Effects of PI3K/AKT/mTOR pathway regulation of HIF-1α on Lanthanum-induced neurotoxicity in rats

Abstract

This study examined the effects of the AKT/mTOR/HIF-1α signaling pathway on learning and memory in offspring rats induced by lanthanum from neuroethology and molecular biology perspectives. 32 pregnant adult Wistar rats were divided into four groups randomly: control group (NC), 0.25%, 0.5% and 1.0% LaCl3 groups (n = 8). All rats were poisoned through free drinking from day 0 of pregnancy to postnatal day 21 (suckling period). All offspring rats were poisoned through free drinking from delactation to postnatal day 48. Offspring rats aged 49-days-old were used as sampling objects to construct an LaCl3 poisoning model of offspring rats. Changes in hippocampal neurons, apoptosis of hippocampal neurons, learning and memory abilities of LaCl3-poisoned animals were measured by Nissl staining, TUNEL method and the shuttle box test, respectively. Expressions of PI3K, AKT, and mTOR, HIF-1α, and VEGF in the hippocampus were tested by qPCR and Western blot. Distributions of PI3K and p-AKT in hippocampal neurons were observed through the immunohistochemical method. With increasing LaCl3 dose, lightning strike time and active avoidance incubation period of offspring rats in the different LaCl3 groups were significantly prolonged. The Nissl body positive neurons of hippocampal neurons gradually declined while apoptosis in cells increased. The expressions of both mRNA (PI3K, AKT, mTOR, HIF-1α, VEGF) and proteins (PI3K, p-AKT, p-mTOR, HIF-1α, VEGF) in the hippocampus of the LaCl3 groups were significantly lower than those of NC group (p < 0.05). LaCl3 poisoning can induce developmental injuries in hippocampal neurons and can increase cell apoptosis. As a result, learning and memory abilities of offspring rats, as well as the expressions of PI3K/AKT/mTOR, are decreased, thus inhibiting activation of HIF-1α and influencing the expression of the downstream VEGF gene.