Activation of apoptosis-linked caspase(s) in NMDA-injured brains in neonatal rats.
Unilateral injection of 50 nmol of N-methyl-D-aspartate (NMDA) into the left posterior striatum of 7 day-old rat pups induces massive neuronal loss in the ipsilateral hemisphere in 5 days. In this model of excitotoxicity, the form of neuronal death (necrosis vs apoptosis) has not been clearly addressed. Here we report evidence of DNA laddering in the ipsilateral hemisphere 24 h after the NMDA injection. Activation of apoptosis-linked caspase(s) was also identified, as evidenced by (i) the formation of caspase-produced 120 kDa alpha-spectrin breakdown product (SBDP120) and (ii) increase in hydrolysis of caspase-3 substrate acetyl-DEVD-7-amido-4-methylcoumarin in the homogenate from the ipsilateral hemisphere. Lastly, we note that i.p. injection (100 mg/kg) of a pan caspase inhibitor Z-D-DCB attenuates the levels of SBDP120. Our results suggest the presence of caspase-activation in this rat pup model of NMDA toxicity.
Nath
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Department of Neuroscience Therapeutics, Parke-Davis Pharmaceutical Research, Division of' Warner-Lambert Company, Ann Arbor, Michigan, 48105, USA. rathna.nath@wl.com
Scott
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Nadimpalli
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Gupta
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Wang
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D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D001927:Brain Diseases / Q000139:chemically induced* / Q000201:enzymology* / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D053938:DNA Fragmentation; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D016202:N-Methylaspartate; D051381:Rats; D017207:Rats, Sprague-Dawley; D013049:Spectrin / Q000378:metabolism
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D013049:Spectrin; D016202:N-Methylaspartate; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases