Functional Therapeutics in Neurology: Oxidative Stress and the
Nervous System
Catherine Willner, MD
Neurology and Pain Management (Board Certified)
The focus of this discussion is the role of oxidative stress and how it
impacts neurological functioning in ways sometimes unique to the human
nervous system. It is important to understand initially some of
the ways in which the nervous system is different from other organ
systems in the body and the extent to which its failure to function can
be a devastating consequence both to the individual and to
society. The cells and tissues of the human nervous system share
many features in common with all other cellular structures in the
body. In this sense, all principles of functional medicine can be
applied in situations where the predominant problem faced by a
clinician seems to be one that is neurological. In fact, it would
be the most appropriate application of the principles of functional
medicine to optimize functioning before a specific disease related to
genomic or environmental risk can be identified. However, getting
to that ideal requires understanding the nervous system in terms of
unique biochemistry, physiology and pathological states that sometimes
set it apart from other systems and these issues deserve attention as
we navigate the web of interconnectedness to apply the principles of
functional medicine. Functional medicine approaches the nervous system
as one part of a web of interconnectedness of all bodily systems and
functions and assesses how to optimize processes that permit healthy
functioning of the whole organism. Functional neurology considers
this web as it impacts the ability of the nervous system to perform
optimally in all of its functions. It is sometimes a struggle to
make the leap between traditional neurology and these paradigms.
But it is also a very exciting challenge. We will look briefly at
some aspects of traditional neurological assessment, then explore the
unique characteristics of the nervous system as they are impacted by
oxidative stress. The final sections of this monograph will deal
with some specifics of the application of these principles to
functional neurology.
Neurologists are taught very precisely to label in space (anatomy),
function (physiology and pathology), time (pathophysiology of acute,
subacute and chronic) and to consider genetics and the environment,
though we are traditionally taught little in terms of how to impact the
latter two. For example, those disorders that we recognize as
being impacted by environmental influences are often considered as
irreversible or too delayed to alter when they result from certain
toxic exposures or severe deficiencies. More emphasis in
traditional neurology is placed on naming and managing than on
prevention or optimization of function or risk assessment. There are,
of course, exceptions, such as disorders associated with B12
deficiencies, or metabolic changes that occur with acute or chronic
alcohol exposure, or the cognitive and other neurological changes
associated with altered thyroid status. We are traditionally
taught that these can be, at least in part, reversed by treatment if
they are recognized early and their recognition is a core aspect in
traditional neurological training. However, in many
circumstances, by the time these disorders have actually resulted in
diagnosable conditions involving the nervous system, the damage is
quite severe. We are only beginning to respect the more subtle
aspects of metabolic dysfunction or applying methods to assess early
failure in the system. For example, consider the longstanding
awareness of neural tube defects, but the delay in appreciating other
dysfunctions which can be reflected in dysfunction of the folate cycle
and homocysteine metabolism.
Also quite traditional in neurological assessment is understanding of
the temporal sequence of pathophysiological events, which is often
useful in attempting to arrive at diagnostic considerations. As
such, acute events, those that occur suddenly, like stroke, migraine or
seizure, are different than the subacute (infection, demyelinating
disorders like multiple sclerosis) or the chronic progressive disorders
that involve cognition and memory (dementias), movement or other bodily
functions, usually considered the “system disorders” like Parkinsonism,
cerebellar disorders, autonomic failure, peripheral neuropathies, and
the combinations (multisystem diseases or atrophy). Those
disorders that cause progressive loss of the functions of the nervous
system have been traditionally labeled as
Table 1: Neurodegenerative Disorders (traditional ones)
Dementias (Alzheimer’s, Pick’s, Lewy Body disorders)
Idiopathic Parkinson’s Disease
Parkinson Plus Syndromes (dementia, the most frequent)
Cerebellar degeneration (olivopontocerebellar atrophy)
Shy-Drager syndrome (autonomic failure)
Progressive supranuclear palsy
Motor neuron disorders (ALS)
Hereditary peripheral neuropathies
neurodegenerative. We have struggled to name them by the tools
that we use in classification (anatomy, physiology and pathophysiology)
with consideration of both the genome and the environment. A list
of some of these traditional diagnoses of the chronically progressive
disorders appears in Table 1. Precisely because we are living
longer as a population, and because our population is aging as a whole,
many people are surviving longer with these diagnoses which impact the
quality of life and extract a large economic burden on our
society. However, it is important to take into consideration that
the other disorders, not specifically considered neurodegenerative,
also are costly to manage. For example, the toll in terms of work
attendance, activities of daily living, and pain and suffering, caused
by migraine alone is quite high.1 The availability of
progressively more expensive pharmaceuticals to treat this disorder has
not completely, at least in any satisfactory way, solved this
problem. And, as with almost every other traditionally labeled
“neurological disease” or disorder, prevention of stroke, migraine,
epilepsy, multiple sclerosis, peripheral neuropathy, the dementias and
the degenerative system disorders should be as much or more of a focus
than their management. And oxidative stress plays a role in every
one of these disorders. We will first deal with some of the
unique features of the nervous system related to its structure and
function.
