Impairment of object recognition memory by maternal bisphenol A exposure is associated with inhibition of Akt and ERK/CREB/BDNF pathway in the male offspring hippocampus.
Bisphenol A (BPA) is a commonly used endocrine-disrupting chemical used as a component of polycarbonates plastics that has potential adverse effects on human health. Exposure to BPA during development has been implicated in memory deficits, but the mechanism of action underlying the effect is not fully understood. In this study, we investigated the effect of maternal exposure to BPA on object recognition memory and the expressions of proteins important for memory, especially focusing on the ERK/CREB/BDNF pathway. Pregnant Sprague-Dawley female rats were orally treated with either vehicle or BPA (0.05, 0.5, 5 or 50 mg/kg BW/day) during days 9-20 of gestation. Male offspring were tested on postnatal day 21 with the object recognition task. Recognition memory was assessed using the object recognition index (index=the time spent exploring the novel object/(the time spent exploring the novel object+the time spent exploring the familiar object)). In the test session performed 90 min after the training session, BPA-exposed male offspring not only spent more time in exploring the familiar object at the highest dose than the control, but also displayed a significantly decreased the object recognition index at the doses of 0.5, 5 and 50 mg/kg BW/day. During the test session performed 24h after the training session, BPA-treated males did not change the time spent exploring the familiar object, but had a decreased object recognition index at 5 and 50 mg/kg BW/day, when compared to control group. These findings indicate that object recognition memory was susceptible to maternal BPA exposure. Western blot analysis of hippocampi from BPA-treated male offspring revealed a decrease in Akt, phospho-Akt, p44/42 MAPK and phospho-p44/42 MAPK protein levels, compared to controls. In addition, BPA significantly inhibited the levels of phosphorylation of CREB and BDNF in the hippocampus. Our results show that maternal BPA exposure may full impair object recognition memory, and that impairment may be related to a decrease in Akt activation and an inhibition of the ERK/CREB/BDNF pathway in the hippocampus. This study also adds new evidence that suggests BPA has an antagonistic effect on the action of estrogen in the brain.
Wang C
，Li Z
，Han H
，Luo G
，Zhou B
，Wang S
，Wang J
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The Protective Effects of Syringic Acid on Bisphenol A-Induced Neurotoxicity Possibly Through AMPK/PGC-1α/Fndc5 and CREB/BDNF Signaling Pathways.
Bisphenol A (BPA), an endocrine disruptor, is commonly used to produce epoxy resins and polycarbonate plastics. Continuous exposure to BPA may contribute to the development of diseases in humans and seriously affect their health. Previous research suggests a significant relationship between the increased incidence of neurological diseases and the level of BPA in the living environment. Syringic acid (SA), a natural derivative of gallic acid, has recently considered much attention due to neuromodulator activity and its anti-oxidant, anti-apoptotic, and anti-inflammatory effects. Therefore, in this study, we aimed to investigate the effects of SA on oxidative stress, apoptosis, memory and locomotor disorders, and mitochondrial function, and to identify the mechanisms related to Alzheimer's disease (AD) in the brain of rats receiving high doses of BPA. For this purpose, male Wistar rats received BPA (50, 100, and 200 mg/kg) and SA (50 mg/kg) for 21 days. The results showed that BPA exposure significantly altered the rats' neurobehavioral responses. Additionally, BPA, by increasing the level of ROS, and MDA level, increased the level of oxidative stress while reducing the level of antioxidant enzymes, such as SOD, CAT, GPx, and mitochondrial GSH. The administration of BPA at 200 mg/kg significantly decreased the expression of ERRα, TFAM, irisin, PGC-1α, Bcl-2, and FNDC5, while it increased the expression of TrkB, cytochrome C, caspase 3, and Bax. Moreover, the Western blotting results showed that BPA increased the levels of P-AMPK, GSK3b, p-tau, and Aβ, while it decreased the levels of PKA, P-PKA, Akt, BDNF, CREB, P-CREB, and PI3K. Meanwhile, SA at 50 mg/kg reversed the behavioral, biochemical, and molecular changes induced by high doses of BPA. Overall, BPA could lead to the development of AD by affecting the mitochondria-dependent apoptosis pathway, as well as AMPK/PGC-1α/FNDC5 and CREB/BDNF/TrkB signaling pathways, and finally, by increasing the expression of tau and Aβ proteins. In conclusion, SA, as an antioxidant, significantly reduced the toxicity of BPA.
