Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India.
Department of Neurology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh160012, India.
ACS Chem Neurosci. 2022 Oct 19;13(20):2942-2961. doi: 10.1021/acschemneuro.2c00270. Epub 2022 Sep 27.
Chronic neuroinflammation-induced anomalous glutamate receptor activation has been identified as one of the important factors in the pathogenesis of autism spectrum disorder (ASD). Thus, the current study was designed to elucidate the neuroprotective effect of the granulocyte colony-stimulating factor (G-CSF), a haemopoietic growth factor, an anti-inflammatory, and a neuroprotectant to decipher the underlying mechanism(s) in the valproic acid (VPA)-induced experimental model of ASD. Experimentally, the ASD rat model was induced by a single dose of VPA (600 mg/kg; i.p.) on gestation day 12.5 to the pregnant female rats. After birth, pups were treated with vehicle, normal saline 0.9% i.p., risperidone (2.5 mg/kg; i.p.), and G-CSF (10, 35, and 70 μg/kg; i.p.) from postnatal day (PND) 23 to 43. All the groups were subjected to various developmental and behavior tests from birth. The rats were sacrificed on PND 55, and their brain was excised and processed for biochemical parameters (oxidative stress, inflammatory markers, BDNF), histological examination (H&E, Nissl staining), NMDA, and AMPA receptor expression by immunohistochemistry, western blot, and real-time polymerase chain reaction evaluation. Also, the possible interaction of the G-CSF with NMDA and AMPA receptors was evaluated using the method. The results of the study showed that in VPA-exposed rats, postnatal treatment of G-CSF rescued all the behavioral abnormalities, oxidative stress, and inflammatory parameters in a dose-dependent manner while risperidone did not show any significant results. The analysis showed the direct interaction of G-CSF with NMDA and AMPA receptors. The upregulated expression of NMDA and AMPA both in the prefrontal cortex as well as hippocampus was alleviated by G-CSF thereby validating its anti-inflammatory and excitoprotective properties. Thus, G-CSF demonstrated neuroprotection against the core symptoms of autism in the VPA-induced rodent model, making it a potential candidate for the treatment of ASD.
慢性神经炎症诱导的异常谷氨酸受体激活已被确定为自闭症谱系障碍（ASD）发病机制的重要因素之一。因此，本研究旨在阐明粒细胞集落刺激因子（G-CSF）的神经保护作用，G-CSF 是一种造血生长因子、抗炎剂和神经保护剂，以阐明其在丙戊酸（VPA）诱导的 ASD 实验模型中的潜在机制。在实验中，通过在妊娠第 12.5 天给雌性大鼠腹腔注射单次剂量的 VPA（600mg/kg）来诱导 ASD 大鼠模型。出生后，从出生后第 23 天到 43 天，用载体、生理盐水 0.9%（腹腔注射）、利培酮（2.5mg/kg；腹腔注射）和 G-CSF（10、35 和 70μg/kg；腹腔注射）处理幼鼠。所有组从出生后开始进行各种发育和行为测试。大鼠于出生后第 55 天处死，取出大脑进行生化参数（氧化应激、炎症标志物、BDNF）、组织学检查（H&E、尼氏染色）、NMDA 和 AMPA 受体免疫组化、western blot 和实时聚合酶链反应评估。此外，还使用 方法评估了 G-CSF 与 NMDA 和 AMPA 受体的可能相互作用。研究结果表明，在 VPA 暴露的大鼠中，G-CSF 的产后治疗以剂量依赖的方式挽救了所有行为异常、氧化应激和炎症参数，而利培酮则没有显示出任何显著的结果。 分析表明 G-CSF 与 NMDA 和 AMPA 受体的直接相互作用。G-CSF 减轻了前额叶皮层和海马中 NMDA 和 AMPA 的上调表达，从而验证了其抗炎和神经保护特性。因此，G-CSF 对 VPA 诱导的啮齿动物模型中的自闭症核心症状表现出神经保护作用，使其成为治疗 ASD 的潜在候选药物。