Function and Structure: The Nervous System
Probably the most important task performed by the nervous system in a
general sense is communication which permits coordination of adaptive
responses both within the brain and throughout the entire
organism. This permits, for example, awareness (perception) of
both internal and external environments, and performance and the
adjustment or fine tuning that can occur fairly rapidly because of the
unique features of that communication. Though such processes are
present in most other organ systems, the nervous system is unique
because of the rapidity with which it can alter function in these very
systems and also because of the distances that can be involved from the
origin of signals. It is also unique because it permits awareness
of, and interaction with the environment (consciousness, memory,
cognition). This system of communication requires electrical potentials
as well as chemical interactions from neurotransmitters or substances
more traditionally considered hormonal. And, the nervous system
allows us to perceive and to react both at a conscious level and in the
sense of autonomic activity, without the requirement of conscious
awareness. When one actually attempts to discuss this system in
depth, the concept of neuroendocrinology becomes apparent.
With respect to anatomy and physiology, there are several unique
features of the nervous system that warrant consideration. Some
of the more obvious are as follows, though they are not discussed in
any rank order of importance. First of all, the nervous system
has unique energy requirements that include fairly consistent access to
oxygen and to glucose, though other carbon-based fuels can be
accommodated. It is a demanding metabolic environment with high
energy requirements partly because of the generalized need to maintain
electrochemical gradients to allow generation of action potentials
appropriately and to allow receptors to function normally.
Mitochondrial function, as the source of this energy, is key to
optimization of function. Second is the method of communication
at synapses by transmitters and receptors, which requires continuous
recycling of both the chemicals and their receptors involved in this
process. This requires a normally functioning genome as well as
access to substrate to make the enzymes, the transmitters and the
receptors. Third, maintenance of membrane structure system is
paramount to normal performance of neurons and the surrounding complex
cellular system of glial cells. Discussion of their complex functions
is beyond our scope, but one of the major functions is to provide
insulation by forming myelin which permits electrical activity that is
sequestered to travel appropriately to the correct destination at
speeds in the range of 100 m/s. Because of the need for
insulation related to such highly complex communications between cells
(both in the brain and at a distance, through the fiber tracts and
peripheral nervous system), the concentration of lipid is unique and
high, both as cell membrane components and in the myelin which
insulates axons, the processes sent out by cells to accomplish this
communication. The relatively high content of polyunsaturated fatty
acid (PUFA) places the brain at significant risk for lipid peroxidation
secondary to free radical damage. Fourth, when considering neurological
uniqueness, it is important to remember that the neurons are, for the
most part, postmitotic tissues. Though potential for regeneration
(especially in the periphery) and plasticity of surviving neurons is
one of the strong points of the system, the limited ability of the
nervous system to regenerate or replace damaged cells does have serious
consequences. Fifth, certain regions of the brain, specifically
the substantia nigra and the striatum, have very high concentrations of
iron which also increases risk of peroxidation. Finally, though
less unique, the nervous system is relatively segregated from the rest
of the body - from the blood stream by the blood brain and blood nerve
barriers, and this portends a separate source for immunological
protection and defense, mostly provided in the CNS by the glial
cells. When the system fails, the consequences can be
devastating. Neuroimmunology is a very complicated and
fascinating subject which we will not be covering in this
monograph. The gut, with its unique role of interaction with the
external environment has similar types of barriers and unique defenses
and many of the same principles of functional medicine can be applied.
