Drug Research and Development Center, Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil.
Fundação Oswaldo Cruz (Fiocruz-CE), Fortaleza, Ceara, Brazil.
J Psychopharmacol. 2020 Jan;34(1):125-136. doi: 10.1177/0269881119875979. Epub 2019 Sep 26.
Schizophrenia (SCZ) is a neurodevelopmental disorder influenced by patient sex. Mechanisms underlying sex differences in SCZ remain unknown. A two-hit model of SCZ combines the exposure to perinatal infection (first-hit) with peripubertal unpredictable stress (PUS, second-hit). N-acetylcysteine (NAC) has been tested in SCZ because of the involvement of glutathione mechanisms in its neurobiology.
We aim to investigate whether NAC administration to peripubertal rats of both sexes could prevent behavioral and neurochemical changes induced by the two-hit model.
Wistar rats were exposed to polyinosinic:polycytidylic acid (a viral mimetic) or saline on postnatal days (PND) 5-7. On PND30-59 they received saline or NAC 220 mg/kg and between PND40-48 were subjected to PUS or left undisturbed. On PND60 behavioral and oxidative alterations were evaluated in the prefrontal cortex (PFC) and striatum. Mechanisms of hippocampal memory regulation such as immune expression of G protein-coupled estrogen receptor 1 (GPER), α7-nAChR and parvalbumin were also evaluated.
NAC prevented sensorimotor gating deficits only in females, while it prevented alterations in social interaction, working memory and locomotor activity in both sexes. Again, in rats of both sexes, NAC prevented the following neurochemical alterations: glutathione (GSH) and nitrite levels in the PFC and lipid peroxidation in the PFC and striatum. Striatal oxidative alterations in GSH and nitrite were observed in females and prevented by NAC. Two-hit induced hippocampal alterations in females, namely expression of GPER-1, α7-nAChR and parvalbumin, were prevented by NAC.
Our results highlights the influences of sex in NAC preventive effects in rats exposed to a two-hit schizophrenia model.
精神分裂症（SCZ）是一种受患者性别影响的神经发育障碍。SCZ 性别差异的潜在机制尚不清楚。SCZ 的双打击模型将围产期感染（第一打击）与青春期前不可预测的应激（PUS，第二打击）相结合。由于谷胱甘肽机制在其神经生物学中的参与，N-乙酰半胱氨酸（NAC）已在 SCZ 中进行了测试。
我们旨在研究 NAC 给药是否可以预防两性青春期大鼠双打击模型引起的行为和神经化学变化。
Wistar 大鼠在出生后第 5-7 天接受聚肌胞苷酸（病毒模拟物）或生理盐水。在 PND30-59 时，它们接受生理盐水或 NAC 220mg/kg，在 PND40-48 时接受 PUS 或不干扰。在 PND60 时，评估前额叶皮层（PFC）和纹状体中的行为和氧化改变。还评估了海马记忆调节的机制，如 G 蛋白偶联雌激素受体 1（GPER）、α7-烟碱型乙酰胆碱受体和钙结合蛋白的免疫表达。
NAC 仅在雌性大鼠中预防感觉运动门控缺陷，而在两性大鼠中预防社会互动、工作记忆和运动活动改变。同样，在两性大鼠中，NAC 预防了以下神经化学改变：PFC 中的谷胱甘肽（GSH）和亚硝酸盐水平以及 PFC 和纹状体中的脂质过氧化。在雌性大鼠中观察到纹状体中 GSH 和亚硝酸盐的氧化改变，并被 NAC 预防。在雌性大鼠中，海马中的两个打击诱导的改变，即 GPER-1、α7-烟碱型乙酰胆碱受体和钙结合蛋白的表达，被 NAC 预防。
我们的结果强调了 NAC 在暴露于双打击精神分裂症模型的大鼠中的预防作用受性别影响。