Helli B
，Navabi SP
，Hosseini SA
，Sabahi A
，Khorsandi L
，Amirrajab N
，Mahdavinia M
，Rahmani S
，Dehghani MA
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Impairment of learning and memory induced by perinatal exposure to BPA is associated with ERα-mediated alterations of synaptic plasticity and PKC/ERK/CREB signaling pathway in offspring rats.
The effect of bisphenol A (BPA) on learning and memory has attracted much attention recently, but its underlying mechanism remains unclear. We aimed to investigate whether the impairment of learning and memory induced by perinatal exposure to BPA was associated with the hippocampal estrogen receptor α (ERα)-mediated synaptic plasticity and PKC/ERK/CREB signaling pathway in different sex offspring rats. Pregnant Sprague-Dawley rats were treated with BPA (1 and 10 μg/mL) through drinking water from gestational day (GD) 6 to postnatal day (PND) 21. After weaning, offspring drank BPA-free water until PND 56. Morris water maze, placement and object recognition, and step-down passive avoidance task were performed. The serum estradiol (E2) levels, histopathology of hippocampus, and the expression of learning and memory related proteins were measured. The results showed that spatial and recognition memory were impaired in BPA-exposed female and male offspring, but the impaired passive avoidance memory presented only in males, not in females. The serum E2 levels were increased in BPA-exposed females and males. BPA altered the morphology and quantity of hippocampal neurons. The levels of ERα, NMDA receptor subunit 2B (NR2B), p-NR2B, AMPA receptor 1 (GluA1), p-GluA1, PSD-95, synapsin I, PKC, p-ERK and p-CREB protein expression were decreased in BPA exposed females and males, and there were interactions of sex × BPA exposure in ERα, p-NR2B and p-ERK levels. These findings suggested that perinatal exposure to BPA has sex-specific effects on learning and memory, which is associated with ERα-mediated impairment of synaptic plasticity and down-regulation of PKC/ERK/CREB signaling pathway.
Wu D
，Wu F
，Lin R
，Meng Y
，Wei W
，Sun Q
，Jia L
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Lycopene attenuates aluminum-induced hippocampal lesions by inhibiting oxidative stress-mediated inflammation and apoptosis in the rat.
Aluminum (Al) causes hippocampal lesions by oxidative stress, which is widely accepted as the primary pathogenesis of Al neurotoxicity. Lycopene (LYC), a naturally carotenoid, has received extensive attention due to its antioxidant effect. In this study, the neuroprotective effects and mechanisms of LYC against aluminum chloride (AlCl3)-induced hippocampal lesions were explored. First, oral administration of LYC (4 mg/kg) alleviated AlCl3-induced (150 mg/kg) cognition impairment and histopathological changes of the hippocampus in rats. Then, LYC significantly attenuated AlCl3-induced oxidative stress, presenting as the reduced reactive oxygen species, malondialdehyde and 8-hydroxy-2'-deoxyguanosine levels, and increased glutathione level and superoxide dismutase activity. Moreover, LYC also protected the hippocampus from AlCl3-induced apoptosis and neuroinflammation, as assessed by protein levels of p53, Bcl-2-associated X protein (Bax), B-cell lymphoma gene 2 (Bcl-2), Cytochrome c (Cyt c), cleaved caspase-3 and nuclear factor kappa B, as well as the mRNA levels of Bax, Bcl-2, tumor necrosis factor alpha, interleukin-6 and interleukin-1 beta. Finally, LYC increased nuclear factor-erythroid-2-related factor 2 (Nrf2) nuclear translocation and its downstream gene expression, including heme oxygenase-1, NAD(P)H: quinone oxidoreductase 1, glutamate cysteine ligase catalytic subunit and superoxide dismutase 1, which were involved in antioxidant, anti-apoptosis, and anti-inflammation. Overall, our findings demonstrate LYC attenuates Al-induced hippocampal lesions by inhibiting oxidative stress-mediated inflammation and apoptosis in the rat.
Cao Z
，Wang P
，Gao X
，Shao B
，Zhao S
，Li Y
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