Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9435109 | Progress in Neurobiology | 2005 | 30 Pages |
Abstract
As much as brain stem death is currently the clinical definition of death in many countries and is a phenomenon of paramount medical importance, there is a dearth of information on its mechanistic underpinnings. A majority of the clinical studies are concerned only with methods to determine brain stem death. Whereas a vast amount of information is available on the cellular and molecular mechanisms of cell death, rarely are these studies directed specifically towards the understanding of brain stem death. This review presents a framework for translational research on brain stem death that is based on systematically coordinated clinical and laboratory efforts that center on this phenomenon. It begins with the identification of a novel clinical marker from patients that is related specifically to brain stem death. After realizing that this “life-and-death” signal is related to the functional integrity of the brain stem, its origin is traced to the rostral ventrolateral medulla (RVLM). Subsequent laboratory studies on this neural substrate in animal models of brain stem death provide credence to the notion that both “pro-life” and “pro-death” programs are at work during the progression towards death. Those programs (mitochondrial functions, nitric oxide, peroxynitrite, superoxide anion, coenzyme Q10, heat shock proteins and ubiquitin-proteasome system) hitherto identified from the RVLM are presented, along with their cellular and molecular mechanisms. It is proposed that outcome of the interplay between the “pro-life” and “pro-death” programs (dying) in this neural substrate determines the final fate of the individual (being dead). Thus, identification of additional programs in the RVLM and delineation of their regulatory mechanisms should shed new lights on future directions for clinical management of life-and-death.
Keywords
EPSCsiNOSCCOMEVeNOSHspIκBΔΨmnNOSMnSODRVLMNF-κBAT1RsEPSCsPKGAT2RSGCUCH-L1CoQ10oxidized form of nicotinamide adenine dinucleotideM2Rsuccinate cytochrome c reductaseLPSNCCRJnkflavin adenine dinucleotideNOSc-Jun N-terminal kinaseMAPKNAD+O2−OH−ONOO−ROSHydrogen peroxiderostral ventrolateral medullaAngiotensin IIsuperoxide anionAIFγ-aminobutyric acidFADMitochondrial functionsexcitatory postsynaptic currentsSoluble guanylyl cyclaseAng IIHydroxyl radicalinducible nitric oxide synthaseendothelial nitric oxide synthaseneuronal nitric oxide synthasecytochrome c oxidaseUbiquitin-proteasome systemSCCRSAPHeart rateapoptosis-inducing factornuclear factor-κBreduced form of nicotinamide adenine dinucleotideSystemic arterial pressurelipopolysaccharidebrain stem deathinhibitory κBNADHNitric oxidenitric oxide synthaseH2O2Heat shock proteinprotein kinase Gmitogen activated protein kinaseHeat shock proteinsPeroxynitriteTranslational researchCoenzyme Q10GABAReactive oxygen species
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Authors
Julie Y.H. Chan, Alice Y.W. Chang, Samuel H.H. Chan,