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Endogenous excitatory amino acid release from brain slices and astrocyte cultures evoked by trimethyltin and other neurotoxic agents

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Abstract

Trimethyltin (TMT) is a toxic alkyltin compound that is known to produce neuronal necrosis in the CNS. The present study examined the effects of TMT on the release of excitatory amino acids (EAA) from cortical slices prepared from adult and aged (24 months old) rats. The calcium dependence of TMT-induced EAA efflux was evaluated and compared to other neurotoxic agents. The actions of TMT were also evaluated in an astrocyte culture model to assess glial contributions to TMT-induced EAA efflux. TMT (10–1000 μM) evoked a dose-related increase in GLU and ASP efflux during a 30 min incubation period and this efflux was sustained or slightly higher during a 15 min recovery period. TMT-stimulated GLU efflux was not altered in aged rats. TMT-induced GLU efflux was significantly reduced by removing extracellular calcium and including 10 μM EGTA in the incubation media. Calcium channel blockers (nifedipine, verapamil, flunarizine, amiloride, neomycin) and MK-801 did not significantly attenuate TMT-induced GLU efflux. Diltiazem (25 μM) produced modest but inconsistent reductions in TMT-induced GLU efflux from brain slices, and significantly inhibited the leakage of lactate dehydrogenase (LDH) from TMT-treated astrocyte cultures. TMT did not increase GLU efflux from glial cultures during a 30 min incubation period, but did significantly elevate GLU efflux during the 15 min recovery period. TMT evoked the release of EAA by both calcium dependent and independent mechanisms in brain slices. TMT at high concentrations also produced a delayed increase in glial GLU efflux. These studies suggest that excitotoxic mechanisms may contribute to TMT-induced neurotoxicity.

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Authors and Affiliations

  1. Department of Pharmacodynamics, College of Pharmacy, University of Florida, JHMHC Box 100487, 32610, Gainesville, Florida

    Ralph Dawson Jr., Tucker A. Patterson & Baerbel Eppler

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  2. Tucker A. Patterson
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Dawson, R., Patterson, T.A. & Eppler, B. Endogenous excitatory amino acid release from brain slices and astrocyte cultures evoked by trimethyltin and other neurotoxic agents. Neurochem Res 20, 847–858 (1995). https://doi.org/10.1007/BF00969697

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