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Trimethyltin (TMT) is a potent neurotoxicant that affects various regions within the central nervous system, including the neocortex, cerebellum, and hippocampus. In the present study, ginsenoside Rd was investigated as a candidate neuroprotective agent in a primary hippocampal neuron culture and mouse models. TMT induced neurotoxicity in a seven-day primary hippocampal neuron culture in a dose-dependent manner (2.5-10 μM). However, pre-treatment with 20 μg/ml ginsenoside Rd for 24 h reversed the toxic action. ICR mice were administered a single injection of 2 mg/kg body weight TMT. Apparent tremor seizure and impaired passive avoidance tests demonstrated significant differences when compared with a saline treated control group. Nissl staining was performed to evaluate the neuronal loss in the hippocampus. In addition, immunostaining of glial fibrillary acidic protein characterized the features of astroglial activation. These results demonstrated that TMT markedly induced Cornu Ammonis 1 subregion neuronal loss and reactive astrocytes in the hippocampus, indicating disrupted hippocampal function. Notably, ginsenoside Rd attenuated the tremor seizures and cognitive decline in behavioral tests. Additionally, significantly reduced neuronal loss (P=0.018) and active astroglials (P=0.003) were observed in the ginsenoside Rd treated group. Ginsenoside Rd prevented TMT-induced cell apoptosis via regulation of B-cell lymphoma 2 (Bcl-2), bcl-2-like protein 4 and caspase-3. These results demonstrate that ginsenoside may be developed as a neuroprotective agent to prevent TMT-induced neurotoxicity. [ABSTRACT FROM AUTHOR]