Nicotinamide mononucleotide alleviates seizures via modulating SIRT1‐PGC‐1α mediated mitochondrial fusion and fission

Abstract

AbstractBoth human and animal experiments have demonstrated that energy metabolism dysfunction in neurons after seizures is associated with an imbalance in mitochondrial fusion/fission dynamics. Effective neuronal mitochondrial dynamics regulation strategies remain elusive. Nicotinamide mononucleotide (NMN) can ameliorate mitochondrial functional and oxidative stress in age‐related diseases. But whether NMN improves mitochondrial energy metabolism to exert anti‐epileptic effects is unclear. This study aims to clarify if NMN can protect neurons from pentylenetetrazole (PTZ) or Mg2+‐free‐induced mitochondrial disorder and apoptosis via animal and cell models. We established a continuous 30‐day PTZ (37 mg/kg) intraperitoneal injection‐induced epileptic mouse model and a cell model induced by Mg2+‐free solution incubation to explore the neuroprotective effects of NMN. We found that NMN treatment significantly reduced the seizure intensity of PTZ‐induced epileptic mice, improved their learning and memory ability, and enhanced their motor activity and exploration desire. At the same time, in vitro and in vivo experiments showed that NMN can inhibit neuronal apoptosis and improve the mitochondrial energy metabolism function of neurons. In addition, NMN down‐regulated the expression of mitochondrial fission proteins (Drp1 and Fis1) and promoted the expression of mitochondrial fusion proteins (Mfn1 and Mfn2) by activating the SIRT1‐PGC‐1α pathway, thereby inhibiting PTZ or Mg2+‐free extracellular solution‐induced mitochondrial dysfunction, cell apoptosis, and oxidative stress. However, combined intervention of SIRT1 inhibitor, Selisistat, and PGC‐1α inhibitor, SR‐18292, eliminated the regulatory effect of NMN pre‐treatment on mitochondrial fusion and fission proteins and apoptosis‐related proteins. Therefore, NMN intervention may be a new potential treatment for cognitive impairment and behavioral disorders induced by epilepsy, and targeting the SIRT1‐PGC‐1α pathway may be a promising therapeutic strategy for seizures.