attenuate DNA laddering in the brain after mild ischemia .

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