Activation of the liver X receptor increases neuroactive steroid levels and protects from diabetes-induced peripheral neuropathy.
Activation of the liver X receptor increases neuroactive steroid levels and protects from diabetes-induced peripheral neuropathy.
复制标题
肝脏X受体的激活增加了神经活性类固醇水平，并保护糖尿病诱导的周围神经病。
DOI：
10.1523/jneurosci.1898-10.2010
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发表时间：
2010-09-08
期刊：
影响因子：
--
通讯作者：
Mitro N
中科院分区：
文献类型：
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作者：
Cermenati G;Giatti S;Cavaletti G;Bianchi R;Maschi O;Pesaresi M;Abbiati F;Volonterio A;Saez E;Caruso D;Melcangi RC;Mitro N
神经活性类固醇在周围神经系统中作为生理调节剂和作为获得性或遗传性周围神经病变的保护剂起作用。近年来，调节神经活性类固醇水平已被研究作为一种潜在的治疗方法，以保护周围神经免受糖尿病引起的损害。肝X受体（LXR）家族的核受体通过其控制胆固醇稳态的能力调节肾上腺类固醇生成。在这里，我们表明，大鼠坐骨神经表达LRXα和β亚型，这些受体的功能。使用合成配体激活肝脏X受体导致神经类固醇水平增加，并保护坐骨神经免受糖尿病诱导的神经病变。LXR配体治疗链脲佐菌素处理的大鼠增加类固醇生成急性调节蛋白在坐骨神经中的表达（一种参与胆固醇转移到线粒体中的分子），酶P450 SCC（负责将胆固醇转化为胆固醇烯醇酮），5α-还原酶（一种参与产生神经活性类固醇的酶）和参与胆固醇流出的经典LXR靶点，如ABCA 1和ABCG 1。这些效应与神经活性类固醇水平增加有关（例如，结果表明，该药物对大鼠坐骨神经的热伤害性活动、神经传导速度和Na+，K+-ATP酶活性均有明显的神经保护作用。这些结果表明，LXR激活可能代表了一种新的药理学途径，以增加局部神经活性类固醇水平，在糖尿病神经病变中发挥神经保护作用。
Neuroactive steroids act in the peripheral nervous system as physiological regulators and as protective agents for acquired or inherited peripheral neuropathy. In recent years, modulation of neuroactive steroids levels has been studied as a potential therapeutic approach to protect peripheral nerves from damage induced by diabetes. Nuclear receptors of the liver X receptor (LXR) family regulate adrenal steroidogenesis via their ability to control cholesterol homeostasis. Here we show that rat sciatic nerve expresses both LRXα and β isoforms and that these receptors are functional. Activation of liver X receptors using a synthetic ligand results in increased levels of neurosteroids and protection of the sciatic nerve from neuropathy induced by diabetes. LXR ligand treatment of streptozotocin-treated rats increases expression in the sciatic nerve of steroidogenic acute regulatory protein (a molecule involved in the transfer of cholesterol into mitochondria), of the enzyme P450scc (responsible for conversion of cholesterol into pregnenolone), of 5α-reductase (an enzyme involved in the generation of neuroactive steroids) and of classical LXR targets involved in cholesterol efflux, such as ABCA1 and ABCG1. These effects were associated with increased levels of neuroactive steroids (e.g., pregnenolone, progesterone, dihydroprogesterone and 3α-diol) in the sciatic nerve, and with neuroprotective effects on thermal nociceptive activity, nerve conduction velocity, and Na+, K+-ATPase activity. These results suggest that LXR activation may represent a new pharmacological avenue to increase local neuroactive steroid levels that exert neuroprotective effects in diabetic neuropathy.