Excitotoxicity induced by l- glutamate (Glu), when examined in a pure neuronal cortical culture, involved widespread apoptosis at concentrations of 1–10 μM as part of a continuum of injury, which at its most servere was purely necrotic. Cells, maintained in chemically defined neurobasal/B27 medium, were exposed at d7 for 2 h to Glu (1–500 μM), and cellular injury was analysed 2 and 24 h after insult using morphology (phase-contrast microscopy), a 3-(4,5-dimethylthiazol - 2-yl)-2,5-diphenyltetrazolium bromide (MTT) viability assay, nuclear staining with 4,6-diamidino-2-phenylindole (DAPI), terminal transferase-mediated dUTP nick end-labelling (TUNEL) and DNA fragmentation by gel electrophoresis. Glu-mediated neurotoxicity was prevented by MK-801 (5 μM), whilst CNQX (20 μM) attenuated injury by 20%. Exposure to intensive insults (100 and 500 μM Glu) induced necrosis characterized by rapid cell swelling (<2 h) and lack of chromatin condensation, confirmed by DAPI nuclear staining. In contrast, mild insults (<20 μM Glu) failed to produce acute neuronal swelling at <2 h, but 24 h after injury resulted in a large number of apoptotic nuclei as confirmed by TUNEL and electrophoretic evidence of DNA fragmentation, which was attenuated by cycloheximide (0.1 μg/ml). Our findings indicate for the first time that physiological concentrations of Glu produce neuronal injury across a continuum involving apoptosis (<20 μM) and increasingly necrosis(>20 μM), dependent on the severity of the initial insult.
Neuropharmacology – Elsevier
Published: Oct 1, 1998
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