Nicotinamide mononucleotide administration after sever hypoglycemia improves neuronal survival and cognitive function in rats

Brain Res Bull. 2020 Jul:160:98-106. doi: 10.1016/j.brainresbull.2020.04.022. Epub 2020 May 5.


Hypoglycemia-induced brain injury is a potential complication of insulin therapy in diabetic patients. Severe hypoglycemia triggers a cascade of events in vulnerable neurons that may lead to neuronal death and cognitive impairment even after glucose normalization. Oxidative stress and the activation of poly (ADP-ribose) polymerase-1 (PARP-1) are key events in this cascade. The production of reactive oxygen species (ROS) induces DNA damage and the consequent PARP-1 activation, which depletes NAD+ and ATP, resulting in brain injury. One of the key precursors of NAD+ is nicotinamide mononucleotide (NMN), which is converted to NAD+ and reduces production of ROS. Here we investigated whether NMN could reduce brain injury after severe hypoglycemia. We used a rat model of insulin-induced severe hypoglycemia and injected NMN (500 mmg/kg, i.p., one week) following 30 min of severe hypoglycemia, at the time of glucose administration. One week after severe hypoglycemia, hippocampal long-term potentiation (LTP), an electrophysiogic assay of synaptic plasticity, was examined and neuronal damage was assessed by Hematoxylin-Eosin staining. ROS accumulation, PARP-1 activation, NAD+ and ATP levels in hippocampus were also measured. Cognitive function was assessed using the Morris water maze 6 weeks after severe hypoglycemia. The addition of NMN reduced neuron death by 83 ± 3% (P < 0.05) after severe hypoglycemia. The hippocampal LTP was significantly reduced by severe hypoglycemia but showed recovery in the NMN addition group. NMN treatment also attenuated the severe hypoglycemia-induced spatial learning and memory impairment. Mechanically, we showed that NMN administration decreased ROS accumulation, suppressed PARP-1 activation, and restored levels of NAD+ and ATP in hippocampus. All these protective effects were reversed by 3-acetylpyridine (3-AP), which generates inactive NAD+. In summary, NMN administration following severe hypoglycemia could ameliorate neuronal damage and cognitive impairment caused by severe hypoglycemia. These results suggest that NMN may be a promising therapeutic drug to prevent hypoglycemia-induced brain injury.

Keywords: Cognitive impairment; Hypoglycemia; Neuronal survival; Nicotinamide mononucleotide; PARP-1; ROS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cognition / drug effects*
  • Drug Administration Schedule
  • Hypoglycemia / drug therapy*
  • Hypoglycemia / pathology
  • Hypoglycemia / psychology
  • Male
  • Neurons / drug effects*
  • Neurons / pathology
  • Neurons / physiology
  • Nicotinamide Mononucleotide / administration & dosage*
  • Rats
  • Rats, Sprague-Dawley
  • Severity of Illness Index*


  • Nicotinamide Mononucleotide