甲酰肽受体FPR2对胶质瘤谷氨酸分泌及神经元损伤的调节作用及可能机制

Gliomas are considered as space occupying lesion, and have been proved to possess the ability of glutamate release, which may induce neuronal damage and glioma-associaed epilepsy. Decreased glutamate release will reduce neuronal damage and glioma-associaed epilepsy. Glioma could express formyl peptide receptor 2 (FPR2). However, whether formyl peptide receptor 2 (FPR2) regulates the glutamate release of glioma and reduces the glioma-associated neuronal damage remains unknown. Our preliminary study found that activating FPR2 increased glutamate uptake of glioma and reduced glutamate-related neuronal injury. Thus we hypothesize that activating FPR2 will increase glutamate transporter (EAAT) expression in gliomas via activating protein kinase C (PKC) and downstream MEK/ERK pathway, and subsequently increase glutamate uptake, reduce glutamate concentration and prevent neurons from glutamate-associated damage at peri-glioma region. We will test the hypotheses in vitro and vivo via pharmacological intervention and intracranial glioma of rat in situ. Successful completion of the study may reveal a novel therapeutic target to reduce neuronal damage and prevent glioma-associated epilepsy.

胶质瘤除了是占位病变之外，还可通过分泌大量谷氨酸引起胶质瘤周围神经元损伤及诱发癫痫。抑制胶质瘤细胞分泌谷氨酸可以减少神经元损伤，具有抗胶质瘤相关性癫痫的作用。胶质瘤细胞表达一定量的甲酰肽受体（FPR2），但FPR2对胶质瘤谷氨酸分泌及神经元损伤的调节作用及机制尚不明确。我们的前期研究发现激活FPR2能够明显促进胶质瘤细胞摄取谷氨酸，从而降低胶质瘤周围的谷氨酸，减少胶质瘤周围神经元损伤。因此本研究拟结合体内、体外研究，通过药物干预及原位脑胶质瘤模型验证如下核心假设：FPR2通过调节胶质瘤细胞蛋白激酶(PKC)及下游的MEK/ERK通路促进胶质瘤细胞在细胞膜上表达谷氨酸摄取蛋白EAAT，从而促进胶质瘤细胞摄取谷氨酸，降低胶质瘤分泌的高谷氨酸对神经元的毒性，对进一步揭示胶质瘤相关性癫痫的机制及寻找抗胶质瘤相关性癫痫药物打下良好的基础。

胶质瘤是除了占位效应还具有分泌谷氨酸造成周围神经损伤及诱发癫痫的作用。通过对FPR2经PKC/ERK通路对胶质瘤谷氨酸分泌的影响及神经元保护作用的研究，总结以下几点发现：1）FPR2在胶质瘤细胞系、原代胶质瘤细胞、胶质瘤组织中均有表达，且在胶质瘤合并癫痫中低表达。2）FPR2可调节PKC/ERK信号通路。3）揭示了FPR2 干预可影响胶质瘤细胞谷氨酸摄取。4）FPR2 可通过PKC/ERK通路促进胶质瘤细胞EAAT1上调且GLS下调而GS由胞核转至胞质分布，同时谷氨酸摄取蛋白 EAAT1 能够在细胞膜上面表达。6）FPR2激动剂对胶质瘤相关性神经元具有保护作用。7）FPR2激动剂可抑制胶质瘤体内成瘤。总而言之，FPR2可能成为胶质瘤的潜在治疗靶点，并起到保护神经元的作用。