Relation of impaired energy metabolism to apoptosis and necrosis following transient cerebral hypoxia-ischaemia

Mehmet, Huseyin; Yue, Xuetian; Penrice, J; Cady, Ernest B.; Wyatt, JS; Sarraf, Catherine; Squier, M. V.; Edwards, A. David

doi:10.1038/sj.cdd.4400353

Cited by 48 publications

(23 citation statements)

References 33 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous investigations by Du et al 3 and Mehmet et al 10 failed to demonstrate apoptotic nuclei by in situ TUNEL immunohistochemical staining by 48 hours after the reversal of relatively mild (not immediately necrotic) degrees of HII. However, exposure of PS on apoptotic cells, which bind annexin V in vivo, occurs much earlier, before the autodigestion of DNA that can be detected by TUNEL staining or gel electrophoresis.…”

Section: Discussionmentioning

confidence: 98%

^99m Tc Annexin V Imaging of Neonatal Hypoxic Brain Injury

D’Arceuil

Rhine

Crespigny

et al. 2000

Stroke

View full text Add to dashboard Cite

Background and Purpose: -Delayed cell loss in neonates after cerebral hypoxic-ischemic injury (HII) is believed to be a major cause of cerebral palsy. In this study, we used radiolabeled annexin V, a marker of delayed cell loss (apoptosis), to image neonatal rabbits suffering from HII. Methods-Twenty-two neonatal New Zealand White rabbits had ligation of the right common carotid artery with reduction of inspired oxygen concentration to induce HII. Experimental animals (nϭ17) were exposed to hypoxia until an ipsilateral hemispheric decrease in the average diffusion coefficient occurred. After reversal of hypoxia and normalization of average diffusion coefficient values, experimental animals were injected with 99m Tc annexin V. Radionuclide images were recorded 2 hours later. Results-Experimental animals showed no MR evidence of blood-brain barrier breakdown or perfusion abnormalities after hypoxia. Annexin images demonstrated multifocal brain uptake in both hemispheres of experimental but not control animals. Histology of the brains from experimental animals demonstrated scattered pyknotic cortical and hippocampal neurons with cytoplasmic vacuolization of glial cells without evidence of apoptotic nuclei by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. Double staining with markers of cell type and exogenous annexin V revealed that annexin V was localized in the cytoplasm of scattered neurons and astrocytes in experimental and, less commonly, control brains in the presence of an intact blood-brain barrier. Conclusions-Apoptosis may develop after HII even in brains that appear normal on diffusion-weighted and perfusion MR. These data suggest a role of radiolabeled annexin V screening of neonates at risk for the development of cerebral palsy.

show abstract

Section: Discussionmentioning

confidence: 98%

^99m Tc Annexin V Imaging of Neonatal Hypoxic Brain Injury

D’Arceuil

Rhine

Crespigny

et al. 2000

Stroke

View full text Add to dashboard Cite

show abstract

“…Neuronal death in ischemia is due to the temporary deprivation of oxygen and glucose which leads to a cascade of events, including glutamate release and excitotoxicity, resulting in cell death via both apoptosis and necrosis [99]. As previously mentioned, excitotoxicity is largely due to the massive increase in calcium ions that occurs, and it is becoming increasingly evident that the mitochondria play an important role in buffering this rise in Ca 2+ [70,71].…”

Section: Mitochondria Play a Role In Apoptosis Of Mature Neuronsmentioning

confidence: 97%

Role of Mitochondria in Neuronal Apoptosis

Gorman¹,

Ceccatelli²,

Orrenius³

2000

Dev Neurosci

View full text Add to dashboard Cite

Apoptosis is a controlled form of cell death that participates in the demise of neuronal cells during development, neurodegenerative disorders and exposure to neurotoxic agents. In recent years, the mitochondria have emerged as being pivotal in controlling apoptosis. They house a number of apoptogenic molecules that are released into the cytoplasm at the onset of apoptosis. These include cytochrome c, apoptosis-inducing factor and various caspases. Mitochondria also play an important role in intracellular Ca²⁺ regulation, which is crucial to excitotoxic neurodegeneration. Alterations in energy (ATP) production by mitochondria (due to hypoxia or mutations in genes encoding mitochondrial proteins of the electron transport chain) can induce apoptosis in neurons or increase their sensitivity to apoptosis.

