NMN administration after sever hypoglycemia improves neuronal survival and cognitive function

https://pubmed.ncbi.nlm.nih.gov/32380185/

Published:                July 2020

 

Highlights

  • Nicotinamide mononucleotide improves learning and memory after severe hypoglycemia.
  • Nicotinamide mononucleotide improves neuronal survival after severe hypoglycemia.
  • Nicotinamide mononucleotide eliminates ROS accumulation after severe hypoglycemia.
  • Nicotinamide mononucleotide suppresses PARP-1 activity after severe hypoglycemia.
  • Nicotinamide mononucleotide prevents severe hypoglycemia-induced LTP inhibition.

 

Abstract

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.

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