Table 2: The Nervous System – Unique Features
High Energy Requirements, Mitochondrial Dependence
High Metabolic Turnover, Excitatory Transmitters
Post-mitotic State
High Lipid Content (specialized membranes, PUFA)
Transmembrane Electrochemical Gradient
Region specific mineral concentration (Fe)
Sequestration (BBB / BNB / myelin)
The list of these features discussed above is presented in Table
2. Now, let’s consider some of the consequences of these features
and how functional neurology might approach the task of enhancing or
protecting these functions in the setting of dysfunction, where the
nervous system might be vulnerable. The specific focus will be on
oxidative stress the consequence of free radical damage and the link to
neurotoxicity and apoptosis or cell death.
NEUROLOGICAL VULNERABILITY: Oxidative Dependence, Free Radical Stress
The nervous system with its high metabolic requirements, uses about 20%
of the oxygen provided from ventilation. Oxygen and oxygen
species are used in the body for several different functions including
the role in the respiratory chain in energy production as ATP is
manufactured by alteration of carbon bonds to form water and carbon
dioxide. Oxidation also plays a role in defense related to
destruction of damaged or foreign substances by free radical attack.
There are elaborate mechanisms of protection for the brain and body,
related to free radical damage: enzymes such as SOD (superoxide
dismutase – requiring Zn, Cu, Mn), glutathione peroxidase (requiring
Se), and catalase (requiring Fe); dietary antioxidants (Vitamins C, E,
among others); and endogenous antioxidants (coenzyme Q10, carnitine,
lipoic acid). But as will be discussed below, free radical
formation is a necessary and essential function of these systems.
It is when the system is not balanced, that function fails. There
are risks in this setting that are both genetic and
environmental. The genetic risks of one of the chronic disorders,
Parkinsonism, are well discussed in a recent review.2 And, in both
acute and chronic disorders there exist evidence-based hypotheses that
both energy metabolism deficits and glutamate-mediated excitatory
transmitter dysfunction may be causative and integral to these
processes and related to damage by reactive oxygen and nitrogen species.
The Basics of Oxidative Stress and Neuronal Function
Mitochondrial function and the respiratory chain provide the mechanism
for production of energy through the formation of high-energy phosphate
bonds. This system is a complex one consisting of membrane,
enzymes, cofactors and substrates and the cellular organelles that
perform this function are the mitochondria, which are maternally
inherited and contain their own DNA (mitochondrial or mtDNA). A
schematic of the system is presented in Figure 1. Getting down to
absolute basics, in the neurons, like every other cell in the body that
utilizes carbon based atoms and oxygen to produce energy, this
complicated system is necessary to maintain cell function. In
addition to providing the energy necessary to produce enzymes or
neurotransmitters, or structural components for the cell, including
complex receptors, one of the most important functions which is
maintained in cells of the nervous system is an electrochemical
gradient or membrane potential, which is unique for cell systems that
can generate an “action potential” or other electrical charge which is
the basis for the rapid fire communication possible in the nervous
system. As mentioned above, the necessity to provide insulation
or sequestration in this system is supported by the formation of
myelin, which is a complicated lipid structure produced by glial cells
in the central nervous system and by Schwann cells in the
periphery. These “supporting cells” including the glia perform
many other protective functions as well by processing or storing many
of the neurotransmitters in the system when they are not acting at
receptors. Obviously, energy is required to accomplish all of
these tasks. It seems obvious that when the mitochondria fail to
produce adequate energy, the result will be suboptimal function at many
levels in the cell, and hence the system in general. However, in
addition to the impact that might be caused by inadequate energy
availability for normal functioning, there is also the risk posed by
the process of extracting such energy in the first place.
