N-Acetylcysteine and the Fight Against Oxidative Stress in Huntington’s Disease

Posted: March 5, 2013 in Uncategorized
Tags: , , , , ,

In my previous entry I discussed how the survival benefit of increased protein p53 inhibits glucose-6-phosphate dehydrogenase, which inturn decreases intracellular glutathione and leads to an increase in reactive oxygen species (ROS).  You can read it here: https://geneticpotential.wordpress.com/2013/03/04/circadian-melotonin-and-huntingtons-disease/.

To help prevent neurogeneration in those diagnosed with Huntington’s Disease we need to find a means to increase intracellular glutathione to combat the ROS.  This is where N-acetylcysteine supplementation comes into play.  N-acetylcysteine (NAC) is a precursor to glutathione.  It also plays a role in modulating the inflammation, glutamatergic, and neurotropic pathways.  New research outlines NAC’s therapeutic use in disorders such as; bipolar disorder, gambling addiction, drug addiction, compulsive disorders, and schizophrenia (Dean, 2011).

Researchers have shown that NAC may be beneficial to those diagnosed with HD.  In one study rats were induced with the disease.  They were given the Wistar strain which inhibits the mitochondria in the striatum.  This is seen in human’s with the disease.  The rats given the strain showed increase ROS and a decrease in antioxidants.  There was an increase in capase 3 expressions as well as p53 in the rats given the Wistar strain.  This is very similar to the mechanisms seen in the human brain.  Capase 3 is important here because it plays a major role in apoptosis, programmed cell death.  An increase in capase 3 leads to an increase in apoptosis.    This lead to neurodegeneration in the rats by means of cognitive decline and motor impairment.  The rats treated with NAC showed a reversal of the symptoms induced by the disease including mitochondrial dysfunction and neurobehavioral deficits (Sandhir, 2012).

Not only is NAC a precursor to glutathione, it is a stimulator of the cystolic enzymes involved in glutathione regeneration.  NAC also has the ability on its own to reduce ROS and it has been shown to prevent apoptosis in cultured neuronal cells and comes with a lack of human toxicity (Benaclocha, 2001).

The other important part of increasing glutathione levels, as I mentioned in my previous article, is through our circadian melatonin levels.  Depression and sleep disorders are very common in patients with HD.  Serotonin is a key player in both aspects.  Serotonin is referred to as our “feel good” neurotransmitter.  Also, when the sunlight goes down our serotonin should be converted into melatonin. I wrote an article about serotonin here:  http://robbwolf.com/2012/10/05/serotonin-deficiency-food-cravings/.

Mouse models have shown an impairment in serotonergenic pathways as the cause for the depression seen in HD patients (Pang, 2009).  Serotonin binding sites in the basal ganglia were decreased in post-mortem human brains.  The basal ganglia is where the decreased GABA and increased dopamine occurs leading to chorea.  Serotonin may play a role in this area as well.  The interesting piece of this study is this same serotonergenic pathway dysfunction was not seen in patients with Parkinson’s disease (Waeber, 1989).  These studies tell us we have a neurotransmitter imbalance problem in the brain causing some symptoms of HD.  To alleviate a decrease in melatonin and to decrease the risk of depression in HD serotonin tissue levels need to remain constant.  5-htp supplementation may be the answer.

In conclusion, patients with HD suffer from increased oxidative stress.  This is due to a decrease in intracellular glutathione.  To increase the levels of that powerful antioxidant supplementing with NAC and restoring tissue levels of serotonin using 5-htp may have positive outcomes in the treatment of HD.

http://www.ncbi.nlm.nih.gov/m/pubmed/22327485/

http://www.ncbi.nlm.nih.gov/m/pubmed/11339849/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044191/

http://hmg.oxfordjournals.org/content/18/4/753.short

http://www.sciencedirect.com/science/article/pii/0306452289900821

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