Aluminum trichloride caused hippocampal neural cells death and subsequent depression-like behavior in rats via the activation of IL-1β/JNK signaling pathway

Aluminum (Al) is an inorganic pollutant that induces nerve cells apoptosis and necroptosis, thereby causing depression and neurodegenerative diseases. IL-1β/JNK signaling pathway can regulate apoptosis and necroptosis. However, it remains unclear whether IL-1β/JNK signaling pathway is involving in the regulation of Al-induced hippocampal neural cells apoptosis and necroptosis. To investigate the mechanism of Al on neural cells apoptosis and necroptosis, rats were orally exposed to different doses of AlCl3 for 90 days. The open-field test results showed that AlCl3 caused depressive behavior in rats. Histopathological evidence showed that AlCl3 induced hippocampal neural cells apoptosis and necrosis. Moreover, Bax/Bcl-2 mRNA expression ratio, caspase-3 activity and mRNA expression and TUNEL positive rates were upregulated, meanwhile, TNF-α mRNA and protein expression levels, TNFR1, RIP1, RIP3 and MLKL proteins levels were increased, while caspase-8 protein level was decreased in the hippocampus of Al-exposed groups. These results proved that AlCl3 induced hippocampal neural cells apoptosis and necroptosis. Combined with histopathology and correlation analysis, we deduced that hippocampal neural cells were more likely to undergo necroptosis at high doses (450 mg/kg) of AlCl3, while <150 mg/kg AlCl3 tended to induce apoptosis. Finally, AlCl3 increased the proteins level of IL-1β, IL-1RI, IL-1RAcP, JNK and p-JNK, indicating that AlCl3 activated IL-1β/JNK signaling pathway. However, the application of IL-1 receptor antagonist (IL-1Ra) inhibited the phosphorylation of JNK and the related genes expression of apoptosis and necroptosis caused by AlCl3. Thus, we concluded that AlCl3 induced hippocampal neural cells death and depression-like behavior in rats by activating IL-1β/JNK signaling pathway.