Traumatic mechanical injury to the hippocampus in vitro causes regional caspase-3 and calpain activation that is influenced by NMDA receptor subunit composition

DeRidder, Michael N.; Simon, Melissa J.; Siman, Robert; Auberson, Yves P.; Raghupathi, Ramesh; Meaney, David F.

doi:10.1016/j.nbd.2005.10.011

Cited by 80 publications

(62 citation statements)

References 58 publications

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“…The observed involvement of NR2B receptors in NMDAmediated excitotoxicity is in good agreement with a recent study using brain slices (Zhou and Baudry, 2006), and the NR2A-mediated neuronal survival has also been demonstrated in a traumatic mechanical injury model in vitro (DeRidder et al, 2006). It is interesting, however, to note that NR2A was also recently reported to be involved in human immunodeficiency virusmediated neurotoxicity (O'Donnell et al, 2006).…”

Section: Discussionsupporting

confidence: 88%

NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death BothIn VitroandIn Vivo

Liu¹,

Wong²,

Aarts³

et al. 2007

J. Neurosci.

709

608

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Well-documented experimental evidence from both in vitro and in vivo models of stroke strongly supports the critical involvement of NMDA receptor-mediated excitotoxicity in neuronal damage after stroke. Despite this, the results of clinical trials testing NMDA receptor antagonists as neuroprotectants after stroke and brain trauma have been discouraging. Here, we report that in mature cortical cultures, activation of either synaptic or extrasynaptic NR2B-containing NMDA receptors results in excitotoxicity, increasing neuronal apoptosis. In contrast, activation of either synaptic or extrasynaptic NR2A-containing NMDA receptors promotes neuronal survival and exerts a neuroprotective action against both NMDA receptor-mediated and non-NMDA receptor-mediated neuronal damage. A similar opposing action of NR2B and NR2A in mediating cell death and cell survival was also observed in an in vivo rat model of focal ischemic stroke. Moreover, we found that blocking NR2B-mediated cell death was effective in reducing infarct volume only when the receptor antagonist was given before the onset of stroke and not 4.5 h after stroke. In great contrast, activation of NR2A-mediated cell survival signaling with administration of either glycine alone or in the presence of NR2B antagonist significantly attenuated ischemic brain damage even when delivered 4.5 h after stroke onset. Together, the present work provides a molecular basis for the dual roles of NMDA receptors in promoting neuronal survival and mediating neuronal damage and suggests that selective enhancement of NR2A-containing NMDA receptor activation with glycine may constitute a promising therapy for stroke.

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Section: Discussionsupporting

confidence: 88%

NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death BothIn VitroandIn Vivo

Liu¹,

Wong²,

Aarts³

et al. 2007

J. Neurosci.

709

608

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“…A similar biphasic pattern of calpainmediated α-spectrin degradation has also been observed by our laboratory in the context of a rat spinal cord injury model (Xiong et al, 2006) and by others in a transient ischemic brain injury model (Neumar et al, 2001). In a recent hippocampal organotypic slice study, stretchinduced injury also showed a biphasic activation of calpain (DeRidder et al, 2006). This repeatedly demonstrated biphasic time course of calpain-mediated proteolysis can potentially be explained by an initial partial ROS-mediated inhibition of calpain activity in the early posttraumatic hrs during which PN generation and evidence of oxidative damage are at their highest level.…”

Section: Interaction Of Peroxynitrite-induced Oxidative and Calpain-msupporting

confidence: 84%

Temporal relationship of peroxynitrite-induced oxidative damage, calpain-mediated cytoskeletal degradation and neurodegeneration after traumatic brain injury

