Evidence for Activation of Caspase‐3‐Like Protease in Excitotoxin‐ and Hypoxia/Hypoglycemia‐Injured Neurons

Abstract

Caspase activation has been shown to be a critical step in several models of neuronal apoptosis such as staurosporine treatment of human neuroblastoma SH-SY5Y cells and potassium deprivation of rat cerebellar granule neurons. One common event is the appearance of caspase-mediated 1 20-kDa nonerythroid ea-spectrin breakdown product (SBDP1 20). Second, inhibitors of the caspase family are effective blockers of such neuronal death. In this study, we report the appearance of caspase-mediated SBDP1 20 in excitotoxin-challenged fetal rat cerebrocortical neurons [N-methyl-o-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate] and rat cerebellar granule neurons (NMDA and kainate). A general caspase inhibitor, carbobenzoxy-Asp-CH 2OC (0) -2 ,6-dichlorobenzene (Z-D-DCB), blocked the formation of SBDP1 20 under these conditions and attenuated the observed NMDA-induced lactate dehydrogenase (LDH) release in both cell types. Furthermore, hydrolytic activity toward a caspase-3-preferred synthetic peptide substrate, acetyl-DEVD-7-amido-4-methylcoumarin, was significantly elevated in NM DA-treated granule neurons. Lastly, oxygen-glucose deprivation (OGD) -challenged cerebrocortical cultures also showed the appearance of SBDP12O. Again, Z-D-DCB blocked the SBDP12O formation as well as attenuated the LDH release from the OGD-challenged neurons. Taken together, the presence of caspase-specific SBDP1 20 and the neuroprotective effects of Z-D-DCB strongly suggest that caspase activation contributes at least in part to excitotoxin-and OGD-induced neuronal death.

HSV-mediated delivery of virally derived anti-apoptotic genes protects the rat hippocampus from damage following excitotoxicity, but not metabolic disruption

“…6,7,27 However, there is some evidence for an apoptotic pathway of neuron death, as demonstrated by the appearance of certain morphological and biochemical features characteristic of apoptosis. [28][29][30][31][32][33] Emerging data support the idea that apoptosis and necrosis in vivo are not distinct, clear-cut pathways, but rather represent a morphological continuum of neuronal death processes.…”

IGF-I receptor activation and BCL-2 overexpression prevent early apoptotic events in human neuroblastoma

“…38 In SH-SY5Y cells, caspase-3 activation also occurs in response to nitric oxide, 71 hypoxia/hypoglycemia, or excitotoxin exposure. 72 The IGF-IR is postulated to play a role in the progression of several tumor types. 73 IGF-IR is overexpressed in most breast cancer cell lines, and IGF-IR autophosphorylation and tyrosine kinase activity correlate with breast malignancy.…”

Requirement of the JIP1 scaffold protein for stress-induced JNK activation

“…Incubation of neurons in glucose-free medium with a reduced oxygen (1%) environment for 4 h (oxygen-glucose deprivation; OGD) causes caspase-3 activation and apoptosis during subsequent culture in normal medium (Nath et al 1998). The basal level of activated JNK in wild-type and Jip1 −/− hippocampal neurons was similar.…”