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Sirtuins Protect Neurons in Mice

Written by Madelyn Huttner, July 7, 2017

Haijun Shao et al. from the Department of Anesthesiology at the Rujin Hospital in the School of Medicine at Shanghai Jiao Tong University determined that the activation of a histone deacetylase diminishes neuropathic pain in mice. Neuropathic pain involves damaged nerves, which can be caused by many diseases, infections and injuries including diabetes and multiple sclerosis. This type of pain causes symptoms such as hyperalgesia (an increased sensitivity to pain), allodynia (an increased sensitivity to touch) and paresthesia (tingling). Researchers in the past have speculated that neuropathic pain stems from gene modifications, specifically abnormal histone acetylation.

Histone acetylation is a fancy way of describing relaxed DNA that is available to be transcribed. DNA is wrapped around histones, which are made of eight proteins and can also be referred to as octamer. Looking like spools of thread, the thread-like DNA circles around each histone. Gene modification can affect how close the spools of thread are to each other.  Acetylation adds an acetyl group to each histone creating more space between threads allowing transcription and gene expression to occur. Conversely, histone deacetylases remove acetyl groups and tighten the DNA coils, limiting DNA transcription. The absence of the enzyme silent information regulator 1 (SIRT1), a histone deacetylase found in the spinal cord, may be the culprit for the development of neuropathic pain.

 

Haijun Shao et al. conducted a study to identify the presence of SIRT1, the co-enyzme nicotinamide adenine dinucleotide (NAD), as well as the byproduct of NAD metabolism, nicotinamide (NAM), in the spinal cords of mice after chronic constriction injury or sham injury. They also tested the effects of NAD on hyperalgesia and mechanical allodynia by injecting this coenzyme into the spinal cords of the mice. The researchers additionally determined if a SIRT1 inhibitor, EX-527, could reverse the anti-nociceptive effect of NAD and resveratrol.

It was found that the amount of spinal SIRT1 expression decreased, and hyperalgesia and allodynia increased after chronic constriction injury versus the sham group, which had no change in spinal SIRT1 levels. They also found that NAD levels were decreased, whereas NAM was increased in chronic constriction injured mice compared to the sham group. This shows that chronic constriction surgery decreases SIRT1 activity and depletion of NAD in the spinal cords of mice.

 

Furthermore, they tested whether NAD outside of the cell could weaken neuropathic pain. NAD injections, one hour before and on the first day after injury showed brief reduction in pain for 48 hours compared to the chronic constriction injured mice treated with saline. The data suggests NAD injected into the spinal cord regulated pain through histone deacetylation with SIRT1.

 

In order to prove that neuropathic pain was resolved through the activation of SIRT1 by NAD, Haijun Shao et al. used a SIRT1 inhibitor, EX-527. Injecting EX-527 one hour before NAD administration blocks the pain preventing benefits of NAD. This evidence demonstrates that SIRT1 consumes the NAD producing an anesthetic effect.

 

The data presented by Haijun Shao et al. implicates the crucial role of NAD activated sirtuins enzymes in neuropathic pain. More research should be conducted in human models to evaluate the effectiveness of intravenous NAD for neuropathic pain.

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