DNA fragmentation indicative of apoptosis following unilateral cerebral hypoxia-ischemia in the neonatal rat

Hill, Irene E.; MacManus, J. P.; Rasquinha, Ingrid; Tuor, Ursula I.

doi:10.1016/0006-8993(95)00145-g

Cited by 131 publications

(65 citation statements)

References 28 publications

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“…The injury resulting is similar to that seen in the term human infant that has been exposed to an H-I insult. We have found recently that BDNF markedly protects against the H-I injury in this model, a portion of which has features of apoptotic-like death (Ferrer et al, 1994;Mehmet et al, 1994;Hill et al, 1995;Sidhu et al, 1997;Silverstein et al, 1997;Hasegawa et al, 1998;Pulera et al, 1998) and is caspase dependent (Cheng et al, 1998;Han et al, 2000). Our results in the present study supporting the involvement of the ERK pathway in this protection may have important clinical implications.…”

Section: Discussionmentioning

confidence: 76%

BDNF Protects the Neonatal Brain from Hypoxic-Ischemic InjuryIn Vivovia the ERK Pathway

Han¹,

2000

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Neurotrophins activate several different intracellular signaling pathways that in some way exert neuroprotective effects. In vitro studies of sympathetic and cerebellar granule neurons have demonstrated that the survival effects of neurotrophins can be mediated via activation of the phosphatidylinositol 3-kinase (PI3-kinase) pathway. Neurotrophin-mediated protection of other neuronal types in vitro can be mediated via the extracellular signalrelated protein kinase (ERK) pathway. Whether either of these pathways contributes to the neuroprotective effects of neurotrophins in the brain in vivo has not been determined. Brain-derived neurotrophic factor (BDNF) is markedly neuroprotective against neonatal hypoxic-ischemic (H-I) brain injury in vivo. We assessed the role of the ERK and PI3-kinase pathways in neonatal H-I brain injury in the presence and absence of BDNF. Intracerebroventricular administration of BDNF to postnatal day 7 rats resulted in phosphorylation of ERK1/2 and the PI3-kinase substrate AKT within minutes. Effects were greater on ERK activation and occurred in neurons. Pharmacological inhibition of ERK, but not the PI3-kinase pathway, inhibited the ability of BDNF to block H-Iinduced caspase-3 activation and tissue loss. These findings suggest that neuronal ERK activation in the neonatal brain mediates neuroprotection against H-I brain injury, a model of cerebral palsy.

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Section: Discussionmentioning

confidence: 76%

BDNF Protects the Neonatal Brain from Hypoxic-Ischemic InjuryIn Vivovia the ERK Pathway

Han¹,

2000

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“…Besides characteristic morphology, the state of integrity of chromatin remains the sole ac ceptable hallmark of apoptosis (Wyllie et al, 1980;Buja et al, 1993;Bortner et al, 1995;Walker et al, 1995). Since the first reports in 1993 of DNA fragmen tation following cerebral ischemia (Heron et al, 1993;Linnik et al, 1993;MacManus et al, 1993;Okamoto et al, 1993;Tominaga et al, 1993), there have been many others on transient global ischemia Sei et al, 1994;Iwai et al, 1995;Nitatori et al, 1995;Charriaut-Marlangue et al, 1996a,b), focal ischemia (MacManus et al, 1994;Li et al, 1995a-c;Linnik et al, 1995;Du et al, 1996), and neonatal hypoxia ischemia Hill et al, 1995) models. The oft-repeated observation of DNA dam age visualized as electrophoretic laddered DNA frag ments of oligonucleosomal size in ischemic rodent brain has led to the suggestion that ischemic cell death may be apoptotic.…”

Section: Discussionmentioning

confidence: 99%

“…These have been in both global (Fer rer et al, 1994;Heron et al, 1993;Iwai et al, 1995;Nitatori et al, 1995;Okamoto et al, 1993;Tortosa et al, 1994) and focal (Li et al, 1995a-c; Linnik et al, 1993 andTominaga et al, 1993;Sei et al, 1994) models of transient brain hemostasis. Some of this evidence came from this laboratory, where we concluded that a component of the apoptotic degra dative machinery is at work in the ischemic neurons (Hill et al, 1995;MacManus 1993MacManus , 1994MacManus , 1995a. In general, an absence of the morphological hallmark in ischemic brain has precluded wide acceptance of an apoptotic mode of cell death being operative fol lowing ischemia (Deshpande et al, 1992).…”

