The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain. Mice with astrocyte-specific alterations of S1pr1 did not develop neuropathic pain and lost their ability to respond to S1PR1 inhibition, strongly implicating astrocytes as a primary cellular substrate for S1PR1 activity. At the molecular level, S1PR1 engaged astrocyte-driven neuroinflammation and altered glutamatergic homeostasis, processes blocked by S1PR1 antagonism. Our findings establish S1PR1 as a target for therapeutic intervention and provide insight into cellular and molecular pathways. As FTY720 also shows promising anticancer potential and is FDA approved, rapid clinical translation of our findings is anticipated.

译文

:化学疗法诱发的疼痛性周围神经病的发展是许多化学疗法(包括硼替佐米)的主要剂量限制性副作用,但其机制仍知之甚少。我们现在报告硼替佐米引起脊髓背角新生鞘脂代谢的失调,从而增加了鞘氨醇-1-磷酸(S1P)受体1(S1PR1)配体,S1P和二氢-S1P的水平。因此,用多种S1PR1拮抗剂(包括FTY720)对S1PR1的遗传和药理破坏可阻断和逆转神经性疼痛。具有S1pr1星形胶质细胞特异性改变的小鼠没有发展成神经性疼痛,也没有丧失对S1PR1抑制的反应能力,强烈暗示星形胶质细胞是S1PR1活性的主要细胞底物。在分子水平上,S1PR1参与星形胶质细胞驱动的神经炎症并改变了谷氨酸能稳态,而S1PR1拮抗作用阻止了该过程。我们的发现将S1PR1确立为治疗干预的目标,并为细胞和分子途径提供了见识。由于FTY720还显示出有希望的抗癌潜力,并且已获得FDA批准,因此有望对我们的发现进行快速的临床翻译。

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