Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Department of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Int J Mol Sci. 2024 Jan 16;25(2):1102. doi: 10.3390/ijms25021102.
Abnormal NAD signaling has been implicated in axonal degeneration in diabetic peripheral neuropathy (DPN). We hypothesized that supplementing NAD precursors could alleviate DPN symptoms through increasing the NAD levels and activating the sirtuin-1 (SIRT1) protein. To test this, we exposed cultured Dorsal Root Ganglion neurons (DRGs) to Nicotinamide Riboside (NR) or Nicotinamide Mononucleotide (NMN), which increased the levels of NAD, the SIRT1 protein, and the deacetylation activity that is associated with increased neurite growth. A SIRT1 inhibitor blocked the neurite growth induced via NR or NMN. We then induced neuropathy in C57BL6 mice with streptozotocin (STZ) or a high fat diet (HFD) and administered NR or NMN for two months. Both the STZ and HFD mice developed neuropathy, which was reversed through the NR or NMN administration: sensory function improved, nerve conduction velocities normalized, and intraepidermal nerve fibers were restored. The NAD levels and SIRT1 activity were reduced in the DRGs from diabetic mice but were preserved with the NR or NMN treatment. We also tested the effect of NR or NMN administration in mice that overexpress the SIRT1 protein in neurons (nSIRT1 OE) and found no additional benefit from the addition of the drug. These findings suggest that supplementing with NAD+ precursors or activating SIRT1 may be a promising treatment for DPN.
异常的 NAD 信号已被牵涉到糖尿病周围神经病变（DPN）中的轴突变性中。我们假设补充 NAD 前体可以通过增加 NAD 水平和激活沉默调节蛋白-1（SIRT1）蛋白来缓解 DPN 症状。为了验证这一点，我们将培养的背根神经节神经元（DRG）暴露于烟酰胺核苷（NR）或烟酰胺单核苷酸（NMN）中，这两种物质都能增加 NAD、SIRT1 蛋白和与神经突生长增加相关的去乙酰化活性。SIRT1 抑制剂阻断了 NR 或 NMN 诱导的神经突生长。然后，我们用链脲佐菌素（STZ）或高脂肪饮食（HFD）诱导 C57BL6 小鼠发生神经病，并给予 NR 或 NMN 两个月。STZ 和 HFD 小鼠均发生了神经病，通过 NR 或 NMN 给药得到逆转：感觉功能改善，神经传导速度正常化，表皮内神经纤维得到恢复。糖尿病小鼠的 DRG 中 NAD 水平和 SIRT1 活性降低，但 NR 或 NMN 治疗可保留这些水平。我们还测试了在神经元中过表达 SIRT1 蛋白的小鼠中给予 NR 或 NMN 的效果，发现药物的添加没有带来额外的益处。这些发现表明，补充 NAD+前体或激活 SIRT1 可能是治疗 DPN 的一种有前途的方法。
