Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury.

Cheng, Yuhui; Deshmukh, Mohanish; D'Costa, Anselm P.; Demaro, Joseph A.; Gidday, Jeffrey M.; Shah, Aarti R.; Sun, Yuling; Jacquin, Mark F.; Johnson, Eugene M.; Holtzman, David M.

doi:10.1172/jci2169

Cited by 479 publications

(404 citation statements)

References 45 publications

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“…Recent studies have also provided additional evidence of caspase-3 activation in other models of cerebral ischemia following strokes in adults and neonates. This includes the mitochondrial release of cytochrome c and activation of caspase-9, a proximal caspase in the caspase-3 apoptotic cascade (Gillardon et al, 1997;Cheng et al, 1998;Namura et al, 1998;Pulera et al, 1998;Kiprianova et al, 1999;Krajewski et al, 1999;Ouyang et al, 1999;Velier et al, 1999;. Several recent studies using caspase inhibitors provide support of these original observations, and demonstrate that injury severity can affect the efficacy of caspase inhibitors in reducing cell death.…”

Section: Ischemia/reperfusion Injurymentioning

confidence: 89%

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

Springer¹

2002

BMB Reports

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Apoptotic cell death is a fundamental and highly regulated biological process in which a cell is instructed to actively participate in its own demise. This process of cellular suicide is activated by developmental and environmental cues and normally plays an essential role in eliminating superfluous, damaged, and senescent cells of many tissue types. In recent years, a number of experimental studies have provided evidence of widespread neuronal and glial apoptosis following injury to the central nervous system (CNS). These studies indicate that injury-induced apoptosis can be detected from hours to days following injury and may contribute to neurological dysfunction. Given these findings, understanding the biochemical signaling events controlling apoptosis is a first step towards developing therapeutic agents that target this cell death process. This review will focus on molecular cell death pathways that are responsible for generating the apoptotic phenotype. It will also summarize what is currently known about the apoptotic signals that are activated in the injured CNS, and what potential strategies might be pursued to reduce this cell death process as a means to promote functional recovery.

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Section: Ischemia/reperfusion Injurymentioning

confidence: 89%

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

Springer¹

2002

BMB Reports

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“…Z-VAD-FMK, a pancaspase inhibitor (36)(37)(38)(39)(40)(41)(42), can inhibit cell death in response to mechanical injury. Interestingly, our results showed that Z-VAD-FMK could inhibit chondrocyte death more effectively in chondroitinase ABC-treated explants than in control explants.…”

Section: Discussionmentioning

confidence: 99%

The effect of glycosaminoglycan loss on chondrocyte viability: A study on porcine cartilage explants

Otsuki¹,

Brinson²,

Creighton³

et al. 2008

Arthritis & Rheumatism

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Objective. Loss of glycosaminoglycan (GAG) is an early event in osteoarthritis. Recent findings showed increased cell death in arthritic cartilage and linkage with extracellular matrix degradation. The aim of this study was to analyze the direct effect of GAG loss on chondrocyte survival and cell death following mechanical injury.Methods. In full-thickness cartilage explants from porcine knee joints, GAG was depleted by digestion with chondroitinase ABC. Explants were subjected to single-impact mechanical injury. Cell viability and the types of cell death were analyzed by Live/Dead cell assay, staining for active caspase 3, and sensitivity to caspase inhibitor.Results. GAG depletion did not directly lead to increased cell death. In chondroitinase ABC-treated explants, but not in control explants, mechanical injury caused an immediate reduction in cell viability (from 84.6% to 71.0%); the reduction was prominent in the superficial zone. This immediate cell death was not inhibited by the pancaspase inhibitor Z-VAD-FMK, suggesting cell necrosis. During subsequent culture, viability in these explants decreased further, to 50.5% on day 3. The second wave of cell death was reduced by the addition of Z-VAD-FMK in chondroitinase ABC-treated explants and was also associated with activation of caspase 3, suggesting apoptotic mechanisms of cell death.Conclusion. These results indicate that GAG loss alone does not directly lead to chondrocyte death. In response to mechanical injury, there is an immediate induction of necrotic cell death that is seen only in GAG-depleted explants and primarily in the superficial zone. During subsequent culture, cell death spreads via apoptotic mechanisms.

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“…Because inhibition of apoptosis, IL-6, or P-selectin has been demonstrated to protect against I/R-induced organ failure in the kidney, 15,[22][23][24] heart, 35,36 brain, 37,38 intestine, 39 and liver, 40 GC-G may also be involved in I/R-induced abnormalities in other organs, such as acute myocardial infarction in the heart or stroke in the brain, which warrants further investigation. Although the exact mechanism by which GC-G is regulated under renal I/R remains undefined, a simple regulatory mechanism could be that renal I/R induces the release of endogenous ligand(s) and modulates GC-G activity to transmit the injury signal leading to apoptosis and inflammation.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Guanylyl Cyclase-G Protects against Acute Renal Injury

Lin

Cheng²,

Hou

et al. 2008

Journal of the American Society of Nephrology

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The membrane forms of guanylyl cyclase (GC) serve as cell-surface receptors that synthesize the second messenger cGMP, which mediates diverse cellular processes. Rat kidney contains mRNA for the GC-G isoform, but the role of this receptor in health and disease has not been characterized. It was found that mouse kidney also contains GC-G mRNA, and immunohistochemistry identified GC-G protein in the epithelial cells of the proximal tubule and collecting ducts. Six hours after ischemia-reperfusion (I/R) injury, GC-G mRNA and protein expression increased three-fold and remained upregulated at 24 h. For determination of whether GC-G mediates I/R injury, a mutant mouse with a targeted disruption of the GC-G gene (Gucy2g) was created. At baseline, no histologic abnormalities were observed in GC-G Ϫ/Ϫ mice. After I/R injury, elevations in serum creatinine and urea were attenuated in GC-G Ϫ/Ϫ mice compared with wild-type controls, and this correlated with less tubular disruption, less tubular cell apoptosis, and less caspase-3 activation. Measures of inflammation (number of infiltrating neutrophils, myeloperoxidase activity, and induction of IL-6 and P-selectin) and activation of NF-B were lower in GC-G Ϫ/Ϫ mice compared with wild-type mice. Direct transfer of a GC-G expression plasmid to the kidneys of GC-G Ϫ/Ϫ mice resulted in a dramatically higher mortality after renal I/R injury, further supporting a role for GC-G in mediating injury. In summary, GC-G may act as an early signaling molecule that promotes apoptotic and inflammatory responses in I/R-induced acute renal injury.

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Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury.

Cited by 479 publications

References 45 publications

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

Apoptotic Cell Death Following Traumatic Injury to the Central Nervous System

The effect of glycosaminoglycan loss on chondrocyte viability: A study on porcine cartilage explants

Disruption of Guanylyl Cyclase-G Protects against Acute Renal Injury

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