McCullers D L, Herman J P
Department of Anatomy and Neurobiology, University of Kentucky Medical Center, Lexington, Kentucky, USA.
J Neurosci Res. 2001 May 1;64(3):277-83. doi: 10.1002/jnr.1076.
The mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) are glucocorticoid-activated transcription factors essential for maintenance of cellular homeostasis. Differential activation of these adrenocorticosteroid receptors (ACR) is thought to influence neuronal viability, particularly under challenging cellular conditions. The present study is designed to determine the effects of receptor blockade and excitotoxic insult on MR and GR mRNA expression and neuronal viability in hippocampus. Male Sprague--Dawley rats were pretreated for 48 hr with vehicle, MR antagonist spironolactone (SPIRO) (50 mg/kg, twice daily, s.c.), or GR antagonist RU486 (25 mg/kg, twice daily, s.c.) and subsequently injected with saline or the glutamate analog kainic acid (KA) (12 mg/kg i.p.). Twenty-four hr post-insult, MR and GR mRNA levels were assessed by in situ hybridization analysis, and hippocampal neurons were counted to assess KA-induced cell loss. MR blockade with SPIRO increased basal MR mRNA levels in hippocampal subregions CA1, CA3, and dentate gyrus (DG) and increased basal GR mRNA levels in CA3. GR blockade with RU486 increased basal GR mRNA levels in CA3. The excitotoxin KA decreased MR mRNA levels in CA1 and CA3, decreased GR mRNA levels in DG, and negated all antagonist-induced increases of ACR mRNAs. Cell counts quantifying KA damage indicated increased CA3 vulnerability to KA insult after treatment with MR antagonist spironolactone but demonstrated no significant cell loss in any other group or region. These results demonstrate dynamic regulation of hippocampal MR and GR mRNAs after ACR antagonist treatment and kainate toxicity, underscoring the potential importance of MR and GR availability to neuronal viability after insult.
盐皮质激素受体（MR）和糖皮质激素受体（GR）是糖皮质激素激活的转录因子，对维持细胞内稳态至关重要。这些肾上腺皮质类固醇受体（ACR）的差异激活被认为会影响神经元的活力，尤其是在具有挑战性的细胞条件下。本研究旨在确定受体阻断和兴奋性毒性损伤对海马中MR和GR mRNA表达以及神经元活力的影响。雄性Sprague-Dawley大鼠用赋形剂、MR拮抗剂螺内酯（SPIRO）（50mg/kg，每日两次，皮下注射）或GR拮抗剂RU486（25mg/kg，每日两次，皮下注射）预处理48小时，随后注射生理盐水或谷氨酸类似物海藻酸（KA）（12mg/kg腹腔注射）。损伤后24小时，通过原位杂交分析评估MR和GR mRNA水平，并对海马神经元进行计数以评估KA诱导的细胞损失。用SPIRO阻断MR可增加海马亚区CA1、CA3和齿状回（DG）的基础MR mRNA水平，并增加CA3中的基础GR mRNA水平。用RU486阻断GR可增加CA3中的基础GR mRNA水平。兴奋性毒素KA降低了CA1和CA3中的MR mRNA水平，降低了DG中的GR mRNA水平，并消除了所有拮抗剂诱导的ACR mRNA增加。量化KA损伤的细胞计数表明，用MR拮抗剂螺内酯治疗后，CA3对KA损伤的易感性增加，但在任何其他组或区域均未显示出明显的细胞损失。这些结果表明，ACR拮抗剂治疗和海藻酸盐毒性后海马MR和GR mRNA受到动态调节，强调了MR和GR的可用性对损伤后神经元活力的潜在重要性。
