Despite reports that quinoline antimalarials including chloroquine (Chq) exhibit idiosyncratic neuropsychiatric effects even at low doses, the drug continues to be in widespread use during pregnancy. Surprisingly, very few studies have examined the potential neurotoxic action of Chq exposure at different points of gestation or how this phenomenon may affect neurophysiological well-being in later life. We therefore studied behavior, and the expression of specific genes and neurochemicals modulating crucial neural processes in offspring of rats exposed to prophylactic dose of Chq during different stages of gestation. Pregnant rats were injected 5 mg/kg/day (3 times) of Chq either during early- (first week), mid- (second week), late- (third week), or throughout- (all weeks) gestation, while controls received PBS injection. Behavioral characterization of offspring between postnatal days 15–20 in the open field, Y-maze, elevated plus and elevated zero mazes revealed that Chq evoked anxiogenic responses and perturbed spatial memory in rats, although locomotor activity was generally unaltered. In the prefrontal cortex (PFC), hippocampus and cerebellum of rats prenatally exposed to Chq, RT-qPCR analysis revealed decreased mRNA expression of presynaptic marker synaptophysin, which was accompanied by downregulation of postsynaptic marker PSD95. Synaptic marker PICK1 expression was also downregulated in the hippocampus but was unperturbed in the PFC and cerebellum. In addition to recorded SOD downregulation in cortical and hippocampal lysates, induction of oxidative stress in rats prenatally exposed to Chq was corroborated by lipid peroxidation as evinced by increased MDA levels. Offspring of rats infused with Chq at mid-gestation and weekly treatment throughout gestation were particularly susceptible to neurotoxic changes, especially in the hippocampus. Interestingly, Chq did not cause histopathological changes in any of the brain areas. Taken together, our findings causally link intrauterine exposure to Chq with postnatal behavioral impairment and neurotoxic changes in rats.

尽管有报道称，包括氯喹 (Chq) 在内的喹啉抗疟药即使在低剂量下也表现出异质的神经精神作用，但该药物在怀孕期间继续广泛使用。令人惊讶的是，很少有研究检查在不同妊娠期暴露于 Chq 的潜在神经毒性作用或这种现象如何影响晚年的神经生理健康。因此，我们研究了在妊娠不同阶段暴露于预防剂量 Chq 的大鼠后代的行为，以及调节关键神经过程的特定基因和神经化学物质的表达。妊娠大鼠在妊娠早期（第一周）、中期（第二周）、晚期（第三周）或整个（所有周）妊娠期间注射 5 mg/kg/天（3 次）Chq，而对照组接受 PBS 注射。出生后第 15-20 天在旷野、Y 迷宫、升高的正迷宫和升高的零迷宫中对后代的行为表征表明，虽然运动活动通常没有改变，但 Chq 会引起大鼠的焦虑反应并扰乱空间记忆。在产前暴露于 Chq 的大鼠的前额叶皮层 (PFC)、海马和小脑中，RT-qPCR 分析显示突触前标志物突触素的 mRNA 表达降低，并伴有突触后标志物 PSD95 的下调。突触标记 PICK1 的表达在海马中也下调，但在 PFC 和小脑中不受干扰。除了记录皮质和海马裂解物中的 SOD 下调外，脂质过氧化证实了产前暴露于 Chq 的大鼠中氧化应激的诱导，如 MDA 水平的增加所证明的那样。在妊娠中期注入 Chq 和在整个妊娠期间每周治疗的大鼠的后代特别容易受到神经毒性变化的影响，尤其是在海马中。有趣的是，Chq 并未引起任何脑区的组织病理学变化。总之，我们的研究结果将宫内暴露于 Chq 与大鼠出生后行为障碍和神经毒性变化联系起来。