Trimethyltin (TMT), a toxic organotin compound, induces neurodegeneration selectively involving the limbic system and especially prominent in the hippocampus. Neurodegeneration-associated behavioral abnormalities, such as hyperactivity, aggression, cognitive deficits, and epileptic seizures, occur in both exposed humans and experimental animal models. Previously, TMT had been used generally in industry and agriculture, but the use of TMT has been limited because of its dangers to people. TMT has also been used to make a promising in vivo rodent model of neurodegeneration because of its region-specific characteristics. Several studies have demonstrated that TMT-treated animal models of epileptic seizures can be used as tools for researching hippocampus-specific neurotoxicity as well as the molecular mechanisms leading to hippocampal neurodegeneration. This review summarizes the in vivo and in vitro underlying mechanisms of TMT-induced hippocampal neurodegeneration (oxidative stress, inflammatory responses, and neuronal death/survival). Thus, the present review may be helpful to provide general insights into TMT-induced neurodegeneration and approaches to therapeutic interventions for neurodegenerative diseases, including temporal lobe epilepsy.

Triethyltin (TET) and trimethyltin (TMT) are neurotoxic organotin compounds which produce different patterns of toxicity in adult animals. Exposure to TET produces behavioral toxicity (decreased motor activity, grip strength, operant response rate and startle response amplitude) which reflects impaired neuromotor function. These deficits are consistent with the reported myelin vacuolation and cerebral edema produced by TET, and with its direct effects on muscle. Exposure to TMT produces both hyperactivity and impaired learning and performance. These impairments are consistent with reported neuronal cell death produced by TMT, particularly in limbic system structures. While the behavioral deficits produced by repeated exposure to TET are reversible when dosing is terminated, the behavioral impairments produced by a single exposure to TMT appears to be irreversible.

We have demonstrated a deficit in working memory and/or consolidation of information in working memory into reference memory by a single oral dose of the neurotoxin trimethyltin(TMT). Moreover, TMT causes loss of hippocampal corticosterone receptors and increases brain glial fibrillary acidic protein(GFAP), an index of the astrocytic reaction to diverse types of CNS lesions. We tried to block the TMT-induced cognitive deficit and these biochemical markers by treating rats with purified mixed gangliosides (GS) for 21 days, starting 2 days before the TMT treatment. As expected, TMT decreased the number of corticosterone receptors in hippocampi and increased the GFAP concentration in hippocampi and to a lesser extent, in frontal cortices, measured more than 8 mon after treatment. The small increase in GFAP in frontal cortices was attenuated by GS but not in hippocampi. The pronounced learning deficits caused by TMT were attenuated to a small extent by GS in the TMT-GS group, when a learning criterion was used for the last session\'s performance of acquired lever-directed behavior. GS also delayed the appearance of significant performance differences between Controls and TMT-treated rats, when probed with a progressive fixed ratio schedule of reinforcement. However, most measures of learning and performance indicated that GS did not block the dysfunctional consequences of TMT treatment but instead caused similar functional decrements in rats treated with water instead of TMT. Corticosterone receptors in hippocampi were reduced to about 65% of Controls in the TMT-Water, TMT-GS, and Water-GS groups. A reduction in corticosterone receptors in hippocampi after TMT treatment probably reflects the loss of one or more cell types (e.g., pyramidal cells), which is supported by the increase in GFAP in this region. However, we did not observe a reciprocal relation between steroid receptors and GFAP after GS alone, indicating that GS did not cause detectable cell loss or cell damage, measured in this manner. Thus, reactive gliosis probably was not a pre-condition for the cognitive dysfunction. The fact that the cognitive deficits are probably related to hippocampal dysfunction supports the notion of a causal relationship between corticosterone receptor reduction and/or their altered function and cognitive impairment of this special type. The possibility that our results demonstrate potential neurobehavioral toxicity of GS is discussed in light of many reports which present data that can be similarly interpreted.