Table 2 Free Radical Targets
Lipid Cell Membranes
Cell Receptor Complexes
Enzymes
Structural Proteins (neurofilaments)
DNA
Mitochondrial buffering*
Viruses, bacteria*
*Normal functions
The work of producing energy via the mitochondria has a price that
includes generating free radicals and other products that have to be
handled by the system. The free radicals are dangerous to many
targets, especially the mitochondrial DNA itself but also to lipid
laden membranes (which are especially available in the nervous system)
but the generation of free radicals is required by the mitochondrial
system or the system cannot function. Free radical damage might
either imply impaired function of the mitochondria, or it might be the
consequence of too high a demand on the system in the absence of the
complement of metabolic factors necessary for the system to
function. The general concept is described as “oxidative
stress.” A list of common targets for free radical damage is
presented in Table 2. Typical sources of oxygen radicals are
depicted in Figure 2.
The generally recognized diseases associated with mitochondrial
disorders, which were traditionally referred to as “mitochondrial
encephalomyopathies” are now more commonly called “mitochondrial
cytopathies” to emphasize the multisystem nature of the dysfunction.
The most common of these are summarized in Table 3. There are
disorders now known to be associated with defects in each of the five
complexes classically described within the mitochondria. Though
most of the proteins and subunits of the mitochondria are actually
encoded by nuclear DNA, there are 13 critical polypeptide subunits of
the electron transport complexes which are formed by mitochondrial
DNA.3 The actual mitochondrial dysfunction can be anything from a
specific point mutation in mitochondrial DNA to large scale deletions
or duplications. The inheritance is variable from maternal, both
dominant and recessive, to acquired or sporadic mutations. Many
changes in function that occur with aging are usually hypothesized to
be related to the consequences of oxidative stress or various toxic
insults, to which the mitochondria seem to be particularly predisposed
because of their relative absence of DNA-repairing enzymes.4
The heterogeneity of these disorders is related to the specific
dysfunction but the major organ systems involved are those that are
most dependent on oxidative metabolism, hence the brain, and muscle
(skeletal and heart) are the most frequently affected, though other
tissues like the kidney and liver are also clearly at risk. The
abnormality most often discussed in the skeletal muscle is the
development of mitochondrial proliferation with abnormal morphology
(which along with patchy atrophy gives the appearance of “ragged red”
fibers on trichrome staining. Interestingly these changes are not
seen frequently with nuclear DNA changes but are quite common with
disorders produced by abnormalities of the mitochondrial DNA.
Table 3 Mitochondrial Disorders
Kearns-Sayre syndrome (ophthalmoplegia, retinal pigmentation,
conduction block, dementia)
LHON (Leber’s hereditary optic neuropathy - subacute blindness in young
adult)
MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and
stroke-like episodes)
MERRF (myoclonic epilepsy, ragged red fibers)
CPEO (chronic progressive external ophthalmoplegia)
Pearson’s syndrome (sideroblastic anemia, pancreatic dysfunction, death
in infancy)
NARP (neuropathy, ataxia, retinitis pigmentosa syndrome)
Maternally inherited myopathy with cardiomyopathy (spares the CNS)
MPTP Induced Parkinsonism as a Model – The Mitochondrial Link
In neurology, the most widely known model that resulted in elucidation
of at least some of the hypothesis about the role of mitochondrial
dysfunction in the neurodegenerative disorders is that of MPTP
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) - induced
Parkinsonism. MPTP is an analog of meperidine (a synthetic
narcotic). This model serves as a classic example to explain a link
between the failure of oxidative metabolism in the mitochondria and
metabolite mediated neurotoxicity. The model of MPTP toxicity is
detailed in Figure 3 and the hypothesis about excitatory receptor
activation that links this to cell destruction, discussed in further
detail below, is presented in Figure 4. As a direct outgrowth of
understanding this model, investigations have led to the delineation of
similar pathology in the so-called “idiopathic” disorders involving
degeneration of the nervous system. There has been evidence
identified for low complex I activity found in brain, muscle, and
platelets of patients with idiopathic Parkinson’s disease.5 Low
complex IV activity has been reported in patients with Alzheimer’s
disease.6 And importantly, several mitochondrial DNA deletions
and point mutations have been reported in both Parkinson’s and
Alzheimer’s tissues, supporting the hypothesis that failure of
oxidative phosphorylation is important as an etiology for the
neurodegenerative disorders. In addition to specific disorders of
mitochondrial function, there is also evidence that those enzyme
systems providing protection from free radicals can be identified as
abnormal in certain familial disorders. Mutations of the gene of
cytosolic copper-zinc superoxide dismutase (SOD1) was discovered in
patients with familial ALS (amyotrophic lateral sclerosis) and
identified as causative in approximately 20% of all the cases of
familial ALS, making it therefore responsible for about 1-2 % of all
cases of ALS.7
These are some of the many examples of disorders of the nervous system
which relate to dysfunction of the mitochondria in general, but the
significance is amplified exponentially when the system to accommodate
generation of free radicals fails, which will be discussed briefly
below. The major producer of such unstable intermediate products
is the mitochondrial electron transport chain. It is estimated
that 2-4% of the oxygen used by mitochondria is for the generation of
free radical species. Studies have suggested that oxidative
damage to mitochondrial DNA might be as much as 10 times higher than
damage to nuclear DNA.8 Progressive damage to mitochondrial
DNA is part of this process and this probably contributes to aging
because of progressive dysfunction of oxidative metabolism.
