Supplementing NAD+ precursors as a promising approach for DPN
1. Introduction
Diabetic peripheral neuropathy (DPN) is one of the most frequent complications of diabetes, ans also a major cause of foot ulcers, disability, and eventual amputation. With the prolongation of the diabetes, about 50% of people with diabetes will eventually develop DPN. Notably, supplementing NAD+ precursors could alleviate DPN symptoms by increasing the NAD+ level and activating the sirtuin-1 (SIRT1) protein.
2. The reversal effect of NAD+ precursors on DPN
In vitro, the Dorsal Root Ganglion neurons (DRGs) isolated from diabetic mice are exposed to the NAD+ precursor Nicotinamide Riboside (NR) or Nicotinamide Mononucleotide (NMN). It is found that the NAD+ level, the SIRT1 protein, and the deacetylation activity are elevated, followed by the boosted neurite growth, the improved nerve function, and the reversal of IENFD loss.
In vivo, supplement of NMN or NR also offsets the neuropathy in C57BL6 mice induced by streptozotocin (STZ) or high fat diet (HFD), as manifested by the improved sensory function, normalized nerve conduction velocities, and restored intraepidermal nerve fibers.
In vivo, supplement of NMN or NR also offsets the neuropathy in C57BL6 mice induced by streptozotocin (STZ) or high fat diet (HFD), as manifested by the improved sensory function, normalized nerve conduction velocities, and restored intraepidermal nerve fibers.
3. The increase of neurite length in a SIRT1-dependent manner post the addition of NMN/NR
SIRT1, one of the most unique NAD+ consuming enzymes, can protect against DPN when activated, which may attribute to the improved mitochondrial function and energy homeostasis. Apart from these, SIRT1 activity in the nucleus can deacetylate the transcriptional and co-transcriptional factors that regulate glucose homeostasis and fat oxidation.
The activation of SIRT1 is critical for axonal regeneration. NMN/NR treatment or transfection with SIRT1 overexpression vector can directly facilitate the neurite growth in cultured DRG neurons, which however is hindered by the SIRT1 inhibitor EX527, hinting the significance of SIRT1.
The activation of SIRT1 is critical for axonal regeneration. NMN/NR treatment or transfection with SIRT1 overexpression vector can directly facilitate the neurite growth in cultured DRG neurons, which however is hindered by the SIRT1 inhibitor EX527, hinting the significance of SIRT1.
4. The association of SARM1 with NMNAT2 in axonal degeneration of DPN
Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) controls the axonal degeneration and regeneration via a well-regulated system comprising NAD+ and NMN. NAD and NMNAT2 can boost vesicular glycolysis and axonal transport to maintain the axonal health. The mitochondrial localization of SARM1 complements the coordinated activity of NMNAT2 that promotes axonal survival.
5. Conclusion
Supplementing NAD+ precursors may be a promising approach for the treatment of DPN. A SARM1 inhibitor coupled with either NR or NMN may be more effective than a single agent alone in preventing or treating DPN.
Reference
Chandrasekaran K, Najimi N, Sagi AR, et al. NAD+ Precursors Reverse Experimental Diabetic Neuropathy in Mice. Int J Mol Sci. 2024;25(2):1102. Published 2024 Jan 16. doi:10.3390/ijms25021102
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