Deng

Thompson

Gao

et al. 2007

Experimental Neurology

135

171

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We assessed the temporal and spatial characteristics of PN-induced oxidative damage and its relationship to calpain-mediated cytoskeletal degradation and neurodegeneration in a severe unilateral controlled cortical impact (CCI) traumatic brain injury (TBI) model. Quantitative temporal time-course studies were performed to measure two oxidative damage markers: 3-nitrotyrosine (3NT) and 4-hydroxynonenal (4HNE) at 30 min, 1, 3, 6, 12, 24, 48, 72 hrs, 7 days after injury in ipsilateral cortex of young adult male CF-1 mice. Secondly, the time course of Ca ++ -activated, calpain-mediated proteolysis was also analyzed using quantitative western-blot measurement of breakdown products of the cytoskeletal protein α-spectrin. Finally, the time course of neurodegeneration was examined using de Olmos silver staining. Both oxidative damage markers increased in cortical tissue immediately after injury (30 min) and elevated for the first 3-6 hrs before returning to baseline. In the immunostaining study, the PN-selective marker, 3NT, and the lipid peroxidation marker, 4HNE, were intense and overlapping in the injured cortical tissue. α-Spectrin breakdown products, which was used as biomarker for calpain-mediated cytoskeletal degradation, were also increased after injury, but the time course lagged behind the peak of oxidative damage and did not reach its maximum until 24 hrs post-injury. In turn, cytoskeletal degradation preceded the peak of neurodegeneration which occurred at 48 hrs post-injury. These studies have led us to the hypothesis that PN-mediated oxidative damage is an early event that contributes to a compromise of Ca ++ homeostatic mechanisms which causes a massive Ca ++ overload and calpain activation which is a final common pathway that results in post-traumatic neurodegeneration.

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“…Recent studies suggest NMDAR subunit composition determines activation of distinct signaling pathways (Liu et al, 2004;Massey et al, 2004;Kim et al, 2005;Li et al, 2006), some of which are linked to cell death (DeRidder et al, 2006). Moreover, mHtt selectively alters NMDAR-mediated current and apoptosis in a non-neuronal cell line expressing recombinant NR1/NR2B but not NR1/NR2A (Chen et al, 1999).…”

Section: Nmdar Current Properties Are Similar For Yac128 and Wild-typmentioning

confidence: 99%

Mitochondrial Sensitivity and Altered Calcium Handling Underlie Enhanced NMDA-Induced Apoptosis in YAC128 Model of Huntington's Disease

Fernandes

Baimbridge²,

Church³

et al. 2007

J. Neurosci.

108

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Expansion of a CAG repeat in the Huntington's disease (HD) gene results in progressive neuronal loss, particularly of striatal mediumsized spiny neurons (MSNs). Studies in human HD autopsy brain tissue, as well as cellular and animal models of HD, suggest that increased activity of NMDA-type glutamate receptors and altered mitochondrial function contribute to selective neuronal degeneration. In this regard, the YAC128 mouse model, expressing full-length human huntingtin with 128 glutamine repeats, has been the focus of much interest. Although NMDA-induced apoptosis is enhanced in YAC128 MSNs, here we report that the initial steps in the death signaling pathway, including NMDA receptor (NMDAR) current and cytosolic Ca 2ϩ loading, are similar to those observed in wild-type MSNs. In contrast, we found that the NMDAR-mediated Ca 2ϩ load triggered a strikingly enhanced loss of mitochondrial membrane potential in YAC128 MSNs, suggesting that NMDAR signaling via the mitochondrial apoptotic pathway is altered. This effect was accompanied by impaired cytosolic Ca 2ϩ clearance after removal of NMDA, a difference that was not apparent after high potassium-evoked depolarization-mediated Ca 2ϩ entry. Inhibition of the mitochondrial permeability transition (mPT) reduced peak cytosolic Ca 2ϩ and mitochondrial depolarization evoked by NMDA in YAC128 MSNs but not wild-type MSNs. Hence, in contrast to YAC models with moderate CAG expansions, the enhanced NMDA-induced apoptosis in YAC128 MSNs is predominantly determined by augmented mitochondrial sensitivity to Ca 2ϩ -induced activation of the mPT. These results suggest that the CAG repeat length influences the mechanism by which mHtt enhances NMDAR-mediated excitotoxicity.

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Traumatic mechanical injury to the hippocampus in vitro causes regional caspase-3 and calpain activation that is influenced by NMDA receptor subunit composition

Cited by 80 publications

References 58 publications

NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death BothIn VitroandIn Vivo

NMDA Receptor Subunits Have Differential Roles in Mediating Excitotoxic Neuronal Death BothIn VitroandIn Vivo

Temporal relationship of peroxynitrite-induced oxidative damage, calpain-mediated cytoskeletal degradation and neurodegeneration after traumatic brain injury

Mitochondrial Sensitivity and Altered Calcium Handling Underlie Enhanced NMDA-Induced Apoptosis in YAC128 Model of Huntington's Disease

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