Nutraceuticals and Metabolic Stimulants
Russell L. Blaylock, MD*


[B]Board Certified Neurosurgeon, Clinical Assistant Professor
University of Mississippi Medical Center, Jackson, Mississippi
Winter 2002[/B

]INTRODUCTION

Neurodegeneration was once considered to be a simple
acceleration of the normal aging process. Aging of the
brain, however, generally produces little deterioration of
neurological function. Neurodegeneration on the other
hand, results in an appreciable loss of cognitive and motor
function. Hence, a significant loss of cognitive ability is
always pathological. In this review I will discuss several
changes that occur with neurodegeneration and offer potential
ways to reduce one’s risk of developing a neurodegenerative
disorder.
THE CENTRAL MECHANISM OF
NEURODEGENERATION
When one reviews the extensive literature on neurodegeneration,
one finds many seemingly unrelated pathological
events, such as excitotoxicity, viral inflammation,
autoimmune reactions, trauma, cerebrovascular impairment,
and metal toxicity. Surprisingly, a single central
mechanism explains all.1 This mechanism is a combination
of excitotoxic injury coupled with free radical damage to
neural tissue. Excitotoxins are neurotransmitters, such as
glutamate or aspartate, that can cause cell death when their
actions are prolonged. These chemicals are thought to play
and important role in ischemic brain damage.
A free radical molecule has an unpaired electron in its
outer orbital, one that robs surrounding molecules of their
electrons, generating a process referred to as oxidation or
oxidative stress. The particles responsible for this oxidative
injury are referred to as reactive oxygen species (ROS). A
related particle, discussed less often in the lay literature, is
the reactive nitrogen species (RNS). Its nitrogen atom interacts
chiefly with amino acids, such as tyrosine, interfering
with numerous biochemical processes in the central nervous
system. When these particles react with tyrosine they form
nitrotyrosine, a measurable marker for RNS damage. As we
shall see, these oxygen and nitrogen products are commonly
found in the tissues of those with neurodegenerative disorders,
such as Alzheimer’s dementia, Parkinson’s disease,
Huntington’s disease and Lou Gehrig’s disease (ALS).
The excitotoxic process entails a complicated series of
reactions involving the release of the amino acid neurotransmitter
glutamate. Glutamate reacts at a series of receptors
on the neuron’s surface that in turn, either directly or
indirectly, control the calcium pore or channel.2 This channel
tightly regulates the entry of calcium into the neuron.
Calcium homeostasis is critical because its loss is the trigger
for numerous abnormal signaling systems in the neuron,
which when over-stimulated can precipitate the
destructive generation of free radicals and inflammatory
reactions that can ultimately lead to the death of the cell.
For this reason, glutamate levels outside the neuron are
carefully regulated. Even small elevations in glutamate can
precipitate the destructive reactions we refer to as excitotoxicity.
Glutamate content outside the neuron is controlled
by a re-uptake system that involves a series of glutamate
transport proteins.3 Should too much calcium enter the neuron,
other cellular mechanisms act to remove it, either by
moving it into the mitochondria, pumping it outside the
neuron, or sequestering it in the endoplasmic reticulum.4
All of these processes require cellular energy. When cellular
energy supplies fall, these protective systems fail.
Calcium acts as a biochemical trigger for numerous
reactions, all of which play a vital role in neuron function,
such as nitric oxide signaling information, activation of
special eicosanoids and regulation of the neuron’s gene
messages.5 When too much calcium enters the cell, it triggers
an excessive production of nitric oxide, a cell-signaling
molecule.6 As the nitric oxide begins to build up, it
interacts with the superoxide radical to produce the highly
reactive and destructive peroxynitrite radical. This radical
wreaks havoc on the mitochondria, producing injury to its
enzymes (electron transport chain) and in addition, damages
mitochondrial DNA.7 A significant loss of cellular
energy production results.
Excess calcium also stimulates the activation of the
enzyme protein kinase C, which activates the membranebound
enzyme, phospholipase A2 ( PLA2).8 This enzyme in
turn releases arachidonic acid from the membrane lipid stores,
where it is then acted upon by two enzymes, cyclooxygenase
(COX) and lipoxygenase (LOX), which convert it into numerous
reactive molecules called prostaglandins and leukotrienes.
Both metabolic products, when present in excess, can drastically
increase free radical production.9
As the level of free radicals begin to rise, they interact
with the lipids in the cell’s various membranes, setting up
a chain reaction called lipid peroxidation. The peroxyl radical
plays a major role in membrane injury as well as injury
to mitochondria.10 As the destructive process spreads
through the membrane, secondary metabolic products are
produced, such as 4-hydroxynonenal, which can be even
more destructive.11
Cellular proteins are building blocks for the hundreds of
enzymes used by each cell to function. Free radicals interact
with both proteins and carbohydrates in the cell, causing
conformational changes in their structure. While free-radical-
altered proteins, called carbonyl products, increase with
aging, they don’t increase to the extent we see in the tissues
of those with neurodegenerative diseases.12,13
Another cell component damaged by free radicals is
DNA. The cell contains two sets of DNA: one type in the
nucleus, and another in each of the cell’s numerous mitochondrion.
Mitochondrial DNA is especially vulnerable to
oxidation reactions, being about 10X more sensitive to free
radical damage.14


* Correspondence:


Russell L. Blaylock, MD
315 Rolling Meadows
Ridgeland, Mississippi 39157
Phone: 601-982-1175
E-mail: dodd@netdoor.com