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Evidence for Activation of Caspase‐3‐Like Protease in Excitotoxin‐ and Hypoxia/Hypoglycemia‐Injured Neurons
Author(s) -
Nath Rathna,
Probert Albert,
McGinnis Kim M.,
Wang Kevin K. W.
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.71010186.x
Subject(s) - staurosporine , kainate receptor , nmda receptor , neuroprotection , caspase 3 , apoptosis , programmed cell death , biology , biochemistry , chemistry , caspase , microbiology and biotechnology , neuroscience , ampa receptor , protein kinase c , enzyme , receptor
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 120‐kDa nonerythroid α‐spectrin breakdown product (SBDP120). Second, inhibitors of the caspase family are effective blockers of such neuronal death. In this study, we report the appearance of caspase‐mediated SBDP120 in excitotoxin‐challenged fetal rat cerebrocortical neurons [ N ‐methyl‐ d ‐aspartate (NMDA), α‐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 2 OC(O)‐2,6‐dichlorobenzene (Z‐D‐DCB), blocked the formation of SBDP120 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 NMDA‐treated granule neurons. Lastly, oxygen‐glucose deprivation (OGD)‐challenged cerebrocortical cultures also showed the appearance of SBDP120. Again, Z‐D‐DCB blocked the SBDP120 formation as well as attenuated the LDH release from the OGD‐challenged neurons. Taken together, the presence of caspase‐specific SBDP120 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.