Trimethyltin-induced neurotoxicity: In vitro and in vivo mechanistic studies

Michael David Kane, Purdue University

Abstract

Organotin compounds are used in a number of industrial applications. Trimethyltin (TMT) is a highly neurotoxic organotin compound that causes a selective, time- and dose-dependent lesion specific to the hippocampus. This lesion is accompanied by reactive astrocytosis and glial fibrillary acidic protein (GFAP) induction. The selective neurotoxicity of TMT has led to its use as a model chemical for the study delayed neuronal cell death. However, the mechanisms underlying TMT-induced neurodegeneration are not fully understood. The overall goal of this project involved identifying the initial cellular event(s) mediated by TMT that lead to neuronal cell death in vitro. Conclusions obtained from the in vitro model provide a mechanistic starting point to investigate TMT-induced hippocampal neurodegeneration. TMT exposure initially led to glutamate and acetylcholine release from differentiated PC12 cells which in turn activate their respective receptors and lead to PKC activation. Pretreatment with a selective PKC inhibitor or PKC down-regulation provided significant protection against TMT-induced cytotoxicity in differentiated PC12 cells, indicating PKC activation plays a role in TMT-induced cytotoxicity. Subsequent experiments revealed TMT induced glutamate release to be sodium dependent suggesting a reversal of the sodium-dependent glutamate transporter in vitro. Excessive glutamate signaling has been shown to be neurotoxic in the hippocampus, a phenomenon known as excitotoxicity. Excitotoxicity has been suggested to underlie other pathologic states that affect the hippocampus, including ischemia and hypoxia. TMT induced glutamate release in vitro suggested excitotoxicity may be involved in TMT-induced hippocampal neurodegeneration. The role of TMT-induced glutamate release and altered glutamate homeostasis in TMT neurotoxicity was investigated in vivo by examining the effects of MK-801, a competitive glutamate excitatory NMDA receptor antagonist, and BW1003C87, a sodium channel antagonist, on TMT-induced hippocampal lesion formation in mice. Both MX-801 and BW1003C87 treatment failed to protect against TMT-induced neuronal cell death in the hippocampus. These results indicate TMT neurotoxicity in vivo is not mediated through the glutamate NMDA receptor. However, BW1003C87 was found to inhibit TMT-induced GFAP induction in vivo suggesting TMT-induced reactive astrocytosis is dependent on sodium channel function.

Degree

Ph.D.

Advisors

Isom, Purdue University.

Subject Area

Pharmacology|Neurology

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