Astrocytic phosphatase and tensin homolog deleted on chromosome 10 regulates neuropathic pain by facilitating 3-hydroxy-3-methylglutaryl-CoA reductase–dependent cholesterol biosynthesis

PTEN公司 张力素 神经病理性疼痛 癌症研究 星形胶质细胞 PI3K/AKT/mTOR通路 医学 小胶质细胞 药理学 化学 内分泌学 生物 内科学 细胞生物学 炎症 中枢神经系统 信号转导
作者
Yehong Fang,Huan Cui,Fan Liu,Si Su,Tao Wang,Bo Yuan,Yikuan Xie,Chao Ma
出处
期刊:Pain [Ovid Technologies (Wolters Kluwer)]
卷期号:163 (12): e1192-e1206 被引量:9
标识
DOI:10.1097/j.pain.0000000000002682
摘要

Abstract Recent studies have noted the role of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in developing neuropathic pain, but the underlying mechanisms are obscure. We found that PTEN was mainly expressed in astrocytes in the rat spinal cord and dramatically downregulated after chronic constriction injury (CCI). Intrathecal injection of a PTEN inhibitor induced pain-related behaviors in naive rats. By contrast, administration of a PTEN protector effectively mitigated CCI-induced pain. Adeno-associated virus–mediated overexpression of astrocytic PTEN in the spinal cord reduced glial activation and neuroinflammation and subsequently alleviated pain-related behaviors. Importantly, astrocyte-specific PTEN knockout ( Pten conditional knockout , Pten CKO) mice showed nociceptive sensitization and glial activation. Proteomic analysis revealed that PTEN overexpression upregulated at least 7 enzymes in the cholesterol biosynthesis pathway and the total cholesterol level in the spinal cord of CCI rats. Furthermore, PTEN directly interacted with enzymes, including 3-hydroxy-3-methylglutaryl-CoA reductase, in the cholesterol biosynthesis pathway. Astrocytic 3-hydroxy-3-methylglutaryl-CoA reductase overexpression alleviated both CCI-induced pain and mechanical allodynia in Pten CKO mice. Finally, cholesterol replenishment attenuated CCI-induced pain and suppressed spinal glial activation. Taken together, these findings imply that spinal astrocytic PTEN plays a beneficial role in CCI-induced pain by regulating cholesterol biosynthesis, and an increased level of PTEN may accelerate cholesterol biosynthesis and reduce glial activation, thereby alleviating neuropathic pain. Recovery of PTEN or cholesterol might be an effective therapeutic strategy for neuropathic pain.
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