In aging mitochondria, there is evidence for lowered electron transport
complex activity and large mitochondrial deletions are increased in
tissues of older individuals.8 Interestingly these findings are
identified in normal aging hearts but there is evidence for
specifically common deletions that occur with aging, found to be even
more prominent in hearts that have suffered ischemic insults.
And, because of the unduplicated role of mitochondrial DNA in
production of subcomplexes discussed above, the finding that mutations
of mtDNA can be as much as 17 times higher than the rate of damage of
nuclear DNA emphasizes the importance of providing mitochondrial
support.9
Glutamate Excitotoxicity and Cell Dysfunction
The relevance of these findings to progressive degenerative disorders
of the nervous system requires an understanding of the consequences of
disrupted oxidative metabolism. Recall that one reason that the
nervous system has such high energy demands is the need to maintain
electrochemical gradients across the cell membrane. In the
absence of adequate energy or substrate to maintain this potential
energy barrier, there are alterations in cell membrane receptors.
The most well understood actors in this story are the excitatory amino
acids, (EAA’s). Glutamate, probably the most abundant free amino
acid in the central nervous system, is one of the excitatory amino acid
neurotransmitters. Though the majority of glutamate is actually housed
within the neuronal storage vesicles, there are high quantities in the
extracellular space. The other major excitatory substance is
aspartate. Analogous to the double-edged sword of mitochondrial
respiratory chain free radical production, these EAA neurotransmitters
are paramount to the brain’s plasiticity of function. However, in
excess, they are toxic to neurons. There are two major receptor
types for glutamate, ionotropic and metabotropic. Ionotropic
receptors are grouped into two major subtypes: NMDA
(N-methyl-D-aspartate) and non-NMDA receptors (the AMPA-kainate
receptor). The metabotropic receptor is coupled to cyclic GMP and
modulates production of intracelluar messengers which also influences
the ionotropic glutamate receptors. Under normal circumstances,
when adequate energy and cell function permit the electrochemical
gradiant to maintain a normal membrane potential, the NMDA receptor is
blocked by magnesium. Loss of the gradient results in loss of the
magnesium ion blocking the NMDA receptor, which when activated by
glutamate, results in influx of calcium into the neuron. Under normal
circumstances, this reaction is self limiting. In models of
neurotoxicity, there is an escalating cascade of damage leading to cell
death.
This same scenerio of excitatory neurotoxicity is postulated in the
mechanism of ischemic and hypoxic damage as seen with stroke or
hemorrhage. In this setting, rather than a clear cut loss of
energy and change in gradient potential, altering the receptor for
glutamate, it is suspected that there might actually be increases in
the amount of glutamate because of failure of the surround to modulate
the substance.10 The consequence is overactivation of the
receptor due to excess amounts of glutamate, then ultimately cell
failure secondary to the same processes discussed above related to
primary gradient potential failure. Both sodium and calcium are
increased intracellularly in this setting.
Exogenous glutamate receptor agonists are known to produce
neurotoxicity. One of the best understood models comes from
clinical insight about lathyrism which results from an AMPA glutamate
receptor agonist found in the foods (chick peas) known to be associated
with this condition, which produces a clinical syndrome similar or
mimicking ALS predominantly with upper motor neuron changes.
