It has been suggested that nitric oxide (NO) plays a role in neuro degeneration. NO as part of our immune response also kills invading bacteria. Each of our cells has hundreds of mitochondria that are essentially ancient bacteria that produce almost all of the energy that cells need to live. As bacteria, mitochondria are exquisitely sensitive to nitric oxide.

In a breakthrough discovery Dr. Gardner has discovered how mitochondria may protect themselves from NO.

Now we speculate about the newly discovered protein flavohemoglobin that protects bacteria from NO may also protect our mitochondria and play a role in HD. If expanded CAGs interfere with our production of flavohemoglobin then the pathology of HD has been discovered. We will know the start of the chain of events that can be the targets for drug intervention. --Jerry 09/01/98
Drugs Aging 1998 Apr;12(4):251-259

Nitric oxide (NO) is involved in important physiological functions of the CNS, including neurotransmission, memory and synaptic plasticity. Depending on the redox state of NO, it can act as a neurotoxin or it can have a neuroprotective action. Data suggest that NO may have a role in the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and Huntington's disease. Additionally, these data indicate that inhibitors of the NO-synthesising enzyme, NO synthase, may be useful as neuroprotective agents in these diseases. In animal models, NOS inhibitors have been shown to prevent the neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and other dopaminergic toxins. However, the clinical effects of NOS inhibitors remain unknown.

Scientists at Children's Hospital Medical Center of Cincinnati have discovered a major mechanism by which bacteria protect themselves against the human immune response - a discovery that opens the door for development of a new class of antibiotics to fight infection.

In the study, to be published in the September edition of Proceedings of the National Academy of Sciences, the researchers have discovered that flavohemoglobin, a protein in bacteria, protects the bacteria from nitric oxide (NO), a toxic chemical secreted by the immune system to help kill disease-causing microorganisms. The protein, which the researchers have re-named nitric oxide dioxygenase (NOD), detoxifies NO, providing protection against infection.

"It's a breakthrough concept," says Andrew Salzman, M.D., director of critical care at Cincinnati Children's and co-discoverer of the mechanism, along with Paul Gardner, Ph.D, and colleagues in the Kindervelt Shock Research Center at Children's. "With this discovery, Dr. Gardner has created a new field of research."

NO is a toxin produced by inflammatory cells that injures or kills bacteria. Over time, however, a mechanism has evolved that prevents NO from damaging bacteria. This detoxification of NO allows bacteria to survive. Without this protection, they would be unable to infect the host. Interestingly, NOD is an old protein, perhaps billions of years old, originating around the time oxygen appeared in the earth's atmosphere.

"It's actually the forerunner of hemoglobin - a protein in red blood cells that carries oxygen," says Dr. Salzman. "It's abundant and present throughout the animal kingdom for transporting oxygen in the blood. It's been known for many years that there is a form of hemoglobin in bacteria, but its function was entirely unknown. It surely wasn't to carry oxygen. Now we've discovered what we believe is the fundamental purpose of this protein - to protect organisms against nitric oxide. So we are now providing an understanding of the evolutionary basis of hemoglobin and the original function of the hemoglobin family - to detoxify nitric oxide."

This evolutionary history has broad and dramatic implications for human health. Overwhelming infection is one of the major reasons for children and adults are admitted to intensive care units. It's also one of the leading causes of death. New antibiotics could change that.

"Bacteria vary enormously in their ability to defend themselves against nitric oxide," says Dr. Salzman. "But if you remove this protein from bacteria, you can kill them with almost nothing. They're exquisitely sensitive to nitric oxide. Yet, if they're exposed to nitric oxide all the time, the bacteria rev up this system to detoxify it."

Dr. Salzman speculates that this may be what predisposes smokers to infection. Smokers constantly bathe their lungs with huge concentrations of NO. It is possible that bacteria in the lungs of smokers become more resistant to the effects of nitric oxide.

So far, Children's scientists have studied only the most common bacteria at the basic level. But because NOD is broadly represented in different bacteria, they have no reason to believe this mechanism is unique to any particular strain.