Inhibition of the transforming growth factor-β/SMAD cascade mitigates the anti-neurogenic effects of the carbamate pesticide carbofuran

摘要: The widely used carbamate pesticide carbofuran causes neurophysiological and neurobehavioral deficits in rodents humans therefore poses serious health hazards around the world. Previously, we reported that gestational exposure has detrimental effects on hippocampal neurogenesis, generation of new neurons from neural stem cells (NSC), offspring. However, underlying cellular molecular mechanisms for carbofuran-impaired neurogenesis remain unknown. Herein, observed chronic day 7 to postnatal 21 altered expression genes transcription factors levels proteins involved TGF-β pathway (i.e. TGF-β; SMAD-2, -3, -7; SMURF-2) rat hippocampus. We found increases signaling increased phosphorylated SMAD-2/3 reduced SMAD-7 expression) hippocampus, which NSC proliferation because p21 cyclin D1 levels. Moreover, carbofuran-altered impaired neuronal differentiation (BrdU/DCX+ BrdU/NeuN+ cells) apoptosis neurodegeneration Blockade with specific inhibitor SB431542 via SMAD-3 siRNA prevented carbofuran-mediated inhibition both cultures suggesting involvement this pathway. Of note, vitro vivo studies indicated attenuation reverses carbofuran's inhibitory associated learning memory deficits. These results suggest inhibits by altering signaling. Therefore, conclude may represent a potential therapeutic target against neurotoxicity disruption.