Glutamate, once the receptor cell is activated, is normally recycled by
active transport back into glial cells or is it to some extent
sequestered in neurons. Its elevation extracellularly can cause
continued reactivation of the both NMDA and non-NMDA receptors which
then allows increased levels of calcium to enter the neuron.
Calcium is normally buffered by intracellular buffering proteins, such
as calbindin or parvalbumin, among others. However, when the
buffering capacity is exceeded, the excess calcium ions may catalyze
activity in specific destructive enzymes that are not normally
activated . These include in the setting of ALS above, xanthine
oxidase, nitric oxide synthase, and phospholipase, all of which produce
free radicals, including reactive oxygen and also reactive nitrogen
species.11
Sustained elevation of calcium in particular is thought to initiate
toxic consequences including activation of catabolic enzymes such as
proteases, phospholipases, and endonucleases which will damage enzymes,
membranes and DNA.12 ¬These can be rapidly lethal. High
intracellular calcium also leads to uncoupling of the mitochondrial
reactions which results in further production of free radicals as well
as energy failure. Other activations including initiation of
protein kinase and lipid kinase cascades, which include for example,
activation of calcium calmodulin kinase (CaMK) and other kinases will
modify the function of ion channels, including the NMDA and
AMPA/kainate receptors.13 And, high intracellular calcium leads
to formation of free radicals by several other mechanisms including
calcium dependent activation of phospholipase A2 which liberates
arachidonic acid which then leads to further free radical production
and lipid peroxidation.
Glutamate Excitotoxicity and Free Radical Production: The Feed Forward
Loop
During normal cell function, stimulation of the NMDA receptors
leads to activation of nitric oxide synthase (NOS) with release of
nitric oxide which occurs as L-arginine is oxidized to citrulline by
NOS. This is a short lived reaction and self limiting under
normal circumstances. Nitric oxide is a potent vasodilator and is
a free radical species itself but it is not thought to cause severe
damage in normal physiology, and as seen with other reactions, its
normal role in metabolism is necessary for health. Once increased
excitotoxicity leads to calcium altered enzyme systems and free radical
generation, there is damage of all the cell components mentioned in our
opening discussion. Superoxide (O2-) produced by xanthine
oxidase, and nitric oxide (NO) produced by NO synthase react to form
peroxynitrite (ONOO-), one of the most potent reactive nitrogen species
which causes nitration of intracelluar proteins containing
tyrosine.14 These changes result in further damage to structural
and enzyme proteins. The changes also increase the demand on the
mitochondria which further upregulate but cannot adequately counter the
production of their own free radicals which then results in more
damage. Peroxynitirite is also indicted in other reactions within
neurons including DNA deamination, strand breaks, and damage to the
mitochondrial complexes I, II and mitochhondrial aconitase.
Ultimately cell death occurs as a result of multiple system failures.
Because of the significant toxicity posed by peroxnitrite, a great deal
of research is ongoing related to the potential roles for the nitric
oxide and NOS systems as they might be pathological in the
neurodegenerative disorders and possible candidates for manipulation to
prevent this cascade of damage. There are a number of disease
models where induction of NOS is suspected as participating in the
progression of pathology. Such changes have been seen in the
experimental model of multiple sclerosis (EAE, experiemental autoimmune
encephalomyelitis) and are widely demonstrated in models of cerebral
ischemia for stroke. Aminoguanidine, an inhibitor of NOS, used in
the model of EAE resulted in a dose dependent reduction of disease
expression.15 Using the MPTP model, researchers have shown that
pretreatment with an inhibitor of NOS (7-nitosindazole) prevented
development of Parkinsonism and typical cognitive changes seen in this
model in baboons exposed to MPTP.16 Application of NOS
synthase inhibitors also provided protection in cortical neuron cell
cultures against the toxic effect of beta-amyloid which is the altered
protein structure known to be associated with the plaques of
Alzheimer’s disease.18 It is also known that exposure of rat microglial
cells in culture to beta-amyloid results in the release of nitric oxide
especially in conditions of inflammatory upregulation.17
Use of arginine analogs has been attempted to interfere with this NOS
pathway, however, most of the substances studied are potent
vasoconstrictors and as such, they interfere with normal function
making clinical application elusive.14
Similar problems have been encountered in attempts to identify
pharmacological substances that block the NMDA receptors. Though
in theory, this might be protective in many settings, including acute
brain injury or ischemia, or in situations of stress during surgeries,
and some of the newer anticonvulsant type medications have some degree
of NMDA blocking activity, when direct application of NMDA inhibitors
has been attempted, significant problems with memory, learning and
overall functioning have resulted. Clinical application has remained
elusive for the most part.
