Electron Microscopic Evidence against Apoptosis as the Mechanism of Neuronal Death in Global Ischemia

Colbourne, Frederick; Sutherland, Garnette R.; Auer, Roland N.

doi:10.1523/jneurosci.19-11-04200.1999

Cited by 306 publications

(181 citation statements)

References 52 publications

(70 reference statements)

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“…4). Similar morphological patterns of degenerating neurons were reported in the hippocampal region following global forebrain ischemia Colbourne et al, 1999). Therefore, hypoxic-ischemic insults to the brain appear to produce neuronal cell oncosis, possibly through mechanisms that involve excitotoxicity and oxidative stress (Table 1).…”

Section: Fas Receptorsupporting

confidence: 55%

Cellular and Molecular Pathways of Ischemic Neuronal Death

Won¹,

Kim²,

Gwag³

2002

BMB Reports

201

172

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Three routes have been identified triggering neuronal death under physiological and pathological conditions. Excess activation of ionotropic glutamate receptors cause influx and accumulation of Ca 2+ and Na + that result in rapid swelling and subsequent neuronal death within a few hours. The second route is caused by oxidative stress due to accumulation of reactive oxygen and nitrogen species. Apoptosis or programmed cell death that often occurs during developmental process has been coined as additional route to pathological neuronal death in the mature nervous system. Evidence is being accumulated that excitotoxicity, oxidative stress, and apoptosis propagate through distinctive and mutually exclusive signal transduction pathway and contribute to neuronal loss following hypoxic-ischemic brain injury. Thus, the therapeutic intervention of hypoxic-ischemic neuronal injury should be aimed to prevent excitotoxicity, oxidative stress, and apoptosis in a concerted way.

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Section: Fas Receptorsupporting

confidence: 55%

Cellular and Molecular Pathways of Ischemic Neuronal Death

Won¹,

Kim²,

Gwag³

2002

BMB Reports

201

172

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“…Since both necrosis and apoptosis are ongoing in ischemia, the separation of the two has been controversial (Colbourne et al, 1999) Caspases have been shown to be critical for programmed cell death in brain (Graham and Chen, 2001). Recently, we found that MPs may play an important role in facilitating the apoptotic process in brain.…”

Section: Endogenous Mmp Inhibitors: Tissue Inhibitors Of Metalloprotementioning

confidence: 99%

Matrix metalloproteinases in neuroinflammation

Rosenberg

2002

Glia

781

667

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Matrix metalloproteinases (MMPs) are a gene family of neutral proteases that are important in normal development, wound healing, and a wide variety of pathological processes, including the spread of metastatic cancer cells, arthritic destruction of joints, atherosclerosis, and neuroinflammation. In the central nervous system (CNS), MMPs have been shown to degrade components of the basal lamina, leading to disruption of the blood-brain barrier (BBB), and to contribute to the neuroinflammatory response in many neurological diseases. Brain cells express both constitutive and inducible MMPs in response to cellular stress. MMPs are tightly regulated to avoid unwanted proteolysis. Secreted as inactive enzymes, the MMPs require activation by other proteases and free radicals. The MMPs are part of a larger class of metalloproteinases (MPs), which includes the recently discovered ADAMs (a disintegrin and metalloproteinase domain) and ADAMTS (a disintegrin and metalloproteinase thrombospondin) families. MPs have complex roles at the cell surface and within the extracellular matrix. At the cell surface, they act as sheddases, releasing growth factors, death receptors, and death-inducing ligands, making them important in cell survival and death. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors that regulate the activity of the MMPs. Synthetic inhibitors have been developed for the treatment of arthritis and cancer. These hydroxymate-based compounds have been shown to reduce injury in experimental allergic encephalomyelitis (EAE), experimental allergic neuritis (EAN), cerebral ischemia, intracerebral hemorrhage, and viral and bacterial infections. MPs have both beneficial and detrimental roles; understanding their expression in various CNS insults will allow for the use of MMP inhibitors in the treatment of neurological disorders. GLIA 39: 279 -291, 2002.

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“…106,107 However, in the adult rat, delayed post-ischemic cell death prevented by hypothermia had a necrotic appearance on detailed electron microscopic criteria. 108 However, it is now clear that apoptotic mechanisms can be involved even in 'necrotic' cell death. Although multiple pathways are likely to be involved in such post-ischemic apoptosis, caspase-3, one of the family of cysteine proteases, is reported to play a crucial role.…”

Section: Suppression Of Apoptosis/ Programmed Cell Death?mentioning

confidence: 99%

Hypothermic neuroprotection

Gunn

Thoresen

2006

NeuroRX

213

128

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Summary:The possibility that hypothermia during or after resuscitation from asphyxia at birth, or cardiac arrest in adults, might reduce evolving damage has tantalized clinicians for a very long time. It is now known that severe hypoxia-ischemia may not necessarily cause immediate cell death, but can precipitate a complex biochemical cascade leading to the delayed neuronal loss. Clinically and experimentally, the key phases of injury include a latent phase after reperfusion, with initial recovery of cerebral energy metabolism but EEG suppression, followed by a secondary phase characterized by accumulation of cytotoxins, seizures, cytotoxic edema, and failure of cerebral oxidative metabolism starting 6 to 15 h post insult. Although many of the secondary processes can be injurious, they appear to be primarily epiphenomena of the 'execution' phase of cell death. Studies designed around this conceptual framework have shown that moderate cerebral hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration in relation to the severity of the cerebral injury, has been associated with potent, long-lasting neuroprotection in both adult and perinatal species. Two large controlled trials, one of head cooling with mild hypothermia, and one of moderate whole body cooling have demonstrated that post resuscitation cooling is generally safe in intensive care, and reduces death or disability at 18 months of age after neonatal encephalopathy. These studies, however, show that only a subset of babies seemed to benefit. The challenge for the future is to find ways of improving the effectiveness of treatment.

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Electron Microscopic Evidence against Apoptosis as the Mechanism of Neuronal Death in Global Ischemia

Cited by 306 publications

References 52 publications

Cellular and Molecular Pathways of Ischemic Neuronal Death

Cellular and Molecular Pathways of Ischemic Neuronal Death

Matrix metalloproteinases in neuroinflammation

Hypothermic neuroprotection

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