NAD<sup>+</sup> Precursors Reverse Experimental Diabetic Neuropathy in Mice
Abnormal NAD<sup>+</sup> signaling has been implicated in axonal degeneration in diabetic peripheral neuropathy (DPN). We hypothesized that supplementing NAD<sup>+</sup> precursors could alleviate DPN symptoms through increasing the NAD<sup>+</sup> levels and acti...
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| Format: | Article |
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MDPI AG
2024-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/2/1102 |
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| author | Krish Chandrasekaran Neda Najimi Avinash R. Sagi Sushuma Yarlagadda Mohammad Salimian Muhammed Ikbal Arvas Ahmad F. Hedayat Yanni Kevas Anand Kadakia Tibor Kristian James W. Russell |
| author_facet | Krish Chandrasekaran Neda Najimi Avinash R. Sagi Sushuma Yarlagadda Mohammad Salimian Muhammed Ikbal Arvas Ahmad F. Hedayat Yanni Kevas Anand Kadakia Tibor Kristian James W. Russell |
| author_sort | Krish Chandrasekaran |
| collection | DOAJ |
| description | Abnormal NAD<sup>+</sup> signaling has been implicated in axonal degeneration in diabetic peripheral neuropathy (DPN). We hypothesized that supplementing NAD<sup>+</sup> precursors could alleviate DPN symptoms through increasing the NAD<sup>+</sup> 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<sup>+</sup>, 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<sup>+</sup> 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. |
| first_indexed | 2024-03-08T09:53:06Z |
| format | Article |
| id | doaj.art-a1276f937c504573a77b0d2abdc6db37 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T09:53:06Z |
| publishDate | 2024-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a1276f937c504573a77b0d2abdc6db372024-01-29T13:57:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-01-01252110210.3390/ijms25021102NAD<sup>+</sup> Precursors Reverse Experimental Diabetic Neuropathy in MiceKrish Chandrasekaran0Neda Najimi1Avinash R. Sagi2Sushuma Yarlagadda3Mohammad Salimian4Muhammed Ikbal Arvas5Ahmad F. Hedayat6Yanni Kevas7Anand Kadakia8Tibor Kristian9James W. Russell10Department of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Anesthesiology, University of Maryland School of Medicine, Baltimore, MD 21201, USADepartment of Neurology, University of Maryland School of Medicine, Baltimore, MD 21201, USAAbnormal NAD<sup>+</sup> signaling has been implicated in axonal degeneration in diabetic peripheral neuropathy (DPN). We hypothesized that supplementing NAD<sup>+</sup> precursors could alleviate DPN symptoms through increasing the NAD<sup>+</sup> 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<sup>+</sup>, 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<sup>+</sup> 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.https://www.mdpi.com/1422-0067/25/2/1102streptozotocinhigh fat dietdiabetic neuropathyNAD<sup>+</sup>mitochondriaSIRT1 |
| spellingShingle | Krish Chandrasekaran Neda Najimi Avinash R. Sagi Sushuma Yarlagadda Mohammad Salimian Muhammed Ikbal Arvas Ahmad F. Hedayat Yanni Kevas Anand Kadakia Tibor Kristian James W. Russell NAD<sup>+</sup> Precursors Reverse Experimental Diabetic Neuropathy in Mice International Journal of Molecular Sciences streptozotocin high fat diet diabetic neuropathy NAD<sup>+</sup> mitochondria SIRT1 |
| title | NAD<sup>+</sup> Precursors Reverse Experimental Diabetic Neuropathy in Mice |
| title_full | NAD<sup>+</sup> Precursors Reverse Experimental Diabetic Neuropathy in Mice |
| title_fullStr | NAD<sup>+</sup> Precursors Reverse Experimental Diabetic Neuropathy in Mice |
| title_full_unstemmed | NAD<sup>+</sup> Precursors Reverse Experimental Diabetic Neuropathy in Mice |
| title_short | NAD<sup>+</sup> Precursors Reverse Experimental Diabetic Neuropathy in Mice |
| title_sort | nad sup sup precursors reverse experimental diabetic neuropathy in mice |
| topic | streptozotocin high fat diet diabetic neuropathy NAD<sup>+</sup> mitochondria SIRT1 |
| url | https://www.mdpi.com/1422-0067/25/2/1102 |
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