piperidines and trimethyltin

We showed that dextromethorphan (DM) provides neuroprotective/anticonvulsant effects and that DM and its major metabolite, dextrorphan, have a high-affinity for sigma(1) receptors, but a low affinity for sigma(2) receptors. In addition, we found that DM has a higher affinity than DX for sigma(1) sites, whereas DX has a higher affinity than DM for PCP sites. We extend our earlier findings by showing that DM attenuated trimethyltin (TMT)-induced neurotoxicity (convulsions, hippocampal degeneration and spatial memory impairment) in rats. This attenuation was reversed by the sigma(1) receptor antagonist BD 1047, but not by the sigma(2) receptor antagonist ifenprodil. DM attenuates TMT-induced reduction in the sigma(1) receptor-like immunoreactivity of the rat hippocampus, this attenuation was blocked by the treatment with BD 1047, but not by ifenprodil. These results suggest that DM prevents TMT-induced neurotoxicity, at least in part, via sigma(1) receptor stimulation.

Topics: Adrenergic alpha-Antagonists; Animals; Avoidance Learning; Behavior, Animal; Dextromethorphan; Ethylenediamines; Immunohistochemistry; Learning Disabilities; Maze Learning; Memory; Nerve Degeneration; Neurotoxicity Syndromes; Piperidines; Radioligand Assay; Rats; Rats, Inbred F344; Receptors, Phencyclidine; Receptors, sigma; Seizures; Sigma-1 Receptor; Trimethyltin Compounds

The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamatergic receptors have been linked to survival signaling, especially when the receptors are allosterically modulated by members of the Ampakine family. While increased glutamatergic communication through AMPA receptors has been shown to protect against toxic conditions that target hippocampal subfield CA1, protection in other subfields has not been shown. Accordingly, positive modulation of AMPA receptors by Ampakine compounds CX727 and CX516 was tested for effects on trimethyltin (TMT) neurotoxicity in rat hippocampal slice cultures. TMT was applied for 4 h followed by a rapid washout and antagonistic quenching of AMPA and N-methyl-D-aspartate (NMDA) receptors. After a 24-h period, the TMT-exposed slices exhibited increased levels of calpain-mediated spectrin breakdown as well as synaptic deterioration. TMT selectively targeted CA3 pyramidal neurons and dentate gyrus (DG) granule cells as evidenced by degeneration and neuronal loss. The cytoskeletal and synaptic damage was reduced when Ampakine modulation was initiated during the postinsult period. Furthermore, the extent of protection was comparable to that produced by the NMDA receptor antagonist AP5. The above results were substantiated by histological experiments, revealing that Ampakine treatment prevented TMT-induced cell loss in CA3 and DG. These results indicate that AMPA receptor signals are part of cellular repair responses following exposure to an environmental toxin.

Topics: Animals; Calpain; Dioxoles; Excitatory Amino Acid Antagonists; Female; Hippocampus; In Vitro Techniques; Male; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Spectrin; Trimethyltin Compounds