2. Academic Validation
  3. Inhibiting the SARM1-NAD+ axis reduces oxidative stress-induced damage to retinal and nerve cells

Inhibiting the SARM1-NAD+ axis reduces oxidative stress-induced damage to retinal and nerve cells

  • Int Immunopharmacol. 2024 Jun 15:134:112193. doi: 10.1016/j.intimp.2024.112193.
Yannan Zhang 1,  Yihua Yao 1,  Juhua Yang 2,  Biting Zhou 3,  Yihua Zhu 4
Affiliations

Affiliations

  • 1 Department of Ophthalmology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China; Department of Ophthalmology, National Regional Medical Center, Binghai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Fujian Institute of Ophthalmology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Provincial Clinical Medical Research Center of Eye Diseases and Optometry, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
  • 2 The School of Pharmacy, Fujian Medical University, Fuzhou, Fujian Province, China.
  • 3 Department of Ophthalmology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China; Department of Ophthalmology, National Regional Medical Center, Binghai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Fujian Institute of Ophthalmology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Provincial Clinical Medical Research Center of Eye Diseases and Optometry, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China. Electronic address: zhoubiting@126.com.
  • 4 Department of Ophthalmology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China; Department of Ophthalmology, National Regional Medical Center, Binghai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China; Fujian Institute of Ophthalmology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China; Fujian Provincial Clinical Medical Research Center of Eye Diseases and Optometry, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China. Electronic address: zhuyihua209@163.com.
PMID: 38723372 DOI: 10.1016/j.intimp.2024.112193
Abstract

Retinal neurodegenerative diseases are a category of refractory blinding eye conditions closely associated with oxidative stress induced by mitochondrial dysfunction in retinal cells. SARM1, a core driver molecule leading to axonal degeneration, possesses NAD+ Enzyme (NADase) activity. However, the role of the SARM1-NAD+ axis in oxidative stress-induced retinal cell death remains unclear. Here, we employed the SARM1 NADase inhibitor DSRM-3716 and established a glucose oxidase (GOx)-induced oxidative stress cell model. We found that compared to the GOx group, the DSRM-3716 pre-treated group reduced the hydrolysis of NAD+, inhibited the elevation of oxidative stress markers induced by GOx, decreased mitochondrial dysfunction, lowered the phosphorylation level of JNK, and attenuated the occurrence of Pyroptosis in retinal and nerve cells, thereby providing protection for neurite growth. Further utilization of the JNK Activator Anisomycin activated JNK, revealed that the JNK/c-Jun pathway down-regulated NMNAT2 expression. Consequently, it reduced cellular NAD+ synthesis, exacerbated mitochondrial dysfunction and cell Pyroptosis, and reversed the protective effect of DSRM-3716 on cells. In summary, the inhibition of SARM1 NADase activity substantially mitigates oxidative damage to retinal cells and mitochondrial damage. Additionally, JNK simultaneously serves as both an upstream and downstream regulator in the SARM1-NAD+ axis, regulating retinal cell Pyroptosis and neurite injury. Thus, this study provides new insights into the pathological processes of retinal cell oxidative stress and identifies potential therapeutic targets for retinal neurodegenerative diseases.

Keywords

Cell pyroptosis; Mitochondria; Oxidative stress; Retinal neurodegenerative diseases; SARM1-NAD(+) axis.

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