Protection of rat spinal cord from ischemia with dextrorphan and cycloheximide: Effects on necrosis and apoptosis

Kato, Hiroyuki; Kanellopoulos, Georgios K.; Matsuo, Sadashige; Wu, Ying; Jacquin, Mark F.; Hsu, Chung Y.; Choi, Dennis W.; Kouchoukos, Nicholas T.

doi:10.1016/s0022-5223(97)70051-5

Cited by 48 publications

(17 citation statements)

References 25 publications

(6 reference statements)

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“…For example, cell loss induced by traumatic (Crowe et al, 1997;Liu et al, 1997) or ischemic (Kato et al, 1997;Mackey et al, 1997;Hayashi et al, 1998;Sakurai et al, 1998) spinal cord injury may be attributed, at least in part, to apoptotic mechanisms. Recently Springer et al (1999) reported that caspase-3 enzymatic activity increases as early as 1 hr after spinal cord trauma, along with cytochrome c release and caspase-9 processing.…”

Section: Discussionmentioning

confidence: 99%

Fas Receptor and Neuronal Cell Death after Spinal Cord Ischemia

Matsushita¹,

Wu²,

Qiu³

et al. 2000

J. Neurosci.

127

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Cell death from spinal cord injury is mediated in part by apoptotic mechanisms involving downstream caspases (e.g., caspase-3). Upstream mechanisms may involve other caspases such as procaspase-8, a 55 kDa apical caspase, which we found constitutively expressed within spinal cord neurons along with Fas. As early as 1.5 hr after transient ischemia, activated caspase-8 (p18) and caspase-8 mRNA appeared within neurons in intermediate gray matter and in medial ventral horn. We also detected evidence for an increase in death receptor complex by co-immunoprecipitation using Fas and anti-procaspase-8 after ischemia. At early time points, Fas and p18 were co-expressed within individual neurons, as were activated caspase-8 and caspase-3. Moreover, we detected p18 in cells before procaspase-3 cleavage product (p20), suggesting sequential activation. The appearance of cytosolic cytochrome c and gelsolin cleavage after ischemia was consistent with mitochondrial release and caspase-3 activation, respectively. Numerous terminal deoxynucleotidyl transferase-mediated DNA nick end-labelingpositive neurons contained p18 or p20 (65 and 80%, respectively), thereby supporting the idea that cells undergoing cell death contain both processed caspases. Our data are consistent with the idea that transient spinal cord ischemia induces the formation of a death-inducing signaling complex, which may participate in caspase-8 activation and sequential caspase-3 cleavage. Death receptors as well as downstream caspases may be useful therapeutic targets for limiting the death of cells in spinal cord. Key words: caspase-8; caspase-3; spinal cord ischemia; Fas; DISC; cell deathSpinal cord injury after trauma or cerebral ischemia is a major cause of morbidity and mortality (Kouchoukos, 1991;Von Oppel et al., 1994;Cheshire et al., 1996). Many injured cells die by a necrotic mechanism characterized by disruption of nuclear and cell membranes and disintegration of cytoplasmic organelles (Garcia et al., 1995). Some cells die by a mechanism resembling apoptosis, as evidenced by caspase activation (Hara et al., 1997;Endres et al., 1998;Namura et al., 1998;Springer et al., 1999).Caspases are important mediators of ischemic cell death. Procaspase-8 [Fas-associated death domain protein (FADD)-like interleukin-1␤ converting enzyme or MORT1-associated CED-3 homolog] is a 55 kDa initiator caspase (Boldin et al., 1996;Fernandes-Alnemri et al., 1996;Muzio et al., 1996). Procaspase-8 can process itself after ligation of the Fas-tumor necrosis factor family of death receptors (Kischkel et al., 1995;Los et al., 1995;Medema et al., 1997). Fas, a 45 kDa membrane receptor, forms a death-inducing signaling complex (DISC) with an adaptor protein, FADD, and procaspase-8 (Nagata and Goldstein, 1995; Nagata, 1997). Active caspase-8 initiates downstream cleavage of caspase-3 by direct or mitochondrial-dependent mechanisms via BH3 interacting death domain agonist cleavage, leading to apoptosis (Kuwana et al., 1998;Stennicke et al., 1998). In addition, activated caspase-3 may...

