Nitric Oxide is a free radical produced by glial cells in the brain as an immune response to infection. It falls into the category of reactive nitrogen species that is often paired with reactive oxygen species. Together these make up RONS (reactive oxygen and nitrogen species). Almost all of these molecules are produced in response to infection and cellular damage. They are highly reactive and can cause cellular damage on their own. Their main function would be to attack the bacteria or whatever is causing the damage to the cells by reversibly binding to their proteins and other molecules, but they also are produced in smaller amounts as a byproduct of metabolic processes.
Normally, these molecules are broken down readily by certain enzymes such as SOD, catalase, and NO synthase after they have done their job so as to prevent them from doing any damage to their own cells. These primary RONS are necessary for normal function within the cell, and may even contribute to certain signalling pathways.
However, in neurodegenerative disorders, there is an excessive amount of RONS. This can be caused by many things, such as the enzymes that break down RONS not functioning correctly, the processes and signals that create RONS being overactive, or overactive microglia and excess inflammation. What happens when there is a lot of RONS, is that they start to react with each other. For example, nitric oxide can react with superoxide to produce peroxynitrite.
Peroxynitrite is one of several secondary RONS that are very bad. These secondary RONS are not as easily broken down by those molecules that break down the primary RONS, and they have no other particular enzymes of their own. This means that they last much longer in the body, and can wreak havoc. Plus, they are even more reactive. Peroxynitrite can bind to amino acids, nitrating them and causing them to lose their function. It can also oxidize molecules that have a transition metal in them such as hemoglobin, myoglobin, and cytochrome c. This changes the transition state of the metal and renders the molecule nonfunctional. This is obviously very bad, and leads to cell damage and death.
As we age, we normally accrue higher amounts of reactive species. In fact this may be one of the main contributors to the breakdown of cells that occurs with normal aging. In neurodegenerative disorders this occurs rapidly in particular neurons, causing a lot of damage and neuronal loss. Anti-oxidants and anti-nitrosatives found in fruits and veggies like blueberries and spinach can help by breaking down some of these reactive species, but more research into finding out more about how we can prevent this process from occurring is definitely warranted.
Oh NO! Nitric Oxide and Neurodegenerative Disorders
I am not sure which of these student writings on nitric oxide to respond to since they are all excellent. I chose this one because it specifically mentions peroyxnitrite which likely plays an important role in many neurodegenerative as well as other diseases.
http://www.ncbi.nlm.nih.gov/pubmed/17237348
The role of peroxynitrite in Alzheimer’s disease has perhaps been studied the most. The KEGG pathway for Alzheimer’s disease lists the damage done by peroxynitrite as follows: protein oxidation, mitochondrial dysfunction, apoptosis, DNA damage, inflammation, and lipid peroxidation. The one element left off this summary chart is tyrosine nitration (the latter is particularly important because it cuts off the neuroprotective phosphatidylinositol 3-kinase/AKT pathway and enhances the neurodestructive p38 MAPK pathway via NMDA receptor activation). The combination of these elements leads to the following brain damage in Alzheimer’s disease: restricted blood flow and glucose transport in the brain (which may cause wandering, delusions, and apathy), reduced release and synthesis of neurotransmitters involved in short-term memory, sleep, mood, social recognition, and alertness, the end to neuron regeneration, the hyperphosphorylation and nitration of tau proteins which limits neurotransmisssion and the transport of nutrients, and the death of neurons.
Polyphenols in various fruits, vegetables, and beverages have the ability to inhibit the formation of peroxynitrite, scavenge them, and reverse part of their oxidative and nitrostative damage.
http://www.ncbi.nlm.nih.gov/pubmed/12676458
The most effective polyphenols are called methoxyphenols because through increased hydrogen donation they partially reverse both oxidation and nitration. Examples of methoxyphenols include eugenol (in various essential oils via aromatherapy), ferulic acid and syringic acid in panax ginseng, sinapic acid, syringic acid, and curcumin. Some of these compounds have been studied for Alzheimer’s disease, other forms of dementia, and other neurodegenerative diseases with varying degrees of success (some such as curcumin are limited by low bioavailability). In any case, the discovery of particularly effective peroxynitrite scavengers or combinations of peroxynitrite scavengers may be an important key to treating many neurodegenerative diseases.
Thank you Professor Julie Mach and to all the students for communicating invaluable knowledge in such a lucid way. You have provided a great service to the rest of us.
Thanks, Lane! Appreciate your kind words and you taking the time to respond and read what we have to say.