The Preventive Effects of Salubrinal against Pyrethroid-Induced Disruption of Adult Hippocampal Neurogenesis in Mice.
The Preventive Effects of Salubrinal against Pyrethroid-Induced Disruption of Adult Hippocampal Neurogenesis in Mice.
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DOI：
10.3390/ijms242115614
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发表时间：
2023-10-26
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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环境因素，包括农药暴露，已被确定为神经变性和认知障碍的重要因素。以前，我们证明了重复暴露于溴氰菊酯诱导内质网（ER）应激，减少海马神经发生，并损害成年小鼠的认知。在这里，我们研究了雌激素受体应激和海马神经发生暴露于溴氰菊酯后，利用药理学和遗传学的方法之间的潜在关系。为了研究ER应激是否与神经发生抑制相关，在经口给予溴氰菊酯（3 mg/kg）前24 h和30 min，对小鼠腹腔注射两次eIf 2 α抑制剂salubrinal（1 mg/kg）。Salubrinal防止海马ER应激，如C/EBP同源蛋白（CHOP）和转录因子4（ATF 4）水平降低和衰减溴氰菊酯诱导的海马齿状回（DG）中BrdU-、Ki-67-和DCX阳性细胞减少所示。为了进一步探索ER应激和成年神经发生之间的关系，我们使用caspase-12敲除（KO）小鼠。caspase-12 KO小鼠表现出显着的保护作用，对溴氰菊酯诱导的减少BrdU，Ki-67，和DCX阳性细胞在海马。此外，溴氰菊酯暴露导致WT小鼠中大部分BrdU和Ki-67阳性细胞的CHOP和半胱天冬酶-12表达显著上调。相反，salubrinal处理的小鼠和caspase-12 KO小鼠在海马中表现出相当低数量的CHOP阳性细胞。总之，这些研究结果表明，暴露于杀虫剂溴氰菊酯触发ER应激介导的抑制成年海马神经发生，这可能随后导致小鼠的学习和记忆缺陷。
Environmental factors, including pesticide exposure, have been identified as substantial contributors to neurodegeneration and cognitive impairments. Previously, we demonstrated that repeated exposure to deltamethrin induces endoplasmic reticulum (ER) stress, reduces hippocampal neurogenesis, and impairs cognition in adult mice. Here, we investigated the potential relationship between ER stress and hippocampal neurogenesis following exposure to deltamethrin, utilizing both pharmacological and genetic approaches. To investigate whether ER stress is associated with inhibition of neurogenesis, mice were given two intraperitoneal injections of eIf2α inhibitor salubrinal (1 mg/kg) at 24 h and 30 min prior to the oral administration of deltamethrin (3 mg/kg). Salubrinal prevented hippocampal ER stress, as indicated by decreased levels of C/EBP-homologous protein (CHOP) and transcription factor 4 (ATF4) and attenuated deltamethrin-induced reductions in BrdU-, Ki-67-, and DCX-positive cells in the dentate gyrus (DG) of the hippocampus. To further explore the relationship between ER stress and adult neurogenesis, we used caspase-12 knockout (KO) mice. The caspase-12 KO mice exhibited significant protection against deltamethrin-induced reduction of BrdU-, Ki-67-, and DCX-positive cells in the hippocampus. In addition, deltamethrin exposure led to a notable upregulation of CHOP and caspase-12 expression in a significant portion of BrdU- and Ki-67-positive cells in WT mice. Conversely, both salubrinal-treated mice and caspase-12 KO mice exhibited a considerably lower number of CHOP-positive cells in the hippocampus. Together, these findings suggest that exposure to the insecticide deltamethrin triggers ER stress-mediated suppression of adult hippocampal neurogenesis, which may subsequently contribute to learning and memory deficits in mice.
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