Neurodegeneration in Excitotoxicity, Global Cerebral Ischemia, and Target Deprivation: A Perspective on the Contributions of Apoptosis and Necrosis

Martin, Lee J.; Al-Abdulla, Nael A.; Brambrink, Ansgar M.; Kirsch, Jeffrey R.; Sieber, Frederick E.; Portera‐Cailliau, Carlos

doi:10.1016/s0361-9230(98)00024-0

Cited by 624 publications

(480 citation statements)

References 164 publications

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“…Evidence is also available that the excitotoxic injury can produce hybrid forms of cell death, existing on a continuum between the classically defined apoptosis and necrosis [38,39,43], and is likely to depend on the degree of insult and the sensitivity of the exposed neurones. Time-dependent studies of glutamate exposure to cultured neuronal populations showed that the excitotoxins induce early necrosis and delayed apoptosis [36,44].…”

Section: Discussionmentioning

confidence: 99%

“…RGCs showed mitochondrial swelling, dilated ER, dissolution of ribosomes in early stages and disintegration of cytoplasmic organelles, change in nuclear morphology and mild chromatin aggregation in advanced stages [43,47-50]. Because apoptosis requires functional mitochondria [51], the presence of swollen and disrupting mitochondria suggested that the event was non-apoptotic.…”

Section: Discussionmentioning

confidence: 99%

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Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study

et al. 2010

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BackgroundExcitotoxicity is involved in the pathogenesis of a number neurodegenerative diseases, and axonopathy is an early feature in several of these disorders. In models of excitotoxicity-associated neurological disease, an excitotoxin delivered to the central nervous system (CNS), could trigger neuronal death not only in the somatodendritic region, but also in the axonal region, via oligodendrocyte N-methyl-D-aspartate (NMDA) receptors. The retina and optic nerve, as approachable regions of the brain, provide a unique anatomical substrate to investigate the "downstream" effect of isolated excitotoxic perikaryal injury on central nervous system (CNS) axons, potentially providing information about the pathogenesis of the axonopathy in clinical neurological disorders.Herein, we provide ultrastructural information about the retinal ganglion cell (RGC) somata and their axons, both unmyelinated and myelinated, after NMDA-induced retinal injury. Male Sprague-Dawley rats were killed at 0 h, 24 h, 72 h and 7 days after injecting 20 nM NMDA into the vitreous chamber of the left eye (n = 8 in each group). Saline-injected right eyes served as controls. After perfusion fixation, dissection, resin-embedding and staining, ultrathin sections of eyes and proximal (intraorbital) and distal (intracranial) optic nerve segments were evaluated by transmission electron tomography (TEM).ResultsTEM demonstrated features of necrosis in RGCs: mitochondrial and endoplasmic reticulum swelling, disintegration of polyribosomes, rupture of membranous organelle and formation of myelin bodies. Ultrastructural damage in the optic nerve mimicked the changes of Wallerian degeneration; early nodal/paranodal disturbances were followed by the appearance of three major morphological variants: dark degeneration, watery degeneration and demyelination.ConclusionNMDA-induced excitotoxic retinal injury causes mainly necrotic RGC somal death with Wallerian-like degeneration of the optic nerve. Since axonal degeneration associated with perikaryal excitotoxic injury is an active, regulated process, it may be amenable to therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study

et al. 2010

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“…The most accepted mechanism is mediated by N-methyl-D-aspartate (NMDA) receptors, causing increased, toxic intracellular calcium ion concentrations and activation of calcium-dependent proteases, such as calpains, and apoptotic protein caspases, which damage vital cell organelles including mitochondria (Zhivotovsky et al, 1997;Martin et al, 1998;Zeron et al, 2004;Jiang et al, 2005;Das et al, 2005;Fernandez et al, 2005). As a result of these intracellular toxicities, these pathways initiated by excess glutamate may lead to either apoptotic (in lower concentrations) or necrotic (in higher concentrations) neuronal death (Das et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Glutamate-related gene expression changes with age in the mouse auditory midbrain

et al. 2007

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Glutamate is the main excitatory neurotransmitter in both the peripheral and central auditory systems. Changes of glutamate and glutamate-related genes with age may be an important factor in the pathogenesis of age-related hearing loss -presbycusis. In this study, changes in glutamate-related mRNA gene expression in the CBA mouse inferior colliculus with age and hearing loss were examined and correlations were sought between these changes and functional hearing measures, such as the auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAEs). Gene expression of 68 glutamate-related genes was investigated using both genechip microarray and real-time PCR (qPCR) molecular techniques for four different age/hearing loss CBA mouse subject groups. Two genes showed consistent differences between groups for both the genechip and qPCR. Pyrroline-5-carboxylate synthetase enzyme (Pycs) showed down-regulation with age and a highaffinity glutamate transporter (Slc1a3) showed up-regulation with age and hearing loss. Since Pycs plays a role in converting glutamate to proline, its deficiency in old age may lead to both glutamate increases and proline deficiencies in the auditory midbrain, playing a role in the subsequent inducement of glutamate toxicity and loss of proline neuroprotective effects. The up-regulation of Slc1a3 gene expression may reflect a cellular compensatory mechanism to protect against age-related glutamate or calcium excitoxicity.

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“…27 Our previous data showed an increased apoptotic reaction in Cx43(ϩ/Ϫ) mice in which astrocytic gap junctional communication was decreased compared to wild-type mice. 18 Representative cases demonstrate that the penumbral lesion of Cre(ϩ) mice show enhanced apoptosis compared to Cre(Ϫ) mice (Figure 2, A and B).…”

Section: Enhanced Apoptosis In the Penumbra Of Cre(ϩ) Micementioning

confidence: 92%

Increased Apoptosis and Inflammation after Focal Brain Ischemia in Mice Lacking Connexin43 in Astrocytes

Nakase

Söhl

Theis

et al. 2004

The American Journal of Pathology

205

150

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Astrocytes secrete cytokines and neurotrophic factors to neurons, consistent with a neurosupportive role for astrocytes. However, in ischemic or metabolic insults, the function of astrocytic gap junctions composed mainly from connexin43 (Cx43) remains controversial. We have previously shown that heterozygous Cx43 null mice subjected to middle cerebral artery occlusion exhibited significantly enhanced stroke volume and apoptosis compared to wild-type mice. In this study, we used mice in which the human GFAP promoter-driven cre transgene deletes the floxed

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Neurodegeneration in Excitotoxicity, Global Cerebral Ischemia, and Target Deprivation: A Perspective on the Contributions of Apoptosis and Necrosis

Cited by 624 publications

References 164 publications

Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study

Wallerian-like axonal degeneration in the optic nerve after excitotoxic retinal insult: an ultrastructural study

Glutamate-related gene expression changes with age in the mouse auditory midbrain

Increased Apoptosis and Inflammation after Focal Brain Ischemia in Mice Lacking Connexin43 in Astrocytes

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