show abstract

“…Secondary energy failure is a concept rather than a mechanism; although there are close associations between secondary energy failure and histologic damage (38), the precise mechanisms leading to secondary energy failure are unclear. It is likely that neurotoxic cascades are activated by both HI associated with the slice preparation and trauma to the cut edges of the brain tissue.…”

Section: Neuroprotection In Rat Brain Slicesmentioning

confidence: 99%

Hypothermia and Amiloride Preserve Energetics in a Neonatal Brain Slice Model

et al. 2005

View full text Add to dashboard Cite

A period of secondary energy failure consisting of a decline in phosphocreatine/inorganic phosphate (PCr/Pi), a rise in brain lactate, and alkaline intracellular pH (pH i ) has been described in infants with neonatal encephalopathy. Strategies that ameliorate this energy failure may be neuroprotective. We hypothesized that a neonatal rat brain slice model undergoes a progressive decline in energetics, which can be ameliorated with hypothermia or amiloride. Interleaved phosphorus ( 31 P) and proton ( 1 H) magnetic resonance (MR) spectra were obtained from 350 m neonatal rat brain slices over 8 h in a bicarbonate buffer at 37°C and at 32°C in 7-and 14-d models.31 P MR spectra were obtained with amiloride in a bicarbonate-free buffer at 37°C in the 14-d model. Findings were similar in 7-and 14-d models. In the 14-d model, there was a Pi doublet structure corresponding to alkaline pH i values of 7.50 Ϯ 0.02 and 7.21 Ϯ 0.04. Compared with the stabilized baseline of 100, at 5 h PCr/Pi was 65 Ϯ 6.3 and lactate/NAA was 187 Ϯ 3 at 37°C, but PCr/Pi and lactate/NAA were not significantly different from baseline at 32°C. Nucleotide triphosphate (NTP)/phosphomonoester (PME) was 0.93 Ϯ 0.23 at 37°C and 1.81 Ϯ 0.21 at 32°C at 5 h. With amiloride exposure in the 14-d model, baseline pH i values were 7.25 Ϯ 0.09 and 6.98 Ϯ 0.02 and NTP/PME was 1.81 Ϯ 0.05; these parameters were not significantly different at 5 h. Our interpretation of these findings is that the brain slice model underwent secondary energy failure, which was delayed with hypothermia or amiloride. Studies in term infants with neonatal encephalopathy (NE) suggest that, although antenatal or genetic factors might predispose some infants to perinatal brain injury (1,2), events in the immediate perinatal period are important in neonatal brain injury (3). A consistent pattern of energy derangement has been observed by several groups in infants with NE due to intrapartum asphyxia using phosphorus ( 31 P) and proton ( 1 H) magnetic resonance (MRS), spectroscopy (4 -7). 31 P and 1 H MR spectra were often normal within the first few hours after resuscitation, but after 8 -24 h there was a progressive decline in PCr/Pi and rise in brain lactate despite adequate oxygenation and circulation in the infant. The nadir of the energetic disturbance was seen after 12-24 h and the magnitude of the fall in PCr/Pi and rise in brain lactate correlated with the subsequent neurodevelopmental abnormality (8,9). This sequence of events was termed "secondary energy failure" to distinguish it from the "primary" decline in PCr and ATP and rise in lactate seen during the insult in experimental animal models of hypoxia-ischemia (HI) (10,11). The biphasic pattern of energy failure during and after HI has been the cornerstone behind the realization that neuroprotective strategies might interrupt the cascade of irreversible injury if administered within hours of a perinatal insult (12), and the concept has been an important catalyst in the development of neuroprotection trials with moderate hypoth...

show abstract

Relation of impaired energy metabolism to apoptosis and necrosis following transient cerebral hypoxia-ischaemia

Cited by 48 publications

References 33 publications

^99m Tc Annexin V Imaging of Neonatal Hypoxic Brain Injury

^99m Tc Annexin V Imaging of Neonatal Hypoxic Brain Injury

Role of Mitochondria in Neuronal Apoptosis

Hypothermia and Amiloride Preserve Energetics in a Neonatal Brain Slice Model

Contact Info

Product

Resources

About