Conclusions and Insights
The unique attributes of the nervous system discussed above, in
combination with the complexities and “double-edged” sword of
mitochondrial function, and generation of free radical species as part
of normal metabolic function lead to the recognition of a
delicate balance that must be fostered to permit healthy human
functioning. But these insights also offer the opportunity to
apply scientific evidence based principles to the optimization of these
systems in an effort to minimize genetic and environmental risk which
have resulted in a myriad of neurological disorders, from migraine to
stroke to MS and to parkinsonism and dementia.
References
1. Lipton R, Stewart W, Von Korff M. Burden of
migraine: societal costs and therapeutic opportunities. Neurology 1997;
48 (suppl 3): S4–S9
2. Mouradian MM. Recent advances in the genetics and
pathogenesis of Parkinson disease. Neurology 2002; 58 (2): 179-185.
3. DiMauro S, Moraes T. Mitochondrial
encephalomyopathies. Arch Neurol 1993;50:1197-1208.
4. Shigenaga MK, Hagen TM, Ames BN. Oxidative
damage and mitochondrial decay in aging. Proc Natl Acad Sci 1994;
91 (23): 10771-10778.
5. Janetzky B, et al. Unaltered aconitase activity,
but decreased complex I activity in substantia nigra pars compacta of
patients with Parkinson’s disease. Neurosci Lett 1994; 169 (1-2)
126-128.
6. Parker WD Jr, Parks JK, Filey CM. Cytochrome
oxidase deficiency in Alzheimer’s disease. Neurol 1990; 40: 1302-1303.
7. Rosen, DR. Mutations in Cu/Zn superoxide dismutase
gene are associated with familial amyotrophic lateral sclerosis. Nature
1993; 362: 59-62.
8. Mecocci P, et al. Oxidative damage to
mitochondrial DNA shows marked age-dependent increases in human brain.
Ann Neurol 1993; 34(4): 609-616.
9. Wallace DC, et al. Sequence analysis of cDNA’s for
the human and bovine ATP synthase beta unit: mitochondrial DNA genes
sustain seventeen times more mutations. Curr Genet 1987;12 (2):
81-90.
10. Nicholls D, Atwell D. The release and uptake of
excitatory amino acids. Trends Pharmacol Sci 1990: 11: 462-468.
11. Brown RH Jr. Superoxide dismutase and familial
amyotrophic lateral sclerosis: new insights into mechanisms and
treatments. Ann Neurol 1996; 39: 145-146.
12. Choi DW, Calcium: Still center-stage in
hypoxic-ischemic neuronal death. Trends Neurosci. 1995; 18: 58-60.
13. Smart TG. Regulation of excitatory and inhibitory
neurotransmitter-gated ion channels by protein phosphorylation.
Curr. Opin. Neurobiol. 1997; 7: 358-367.
14. Beckman JS. The double-edged role of nitric oxide
in brain function and superoxide-mediated injury. J Dev Physiol
1991; 15(1): 53-59.
15. Cross AH, et al. Aminoguanidine, an inhibitor of
inducible nitric oxide synthase, ameliorates experimental autoimmune
encephalomyelitis in SJL mice. J Clin Invest 1994; 93: 2684-2690.
16. Hantraye P, et al. Inhibition of neuronal
nitric oxide synthase prevents MPTP-induced parkinsonism in
baboons. Nat Med 1996; 2(9): 1017-1021.
17. Resink AM, Brahmbhatt HP, Cordell B, Dawson VL,
Dawson DM. Nitric oxide mediates a component of B-amyloid neurotoxicity
in cortical neuronal cell cultures. Soc Neurosci Abstr 1995; 21:
1010.
18. Goodwin JL, Uemura E, Cunnick JE.
Microglial release of nitric oxide by the synergistic action of
beta-amyloid and IFN-gamma. Bran Res 1995; 692: 207-214.