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

Abstract

Trimethyltin (TMT) toxicity causes histopathological damage in the hippocampus and induces seizure behaviors in mice. The lesions and symptoms recover spontaneously over time; however, little is known about the precise mechanisms underlying this recovery from TMT toxicity. We investigated changes in the brain-derived neurotrophic factor/extracellular signal-regulated kinases (BDNF/ERK) signaling pathways in the mouse hippocampus following TMT toxicity. Mice (7 weeks old, C57BL/6) administered TMT (2.6 mg/kg intraperitoneally) showed acute and severe neurodegeneration with increased TUNEL-positive cells in the dentate gyrus (DG) of the hippocampus. The mRNA and protein levels of BDNF in the hippocampus were elevated by TMT treatment. Immunohistochemical analysis showed that TMT treatment markedly increased phosphorylated ERK1/2 expression in the mouse hippocampus 1-4 days after TMT treatment, although the intensity of ERK immunoreactivity in mossy fiber decreased at 1-8 days post-treatment. In addition, ERK-immunopositive cells were localized predominantly in doublecortin-positive immature progenitor neurons in the DG. In primary cultured immature hippocampal neurons (4 days in vitro), BDNF treatment alleviated TMT-induced neurotoxicity, via activation of the ERK signaling pathway. Thus, we suggest that BDNF/ERK signaling pathways may be associated with cell differentiation and survival of immature progenitor neurons, and will eventually lead to spontaneous recovery in TMT-induced hippocampal neurodegeneration.

Social Buffering Prevents Stress-Induced Decreases in Dendritic Length, Branching in Dentate Granule Cells and Hippocampus-Related Memory Performance

“…BDNF induction has been known to play a critical role in mediating morphological and synaptic plasticity in DG granule cells [12][13][14]. Moreover, BDNF is found to induce these morphological and synaptic changes likely via phosphorylation of local extracellular signalregulated kinases (ERK) and ERK-dependent cAMP response element binding protein (CREB) phosphorylation [15][16][17]. Thus, the present study was designed to assess whether the present stressor regimen may cause changes in local ERK and CREB expression and phosphorylation in DG.…”

Protective Effects of Scolopendra Water Extract on Trimethyltin-Induced Hippocampal Neurodegeneration and Seizures in Mice

“…The primary culture of hippocampal neurons has been previously described [12,15]. Briefly, hippocampi were dissected from C57BL/6 mice pups at 17-18 gestational days.…”

“…An LDH cytotoxicity assay kit from BioVision (Mountain View, CA, USA) was used in the way recommended by the manufacturer. The optical density values were quantified by measuring absorbance at a wavelength of 450 nm using a microplate reader (EMax, Molecular Devices, Sunnyvale, CA, USA) [12].…”

“…After a 2 h of incubation at 37 • C with 5% CO 2 , the resulting formazan crystals were dissolved in MTT solubilization solution (Sigma-Aldrich) and quantified using an Emax spectrophotometer (Molecular Devices) by measuring the absorbance at 595 nm. The background absorbance at 690 nm was subtracted [12].…”

“…Humans accidentally exposed to TMT develop a syndrome characterized by seizures, disorientation, and confusion [8,10]. In experimental animals, TMT administration induces severe hippocampal damage and consequent behavioral alterations such as ataxia, aggression, tail mutilation, vocalization, and seizures [11,12]. These behavioral features mimic those of individuals occupationally or accidentally exposed to TMT, and the similar temporal correlation between the time of cell death and the onset of the seizure behavior may suggest a causal relationship between TMT-induced hippocampal damage and seizure behavior [13,14].…”