During liver CI/WR injury: 1) selective apoptosis of endothelial cells occurs; 2) caspase 3 is activated only in endothelial cells; and 3) a caspase inhibitor reduces endothelial cell apoptosis and prolongs animal survival after OLT. The pharmacologic use of caspase inhibitors could prove useful in clinical transplantation.

Calcium influx is believed to play a critical role in the cascade of biochemical events leading to neuronal cell death in a variety of pathological settings, including cerebral ischemia. The synthetic t-conotoxin peptide , which selectively blocks depolarization-induced calcium fluxes through neuronal N-type voltage-sensitive calcium channels, protected the pyramidal neurons in the CAl subfield of the hippocampus from damage caused by transient forebrain ischemia in the rat model of four-vessel occlusion. SNX-111 provided neuroprotection when a single bolus inj,ection was administered intravenously up to 24 hr after the ischemic insult. These results suggest that the window of opportunity for therapeutic intervention after cerebral ischemia may be much longer than previously thought and point to the potential use of t-conopeptides and their derivatives in the prevention or reduction of neuronal damage resulting from ischemic episodes due to cardiac arrest, head trauma, or stroke. Microdialysis studies showed that SNX-1ll was 3 orders of magnitude less potent in blocking potassium-induced glutamate release in the hippocampus than the conopeptide SNX-230, which, in contrast to SNX-11l, failed to show any efficacy in the four-vessel occlusion model of ischemia. These results imply that the ability of a conopeptide to block excitatory amino acid release does not correlate with its neuroprotective efficacy.Transient global ischemia of the forebrain, experimentally induced in rats by occlusion of the four major blood vessels supplying the brain, results in degeneration of a majority of the pyramidal neurons in the CAl region of the hippocampus (1). Neuronal damage following global forebrain ischemia has been attributed to increases in extracellular concentration of excitatory neurotransmitters such as glutamate and the resultant influx of calcium into neurons, which initiates a cascade of calcium-dependent intracellular degradative processes (2-4). However, selective antagonists of excitatory amino acid receptors-in particular, N-methyl-D-aspartate (NMDA) antagonists-have not been effective in protecting the vulnerable CAl neurons in the four-vessel occlusion model of transient forebrain ischemia in rats (5-7). Similarly, classical calcium channel antagonists such as the dihydropyridines, which block L-type calcium channels, have also failed to protect neurons from the consequences of ischemia when administered after the ischemic episode (8, 9). To develop therapies for preventing the brain damage caused by ischemia, we have investigated the utility of selectively blocking N-type calcium channels.Numerous studies suggest that the N-type calcium channels at presynaptic nerve terminals mediate a substantial portion of the calcium-dependent transmitter release in the The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.brain (10-12). The N-type channel has bee...

No abstract

Reactive oxygen intermediates (ROI) have been implicated as mediators of hepatocyte death resulting from a variety of forms of liver injury. To delineate the mechanisms that underlie ROI-induced apoptosis, the roles of caspase activation and nuclear factor-kappaB (NF-kappaB) signaling were determined in the rat hepatocyte cell line RALA255-10G after treatment with H(2)O(2) or the superoxide generator menadione. By 8 h, H(2)O(2) and menadione caused 26% and 33% cell death, respectively. Death from both ROI occurred by apoptosis as indicated by morphology under fluorescence microscopy, the induction of caspase activation and DNA fragmentation, and the cleavage of poly(ADP-ribose) polymerase. Despite the presence of caspase activation in both forms of apoptosis, caspase inhibition blocked H(2)O(2)- but not menadione-induced apoptosis. In contrast, inhibition of NF-kappaB activation decreased cell death from both ROI. Different ROI, therefore, induce distinct apoptotic pathways in RALA hepatocytes that are both caspase dependent and independent. In contrast to the known protective effect of NF-kappaB activation in tumor necrosis factor-alpha-induced hepatocyte apoptosis, NF-kappaB promotes hepatocellular death from ROI in these cells.

No abstract