Prevention of Nitric Oxide-Induced Neuronal Injury Through the Modulation of Independent Pathways of Programmed Cell Death

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

Nicotinamide reduces hypoxic ischemic brain injury in the newborn rat

“…In adult animals nicotinamide prevents depolarization of the mitochondrial membrane, prevents pore formation in the mitochondrial membrane and reduces release of cytochrome c into the cytoplasm [9,10] and reduces activation of caspase-9, which reduces the activation of caspase-3, all of which may be secondary to nicotinamides effect on oxidants and free radicals. Nicotinamide in adult animals inhibits poly(ADP-ribose) polymerase, reduces apoptotic DNA fragmentation, and phosphatidyl serine exteriorization [25]. In the present study the data showed that nicotinamide reduced the increase in caspase-3 activity caused by hypoxic ischemia.…”

Erythropoietin: Elucidating new cellular targets that broaden therapeutic strategies

“…Reactive oxygen species can involve superoxide free radicals, hydrogen peroxide, singlet oxygen, nitric oxide (NO), and peroxynitrite (Chong et al, 2005e). Most species are produced at low levels during normal physiological conditions and are scavenged by endogenous antioxidant systems that include superoxide dismutase (SOD), glutathione peroxidase, catalase, and small molecule substances such as vitamins C and E. Other closely linked pathways to oxidative stress may be tempered by different vitamins, such as vitamin D 3 (Regulska et al, 2007) and the amide form of niacin or vitamin B 3 , nicotinamide (Chlopicki et al, 2007;Chong et al, 2002d;Feng et al, 2006;Hara et al, 2007;Ieraci and Herrera, 2006;Lin et al, 2000;.…”

“…Mitochondrial membrane transition pore permeability is increased Di Lisa et al, 2001;Kang et al, 2003b;Lin et al, 2000) and leads to a significant loss of mitochondrial NAD + stores and subsequent apoptotic cell injury (Chong et al, 2005g;. In addition, mitochondria are a significant source of superoxide radicals that are associated with oxidative stress (Chong et al, 2005e;.…”

Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease

“…This can trigger the loss of NAD + and ATP, leading to the death of a cell. Furthermore, oxidative stress can trigger the opening of mitochondrial membrane permeability transition pore [41,59,104,122] and subsequently result in the release of NAD + from mitochondria [59]. During conditions of oxidative stress and energy depletion in neurons, poly(ADP-ribosylation) activation and loss of NAD + stores in mitochondria have been shown to lead to apoptotic injury.…”