[Abstract unavailable

No abstract

No abstract

No abstract

The present work serves to illustrate that EPO can offer novel cytoprotection during ischemic vascular injury through direct modulation of Akt1 phosphorylation, mitochondrial membrane potential, and cysteine protease activity.

1 Erythropoietin (EPO) plays a significant role in the hematopoietic system, but the function of EPO as a neuroprotectant and anti-inflammatory mediator requires further definition. We therefore examined the cellular mechanisms that mediate protection by EPO during free radical injury in primary neurons and cerebral microglia. 2 Neuronal injury was evaluated by trypan blue, DNA fragmentation, phosphatidylserine (PS) exposure, Akt1 phosphorylation, Bad phosphorylation, mitochondrial membrane potential, and cysteine protease activity. Microglial activation was assessed through proliferating cell nuclear antigen and PS receptor expression. 3 EPO provides intrinsic neuronal protection that is both necessary and sufficient to prevent acute genomic DNA destruction and subsequent membrane PS exposure, since protection by EPO is completely abolished by cotreatment with an anti-EPO neutralizing antibody. 4 Extrinsic protection by EPO is offered through the inhibition of cerebral microglial activation and the suppression of microglial PS receptor expression for the prevention of neuronal phagocytosis. In regards to microglial chemotaxis, EPO modulates neuronal poptotic membrane PS exposure necessary for microglial activation primarily through the regulation of caspase 1. 5 EPO increases Akt1 activity, phosphorylates Bad, and maintains neuronal nuclear DNA integrity through the downstream modulation of mitochrondrial membrane potential, cytochrome c release, and caspase 1, 3, and 8-like activities. 6 Elucidating the intrinsic and extrinsic protective pathways of EPO that mediate both neuronal integrity and inflammatory microglial activation may enhance the development of future therapies directed against acute neuronal injury.

No abstract

Summary: Neuronal injury may be dependent upon the gen eration of the free radical nitric oxide (NO) and the subsequent induction of programed cell death (PCD). Although the nature of this injury may be both preventable and reversible, the un derlying mechanisms that mediate PCD are not well under stood. Using the agent nicotinamide as an investigative tool in primary rat hippocampal neurons, the authors examined the ability to modulate two independent components of PCD, namely the degradation of genomic DNA and the early expo sure of membrane phosphatidylserine (PS) residues. Neuronal injury was determined through trypan blue dye exclusion, DNA fragmentation, extemalization of membrane PS residues, cys teine protease activation, and the measurement of intracellular pH (pHJ Exposure to the NO donors SIN-I and NOC-9 (300 f,LmoIlL) alone rapidly increased genomic DNA fragmentation from 20 ± 4% to 71 ± 5% and membrane PS exposure from 14 ± 3% to 76 ± 9% over a 24-hour period. Administration of a Neuronal injury can be initiated by several differ ent stimuli that ultimately lead to either apoptosis or necrosis. Neuronal apoptosis or programed cell death (PCD) is an active, controlled, and deliberate process of cell destruction that is present during cell development and injury (Kerr et aI., 1972). In contrast, neurons that undergo necrosis suffer diffuse organelle damage with