Neurological and psychiatric side effects accompany the high-dose interferon-alpha (IFNA) therapy. The primary genes responsible for these complications are mostly unknown. Our genome-wide search in mouse and rat genomes for the conservative genes containing IFN-stimulated response elements (ISRE) in their promoters revealed a new potential target gene of IFNA, Grin3α, which encodes the 3A subunit of NMDA receptor. This study aimed to explore the impact of IFNA on the expression of Grin3α and Ifnα genes and neurotransmitters endo/exocytosis in the mouse brain. We administered recombinant human IFN-alpha 2b (rhIFN-α2b) intracranially, and 24 h later, we isolated six brain regions and used the samples for RT-qPCR and western blot analysis. Synaptosomes were isolated from the cortex to analyze endo/exocytosis with acridine orange and L-[14C]glutamate. IFNA induced an increase in Grin3α mRNA and GRIN3A protein, but a decrease in Ifnα mRNA and protein. IFNA did not affect the accumulation and distribution of L-[14C]glutamate and acridine orange between synaptosomes and the extra-synaptosomal space. It caused the more significant acridine orange release activated by NMDA or glutamate than from control mice's synaptosomes. In response to IFNA, the newly discovered association between elevated Grin3α expression and NMDA- and glutamate-evoked neurotransmitters release from synaptosomes implies a new molecular mechanism of IFNA neurotoxicity.

神经和精神方面的副作用伴随着大剂量干扰素-α (IFNA) 治疗。导致这些并发症的主要基因大多是未知的。我们在小鼠和大鼠基因组中对启动子中含有 IFN 刺激反应元件 (ISRE) 的保守基因进行全基因组搜索，揭示了一个新的潜在靶基因 IFNA，Grin3α，它编码 NMDA 受体的 3A 亚基。本研究旨在探讨 IFNA 对小鼠大脑中Grin3α和Ifnα基因的表达以及神经递质内/胞吐作用的影响。我们给予重组人 IFN-α 2b (rhIFN- α2b）在颅内，24 小时后，我们分离出六个大脑区域，并将样本用于 RT-qPCR 和蛋白质印迹分析。从皮层分离突触体以分析吖啶橙和 L-[14C]谷氨酸的内吞/胞吐作用。IFNA 诱导Grin3α mRNA 和 GRIN3A 蛋白增加，但减少Ifnα mRNA 和蛋白。IFNA不影响突触体和突触体外空间之间L-[14C]谷氨酸和吖啶橙的积累和分布。与对照小鼠的突触体相比，它导致由 NMDA 或谷氨酸激活的吖啶橙释放更显着。作为对 IFNA 的反应，新发现的Grin3α升高之间的关联表达和突触体释放 NMDA 和谷氨酸诱发的神经递质意味着 IFNA 神经毒性的新分子机制。