Background: Diffuse intrinsic pontine glioma (DIPG) is a devastating childhood brainstem tumor. The median survival of DIPG is 16–24 months independent of the treatment received. Therefore, new therapeutic strategies against DIPG are urgently needed. Substance P (SP) peptide, through the neurokinin neurokinin-1 receptor (NK-1R), is involved in glioma progression. It induces glioma cell proliferation by activating MAPKs (p38 MAPK, ERK1/2, and JNK), c-Myc, AP-1, and NF-κB and induces antiapoptotic effects via PI3K/Akt/mTOR in glioma cells. SP favors glycogen breakdown that is essential for glycolysis. The SP/NK-1R system also regulates the migration and invasion of glioma cells, stimulates angiogenesis, and triggers inflammation which contributes to glioma progression. Moreover, all glioma cells express NK-1R, and NK-1R is essential for the viability of glioma cells and not of normal cells. In contrast, in glioma, NK-1R antagonists, such as the drug aprepitant, penetrate the brain and reach therapeutic concentrations, thereby inhibiting mitogenesis, inducing apoptosis, and inhibiting the breakdown of glycogen in glioma cells. In addition, they inhibit angiogenesis and exert antimetastatic and anti-inflammatory effects. The combination of radiotherapy with NK-1R antagonists produces radiosensitization and radioneuroprotection, reduces both peritumoral- and radiation-induced inflammation, and also provides antinausea and antivomiting effects.Objective:This review updates the involvement of the SP/NK-1R system in glioma promotion and progression and the potential clinical application of NK-1R antagonist drugs in DIPG therapy.Conclusions:NK-1R plays a crucial role in glioma progression and NK-1R antagonists such as aprepitant could be used in combination with radiotherapy as a potent therapeutic strategy for the treatment of patients with DIPG.
背景：弥漫性内生型脑桥胶质瘤（DIPG）是一种致命性的儿童脑干肿瘤。无论接受何种治疗，其中位生存期仅为16-24个月，因此亟需针对DIPG的新型治疗策略。P物质（SP）肽通过神经激肽-1受体（NK-1R）参与胶质瘤进展过程：通过激活MAPKs（p38 MAPK、ERK1/2和JNK）、c-Myc、AP-1及NF-κB诱导胶质瘤细胞增殖，并经由PI3K/Akt/mTOR通路产生抗凋亡效应。SP促进糖原分解，此为糖酵解关键步骤。SP/NK-1R系统还调控胶质瘤细胞的迁移侵袭能力，刺激血管生成并引发炎症反应，共同推动胶质瘤进展。值得注意的是，所有胶质瘤细胞均表达NK-1R，且该受体对胶质瘤细胞（而非正常细胞）的存活至关重要。与之相对，NK-1R拮抗剂（如药物阿瑞匹坦）可穿透血脑屏障达到治疗浓度，从而抑制胶质瘤细胞有丝分裂、诱导细胞凋亡、阻断糖原分解，同时抑制血管生成并产生抗转移、抗炎效应。放疗联合NK-1R拮抗剂可产生放射增敏与放射神经保护作用，减轻瘤周及辐射诱导的炎症反应，兼具止吐功效。 目的：本文综述SP/NK-1R系统在胶质瘤发生发展中的作用机制，探讨NK-1R拮抗剂在DIPG治疗中的潜在临床应用价值。 结论：NK-1R在胶质瘤进展中发挥关键作用，以阿瑞匹坦为代表的NK-1R拮抗剂联合放疗可作为治疗DIPG患者的有效策略。
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