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Reversible and irreversible neuronal damage caused by excitatory amino acid analogues in rat cerebellar slices

1986; Elsevier BV; Volume: 18; Issue: 2 Linguagem: Inglês

10.1016/0306-4522(86)90163-6

1873-7544

Ferenc Hajós, G. Garthwaite, John Garthwaite,

Epilepsy research and treatment

Slice preparations of the developing rat cerebellum were used to investigate the light and electron microscopic correlates of reversible and irreversible neuronal injury caused by the neurotoxic excitatory amino acid receptor agonists, kainate and N-methyl-d-aspartate. The slices were examined after various periods of exposure to the agonists (up to 30 min) with or without a 90 min recovery period in agonist-free medium. N-Methyl-d-aspartate (100 μM) caused necrosis of deep nuclear neurons and differentiating granule cells, the exposure times necessary to induce non-recoverable damage (leading to necrosis), being, respectively, 10 min and 20–30 min. Exposure periods of only 2–4 min with kainate (100 μM) were needed for Golgi cells to subsequently undergo necrosis. Other cell types (Purkinje, granule and deep nuclear neurons) were altered histologically by kainate but most recovered fully from 30 min exposures. Before the recovery period, the worst affected of these cells (deep nuclear neurons) displayed increased cytoplasmic and nuclear electron density and microvacuolation due to swelling of Golgi cisterns but little or no chromatin clumping or mitochondrial expansion. The neurons which were injured irreversibly by the agonists within 30 min displayed, near the time of lethal injury, increased cytoplasmic and nuclear electron lucency, marked focal aggregation of chromatin and swelling of Golgi apparatus. Mitochondrial swelling did not appear to precede lethal injury and even after exposure times sufficient, or more than sufficient, to lead to necrosis, large numbers of mitochondria remained in a condensed configuration. The significance of the histological changes is discussed and they are compared with those occurring in other pathological conditions. The time scales required for the receptor agonists to induce irreversible cellular lesions would be consistent with this being a process which is responsible for acute neuronal necrosis in the brain.