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Section: Discussionmentioning

confidence: 99%

Fas Receptor and Neuronal Cell Death after Spinal Cord Ischemia

Matsushita¹,

Wu²,

Qiu³

et al. 2000

J. Neurosci.

127

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“…Caspase-3 is regarded as a critical executioner of apoptosis in several in vitro cell culture systems (Nicholson and Thornberry, 1997) and caspase-3 activation has been observed in vivo after TBI (Pike et al, 1998a;Yakovlev et al, 1997) and cerebral ischemia (Chen et al, 1998;Endres et al, 1998;Kitagawa et al, 1998;Namura et al, 1998). Apoptotic cell death has also been observed in animal models of TBI (Cólicos and Dash, 1996;Conti et al, 1998;Eldadah et al, 1996;Newcomb et al, 1999;Pravdenkova et al, 1996;Rink et al, 1995), spinal cord injury (Crowe et al, 1997;Kato et al, 1997;Katoh et al, 1996;Liu et al, 1997), and cerebral ischemia (Charriaut-Marlangue et al, 1998). Our laboratory has recently reported apoptotic cell death and independent or concurrent activation of calpains and caspase-3 proteases (Pike et al, 1998a) in various brain regions following lateral cortical impact traumatic brain injury in rodents.…”

Section: Introductionmentioning

confidence: 88%

Stretch Injury Causes Calpain and Caspase-3 Activation and Necrotic and Apoptotic Cell Death in Septo-Hippocampal Cell Cultures

Pike¹,

Zhao²,

Newcomb³

et al. 2000

Journal of Neurotrauma

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Traumatic brain injury (TBI) results in numerous central and systemic responses that complicate interpretation of the effects of the primary mechanical trauma. For this reason, several in vitro models of mechanical cell injury have recently been developed that allow more precise control over intra- and extracellular environments than is possible in vivo. Although we recently reported that calpain and caspase-3 proteases are activated after TBI in rats, the role of calpain and/or caspase-3 has not been examined in any in vitro model of mechanical cell injury. In this investigation, varying magnitudes of rapid mechanical cell stretch were used to examine processing of the cytoskeletal protein alpha-spectrin (280 kDa) to a signature 145-kDa fragment by calpain and to the apoptotic-linked 120-kDa fragment by caspase-3 in septo-hippocampal cell cultures. Additionally, effects of stretch injury on cell viability and morphology were assayed. One hour after injury, maximal release of cytosolic lactate dehydrogenase and nuclear propidium iodide uptake were associated with peak accumulations of the calpain-specific 145-kDa fragment to alpha-spectrin at each injury level. The acute period of calpain activation (1-6 h) was associated with subpopulations of nuclear morphological alterations that appeared necrotic (hyperchromatism) or apoptotic (condensed, shrunken nuclei). In contrast, caspase-3 processing of alpha-spectrin to the apoptotic-linked 120-kDa fragment was only detected 24 h after moderate, but not mild or severe injury. The period of caspase-3 activation was predominantly associated with nuclear shrinkage, fragmentation, and apoptotic body formation characteristic of apoptosis. Results of this study indicate that rapid mechanical stretch injury to septo-hippocampal cell cultures replicates several important biochemical and morphological alterations commonly observed in vivo brain injury, although important differences were also noted.

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“…Kato et al [20] have reported that neurons in the spinal cord undergo apoptosis after ischemic insults. These studies have two common features, in that morphological change suggestive of apoptosis is strongly expressed within 24 ∼ 48 hours after reperfusion among the ischemic spinal neurons, and that the apoptotic cells were scattered within areas that contained necrotic cells.…”

Section: Original Cardiovascularmentioning

confidence: 99%