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confidence: 99%

“…Since our own studies showed that apoptotic laddered DNA appeared in brain following transient ischemia (Hill et al, 1995;MacManus et al, 1993MacManus et al, , 1994MacManus et al, , 1995a, we undertook to detect higher-order chromatin fragments. While these studies were in progress [described in abstract form in MacManus et al (1995b)], a report appeared describing the appearance of 300-kbp fragments of DNA following ischemia produced by middle cerebral artery occlu sion, with evidence of subsequent breakdown to smaller pieces (Charriaut-Marlangue et al, 1995).…”

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confidence: 99%

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Detection of Higher-Order 50- and 10-kbp DNA Fragments before Apoptotic Internucleosomal Cleavage after Transient Cerebral Ischemia

MacManus

Rasquinha

Tuor

et al. 1997

J Cereb Blood Flow Metab

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Summary: DNA fragments of SO and 10 kbp were found in ischemic brain in adult rats following two-vessel occlu sion or in neonates following hypoxia-ischemia. These higher-order fragments were detected before any laddered oligonucleosomal DNA fragmentation characteristic of apoptosis. Both the SO-and 10-kbp fragments were also detected during necrosis produced by decapitation, but these led to smeared smaller fragments, not laddered pat terns. End-group analysis showed the presence of both 3' OH and S;-OH ends in both the SO-and lO-kbp fragments

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“…Secondary injury involves a cascade of biochemical changes that contribute to delayed tissue damage and cell death (Faden, 1996). Although the focus of research on secondary brain injury historically has been on mechanisms related to necrosis (Trump and Bulger, 1967), recent studies have suggested a potential role for apoptosis in cell loss after stroke, spinal cord injury, or traumatic brain injury (TBI) (Linnik et al, 1993;MacManus et al, 1993;K ihara et al, 1994;Sei et al, 1994;Beilharz et al, 1995;Hill et al, 1995;Islam et al, 1995;Iwai et al, 1995;Li et al, 1995a,b;Rink et al, 1995;Hara et al, 1997).…”

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confidence: 99%

Activation of CPP32-Like Caspases Contributes to Neuronal Apoptosis and Neurological Dysfunction after Traumatic Brain Injury

et al. 1997

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We examined the temporal profile of apoptosis after fluid percussion-induced traumatic brain injury (TBI) in rats and investigated the potential pathophysiological role of caspase-3-like proteases in this process. DNA fragmentation was observed in samples from injured cortex and hippocampus, but not from contralateral tissue, beginning 4 hr after TBI and continuing for at least 3 d. Double labeling of brain with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and an antibody directed to neuronal nuclear protein identified apoptotic neurons with high frequency in both traumatized rat cortex and hippocampus. Cytosolic extracts from injured cortex and hippocampus, but not from contralateral or control tissue, induced internucleosomal DNA fragmentation in isolated nuclei with temporal profiles consistent with those of DNA fragmentation observed in vivo. Caspase-3 mRNA levels, estimated by semiquantitative RT-PCR, were elevated fivefold in ipsilateral cortex and twofold in hippocampus by 24 hr after TBI. Caspase-1 mRNA content also was increased after trauma, but to a lesser extent in cortex. Increased caspase-3-like, but not caspase-1-like, enzymatic activity was found in cytosolic extracts from injured cortex. Intracerebroventricular administration of z-DEVD-fmk-a specific tetrapeptide inhibitor of caspase-3-before and after injury markedly reduced post-traumatic apoptosis, as demonstrated by DNA electrophoresis and TUNEL staining, and significantly improved neurological recovery. Together, these results implicate caspase-3-like proteases in neuronal apoptosis induced by TBI and suggest that the blockade of such caspases can reduce post-traumatic apoptosis and associated neurological dysfunction.

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DNA fragmentation indicative of apoptosis following unilateral cerebral hypoxia-ischemia in the neonatal rat

Cited by 131 publications

References 28 publications

BDNF Protects the Neonatal Brain from Hypoxic-Ischemic InjuryIn Vivovia the ERK Pathway

BDNF Protects the Neonatal Brain from Hypoxic-Ischemic InjuryIn Vivovia the ERK Pathway

Detection of Higher-Order 50- and 10-kbp DNA Fragments before Apoptotic Internucleosomal Cleavage after Transient Cerebral Ischemia

Activation of CPP32-Like Caspases Contributes to Neuronal Apoptosis and Neurological Dysfunction after Traumatic Brain Injury

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