Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El Aini St, Cairo, 11562, Egypt.
Inflammopharmacology. 2022 Oct;30(5):1891-1907. doi: 10.1007/s10787-022-01031-w. Epub 2022 Jul 25.
Schizophrenia is a common mental disorder affecting patients' thoughts, behavior, and cognition. Recently, the NRG1/ErbB4 signaling pathway emerged as a candidate therapeutic target for schizophrenia. This study investigates the effects of aripiprazole and sertindole on the NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways in ketamine-induced schizophrenia in rats. Young male Wistar rats received ketamine (30 mg/kg, intraperitoneally) for 5 consecutive days and aripiprazole (3 mg/kg, orally) or sertindole (2.5 mg/kg, orally) for 14 days. The proposed pathway was investigated by injecting LY294002 (a selective PI3K inhibitor) (25 μg/kg, intrahippocampal injection) 30 min before the drugs. Twenty-four hours after the last injection, animals were subjected to behavioral tests: the open field test, sucrose preference test, novel object recognition task, and social interaction test. Both aripiprazole and sertindole significantly ameliorated ketamine-induced schizophrenic-like behavior, as expected, because of their previously demonstrated antipsychotic activity. Besides, both drugs alleviated ketamine-induced oxidative stress and neurotransmitter level changes in the hippocampus. They also increased the gamma-aminobutyric acid and glutamate levels and glutamate decarboxylase 67 and parvalbumin mRNA expression in the hippocampus. Moreover, aripiprazole and sertindole increased the NRG1 and ErbB4 mRNA expression levels and PI3K, p-Akt, and mTOR protein expression levels. Interestingly, pre-injecting LY294002 abolished all the effects of the drugs. This study reveals that the antipsychotic effects of aripiprazole and sertindole are partly due to oxidative stress reduction as well as NRG1/ErbB4 and PI3K/AKT/mTOR signaling pathways activation. The NRG1/ErbB4 and PI3K signaling pathways may offer a new therapeutic approach for treating schizophrenia in humans.
精神分裂症是一种常见的精神障碍，影响患者的思维、行为和认知。最近，NRG1/ErbB4 信号通路被认为是精神分裂症的一个潜在治疗靶点。本研究探讨了阿立哌唑和 sertindole 对氯胺酮诱导的精神分裂症大鼠 NRG1/ErbB4 和 PI3K/AKT/mTOR 信号通路的影响。年轻雄性 Wistar 大鼠连续 5 天腹腔注射氯胺酮（30mg/kg），然后连续 14 天灌胃给予阿立哌唑（3mg/kg）或 sertindole（2.5mg/kg）。通过在药物注射前 30 分钟向海马内注射 LY294002（一种选择性 PI3K 抑制剂）（25μg/kg）来研究所提出的通路。末次注射后 24 小时，动物进行行为测试：旷场实验、蔗糖偏好实验、新物体识别任务和社会交往实验。正如预期的那样，阿立哌唑和 sertindole 均显著改善了氯胺酮诱导的精神分裂样行为，这是因为它们具有先前证明的抗精神病活性。此外，两种药物均减轻了氯胺酮诱导的海马氧化应激和神经递质水平变化。它们还增加了海马中的γ-氨基丁酸和谷氨酸水平以及谷氨酸脱羧酶 67 和 parvalbumin mRNA 的表达。此外，阿立哌唑和 sertindole 增加了 NRG1 和 ErbB4 mRNA 的表达水平以及 PI3K、p-Akt 和 mTOR 蛋白的表达水平。有趣的是，预先注射 LY294002 消除了药物的所有作用。本研究揭示，阿立哌唑和 sertindole 的抗精神病作用部分归因于氧化应激的减少以及 NRG1/ErbB4 和 PI3K/AKT/mTOR 信号通路的激活。NRG1/ErbB4 和 PI3K 信号通路可能为治疗人类精神分裂症提供一种新的治疗方法。
