Possible Role of the Glycogen Synthase Kinase-3 Signaling Pathway in Trimethyltin-Induced Hippocampal Neurodegeneration in Mice

Abstract

Trimethyltin (TMT) is an organotin compound with potent neurotoxic effects characterized by neuronal destruction in selective regions, including the hippocampus. Glycogen synthase kinase-3 (GSK-3) regulates many cellular processes, and is implicated in several neurodegenerative disorders. In this study, we evaluated the therapeutic effect of lithium, a selective GSK-3 inhibitor, on the hippocampus of adult C57BL/6 mice with TMT treatment (2.6 mg/kg, intraperitoneal [i.p.]) and on cultured hippocampal neurons (12 days in vitro) with TMT treatment (5 µM). Lithium (50 mg/kg, i.p., 0 and 24 h after TMT injection) significantly attenuated TMT-induced hippocampal cell degeneration, seizure, and memory deficits in mice. In cultured hippocampal neurons, lithium treatment (0–10 mM; 1 h before TMT application) significantly reduced TMT-induced cytotoxicity in a dose-dependent manner. Additionally, the dynamic changes in GSK-3/β-catenin signaling were observed in the mouse hippocampus and cultured hippocampal neurons after TMT treatment with or without lithium. Therefore, lithium inhibited the detrimental effects of TMT on the hippocampal neurons in vivo and in vitro, suggesting involvement of the GSK-3/β-catenin signaling pathway in TMT-induced hippocampal cell degeneration and dysfunction.

Involvement of BDNF/ERK signaling in spontaneous recovery from trimethyltin-induced hippocampal neurotoxicity in mice

“…Seizures developed rapidly on day 1 after TMT treatment, peaked on day 2, and then decreased (Fig. 1A, n = 10 mice/group), consistent with data from our previous studies on TMT treatment in mice (Kim et al, 2013; Kim et al, 2014a; Kim et al, 2014b; Lee et al, 2014). Clinical symptoms in the recovery stage (days 4–8 post-injection) were significantly decreased compared to the peak stage (day 2 post-injection; Fig.…”

“…Neurodegeneration from TMT toxicity results from complex events, including neuroinflammation, glutamate excitotoxicity, intracellular calcium overload, oxidative stress, mitochondrial dysfunction, and impaired neurotransmission (Corvino et al, 2013; Doctor et al, 1982; Geloso et al, 2011; Kim da and Kim, 2015; Naalsund et al, 1985; Piacentini et al, 2008). Mice exposed to TMT exhibit seizure behaviors, but these symptoms resolve spontaneously (Kim et al, 2013). Consistently, TMT induces neuronal degeneration, but the lesion subsequently recovers, and it has been shown that newborn neurons replace the damaged ones in the SGZ (Harry et al, 2004; Ogita et al, 2005).…”

“…The primary hippocampal cell culture method has been previously described (Kim et al, 2013; Yang et al, 2011). Briefly, hippocampi were dissected from C57BL/6J mice pups at postnatal day 1, and prepared for culturing.…”

“…TMT-treated animals show neuronal death and glial activation in the hippocampus (Fiedorowicz et al, 2001; Kim et al, 2014b). They also exhibit cognitive deficits and behavioral changes, including memory loss, learning impairment, hyperactivity, aggression, and seizures (Besser et al, 1987; Fabrizi et al, 2015; Kim et al, 2013). …”

Nestin expression and glial response in the hippocampus of mice after trimethyltin treatment

“…TMT treatment markedly increased FJB-positive degenerating neurons in the GCL 4 days post-treatment (Fig. 1C), in agreement with the quantitative results of our previous studies (Yang et al, 2012;Kim et al, 2013).…”