Dept. of Pharmacological Sciences, Università degli Studi di Milano, Milano, Italy.
Neurochem Int. 2012 May;60(6):616-21. doi: 10.1016/j.neuint.2012.02.025. Epub 2012 Mar 3.
Neuroactive steroid levels are decreased in the central nervous system (CNS) of streptozotocin (STZ) diabetic rats. In agreement, they exert protective effects in this experimental model, counteracting degenerative events occurring in the CNS. Therefore, an interesting therapeutic strategy could be to increase their levels directly in the CNS. In this study we have evaluated whether activation of translocator protein-18kDa (TSPO) or liver X receptors (LXRs) may affect the levels of neuroactive steroids present in the CNS of diabetic and non-diabetic animals. We observed that the treatment with either Ro5-4864 (i.e., a ligand of TSPO) or with GW3965 (i.e., a ligand of LXRs) induced an increase of neuroactive steroids in the spinal cord, the cerebellum and the cerebral cortex of STZ-rats, but not in the CNS of non-pathological animals. Interestingly, the pattern of induction was different among the three CNS areas analyzed and between the two pharmacological tools. In particular, the activation of LXRs might represent a promising neuroprotective strategy, because the treatment with GW3965, at variance to Ro5-4864 treatment, did not induce significant changes in the plasma levels of neuroactive steroids. This suggests that activation of LXRs may selectively increase the CNS levels of neuroactive steroids avoiding possible endocrine side effects exerted by the systemic treatment with these molecules. Interestingly GW3965 treatment induced an increase of dihydroprogesterone in the spinal cord of diabetic animals in association with an increase of myelin basic protein expression. Thus we demonstrated that LXR activation was able to rescue CNS symptoms of diabetes.
神经活性甾体水平在链脲佐菌素（STZ）糖尿病大鼠的中枢神经系统（CNS）中降低。 一致地，它们在该实验模型中发挥保护作用，抵消 CNS 中发生的退行性事件。 因此，一种有趣的治疗策略可能是直接在 CNS 中增加它们的水平。 在这项研究中，我们评估了激活转位蛋白-18kDa（TSPO）或肝 X 受体（LXRs）是否会影响糖尿病和非糖尿病动物 CNS 中存在的神经活性甾体水平。 我们观察到，用 Ro5-4864（即 TSPO 的配体）或 GW3965（即 LXRs 的配体）治疗会导致 STZ 大鼠脊髓、小脑和大脑皮层中的神经活性甾体增加，但不会导致 CNS 中的神经活性甾体增加非病理动物。 有趣的是，三种 CNS 区域分析和两种药理学工具之间的诱导模式不同。 特别是，LXR 的激活可能代表一种有前途的神经保护策略，因为 GW3965 的治疗与 Ro5-4864 治疗不同，不会导致神经活性甾体的血浆水平发生显著变化。 这表明激活 LXRs 可能选择性地增加 CNS 中神经活性甾体的水平，避免这些分子全身治疗可能产生的内分泌副作用。 有趣的是，GW3965 治疗诱导糖尿病动物脊髓中二氢孕酮增加，同时髓鞘碱性蛋白表达增加。 因此，我们证明 LXR 激活能够挽救糖尿病的 CNS 症状。
