BOK_FINISH_9a.indd



to the production of NO. First through oxidation producing a transcription
factor, NF kappa B, which then stimulates inflammatory cytokines. Then these
cytokines induce NO production, which if not reduced by glutathione, will cause
peroxynitrite to build in the mitochondria, damaging DNA and enzymes. This
cell damage would in turn reduce mitochondrial energy and production of ATP
levels.
Evidence has accumulated for a number of years that glutamate released in
excess, acting via NMDA receptors, mediates neurotoxicity in stroke, Alzheimer’s
and Huntington’s diseases. Because glutamate, via NMDA receptors, stimulates
NO formation, one might expect excess NMDA receptor stimulation to destroy
Nitric Oxide Synthase (NOS) neurons. Surprisingly, NOS neurons are resistant to
NMDA neurotoxicity. If NMDA stimulates NOS neurons to make NO, but these
cells are themselves resistant to neurotoxicity, could the released NO damage other
cells? Exposure of cerebral cortical cultures to NMDA kills 60–90% of neurons,
with NOS-diaphorase cells being undamaged. Why are NOS neurons resistant to
NMDA toxicity? Presumably, NO is never released in the interior of NOS cells,
which accordingly are resistant to NO damage. Glutamate receptors are selective
for calcium ions; larger amounts of NO can force the calcium channels to fire more
rapidly which can lead to apoptosis or programmed cell death. (See Glutamate)
The body’s antioxidant superoxide dismutase prevents the conversion of
nitric oxide to peroxynitrite forming hydrogen peroxide. Nitrite reductase not
only prolongs the effective ‘life time’ of NO, but also reduces the concentration
of its highly reactive secondary metabolites: Peroxynitrite, hydrogen peroxide, and
dinitrotrioxide all have been linked to cell death (apoptosis) through protein nitration
and increased mutagenesis. Acute neural toxicity is linked to the overproduction
of the secondary NO metabolite peroxynitrite, which inhibits respiratory enzymes
and also damages DNA by covalent bond formation to DNA and removal of
bases. In glial cells the stimulation of NOS activity causes significant damage
to the mitochondrial activities of neighboring neurons. Both a NOS inhibitor
and interferon-/ß and antioxidants exhibit neuroprotective properties because they
limit the formation of highly reactive nitrogen containing radicals.
NO regulates the function, growth, death and survival of many immune and
inflammatory cell types. mast cells and their potent chemical mediators are
known to initiate and modulate a number of important inflammatory cascades. In
Multiple Sclerosis besides T-Lymphocytes and Macrophages it is found that Mast
Cells also are indicated in central and peripheral nervous system demyelination.
Mast Cells surround blood vessels in the brain, are juxtaposed to neurons. Mast
Cells (activated by Myelin Basic Protein), have been shown to secrete vasoactive and
inflammatory mediators in response to neuropeptides and direct nerve stimulation
and can participate in the regulation of the Blood-Brain Barrier permeability, as
well as in myelin destruction.
Kidney failure patients suffer from neurological complications and a recent
study shows how free radicals and NO interact to produce oxidative stress that
helps produce this nerve damage. A powerful antioxidant (des-methyl-tirilizad)
was found to serve some protection from brain dysfunction during kidney failure.