Chronic glutamate excitotoxicity has been thought to be involved in numerous neurodegenerative disorders. A small but significant loss of membrane cholesterol has been reported following a short stimulation of ionotropic glutamate receptors (iGluRs). We investigated the alteration of brain cholesterol following chronic glutamate treatment. The alteration of cholesterol levels was evaluated in the hippocampus from the adult rats that received the subcutaneous injection with monosodium l-glutamate at 1, 3, 5, and 7 days of age. The regulation of CYP46A1, LXRα, and ApoE levels were assayed following subtoxic glutamate treatment in SH-SY5Y cells as well as HT-22 cells lacking iGluRs. The ratio of 24S-hydroxycholesterol to cholesterol was elevated in the adult rats exposed to monosodium l-glutamate before the weaning age, compared to the control. The blockers of NMDA receptor (MK801) and mGluR5 (MPEP) attenuated the glutamate-induced loss of cholesterol and elevation of 24S-hydroxycholesterol level in SH-SY5Y cells. The induction of the mRNA levels of CYP46A1, LXRα, and ApoE by glutamate was observed in both SH-SY5Y cells and HT-22 cells; additionally, MK801 and MPEP attenuated the increases in these genes in SH-SY5Y cells. The increase in the binding of LXRα proteins with ApoE promoter following glutamate treatment was attenuated by MK801. The luciferase assay indicated the binding of CREB protein with CYP46A1 promoter, and the glutamate-induced CREB expression was inhibited by MK801. The results suggest that glutamate, the major excitatory neurotransmitter, may affect the metabolism and redistribution of cholesterol in the neuronal cells via its specific receptors during chronic exposure.

中文翻译：

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谷氨酸通过CYP46A1和ApoE的上调影响脑内胆固醇的稳态。

慢性谷氨酸兴奋性毒性被认为与许多神经退行性疾病有关。据报道，短暂刺激离子型谷氨酸受体（iGluRs）后，膜胆固醇的损失很小但很明显。我们调查了慢性谷氨酸治疗后脑胆固醇的变化。在成年大鼠的海马中评估胆固醇水平的变化，该成年大鼠在1、3、5和7天龄接受皮下注射谷氨酸一钠注射。在SH-SY5Y细胞和缺乏iGluRs的HT-22细胞中，在进行亚毒性谷氨酸处理后，测定了CYP46A1，LXRα和ApoE的水平。与对照组相比，成年大鼠在断奶前暴露于谷氨酸一钠的24S-羟基胆固醇与胆固醇的比例升高。NMDA受体（MK801）和mGluR5（MPEP）的阻滞剂减弱了SH-SY5Y细胞中谷氨酸诱导的胆固醇损失和24S-羟基胆固醇水平的升高。在SH-SY5Y细胞和HT-22细胞中均观察到谷氨酸对CYP46A1，LXRα和ApoE mRNA水平的诱导。此外，MK801和MPEP减弱了SH-SY5Y细胞中这些基因的增加。谷氨酸处理后，LXRα蛋白与ApoE启动子的结合增加被MK801减弱。荧光素酶测定表明CREB蛋白与CYP46A1启动子结合，并且谷氨酸诱导的CREB表达被MK801抑制。结果表明，主要的兴奋性神经递质谷氨酸