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BLOOD-BRAIN-BARRIER
In
its neuroprotective role, the blood-brain-barrier (BBB) blocks agents
from entering the brain. This protective mechanism has been in place
since man first walked the earth. If this mechanism was not in place,
the brain would self-destruct within a few weeks, as invaders, including
natural sugars, foods, and amino acids, would cause a biochemical
implosion capable of killing the host (the human body).
Getting
helpful and therapeutic agents to cross the BBB without allowing
dangerous agents access to the delicate brain-balance is a very
intricate process involving many years of specialized research.
The
blood-brain-barrier (BBB) participates in the active regulation
of the amino acid content of the brain (2006 American Society
for Nutrition: J. Nutr. 136:218S-226S). As such, amino acid
formulas must be engineered to allow for safe transport across the
BBB.
Since the brain is the only organ for which amino-acid transport
is limited (a), blind amino acids, such as L-arginine, are blocked
from making successful transport over the BBB.
Amino acids, in their natural state, such as those found in all
forms of protein, occur with their brother and sister amino acids,
L-carnitine, L-phenylalanine, etc. But when the amino acids are
separated from each other, as in the case of free-form L-arginine,
they become “blind” and have no biochemical identity.
When this occurs, toxic NO by-products can be generated, and BBB
access is blunted.
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Competition
for transport over the blood-brain barrier (BBB) occurs
at physiological plasma concentrations (a) effectively
negating the complete transfer of free-form amino acids
(Blind Amino Acids) across the blood-brain-barrier.
A prime example is L-lysine. If free-form L-lysine and
L-arginine are combined in the same formula, or in the
gut at the same time, they negate each other, as they
compete for BBB transport.
The blood-brain barrier (BBB) is an effective way to
protect the brain from common infections and invaders
that cause brain-imbalances (a)(b)(c)(d). If the wrong
agents are allowed to cross the BBB, or to piggy-back
on agents that cross the BBB, serious brain infections
can occur, which are very difficult to treat or cure.
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As
such, it is imperative that therapeutic agents, whether amino acids
or drugs, are properly engineered to cross the blood-brain-barrier
unobstructed, and without carrying dangerous agents into the brain
(b)(d).
The
most promising new research in this field is the development of
nanomolecules. Nanotechnology is now the fastest growing science
globally, and has lead to the design of specific minuscule particles,
known as nanomolecules, which allow blind amino acids, such as L-arginine,
free access to blood-brain-barrier transport.
Nano-driven
blood-brain-barrier transport molecules (nanomolecules) are meticulously
designed to “cross” the BBB without inducing brain infections
or other side effects related to invasion of the blood-brain-barrier
(a)(b)(c)(d).
Nanomolecules
are at the forefront of medical research (www.EdibleComputerChips.com),
as they are small enough to cross the blood-brain-barrier to deliver
cancer-drugs, chemo-therapy, and other therapeutic agents.
Properly
designed Nanomolecules involve the biochemical attachment of a therapeutic
agent, such as a cancer-drug, with a brain-friendly nanoparticle
in order to access one of the four pathways specific to BBB cross-over.
Plant
glycosides can be engineered to cross the blood-brain-barrier attached
to a therapeutic agent, such as those designed to transport the
amino acid L-arginine. Since a nanoparticle is incredibly small,
a delicate extraction process is required to produce glycosides
that can attach to an amino acid molecule, and transport it safely
over the blood-brain-barrier.
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Only
a specific transport system (STS) will allow the amino
acid L-arginine to cross the blood-brain-barrier (a).
BBB amino acid transport systems are referred to as
“Blind Amino Acid™ Riders” as they
allow an amino acid to ride across the blood-brain-barrier
by piggybacking on a glycoside nanomolecule. Nanoparticles
derived from natural plant glycosides are the only Blind
Amino Acids Riders proven safe for human consumption.
Arginine researchers have been diligently searching
for ideal Blind Amino Acid™ Riders BAAR) since
1983, one year after the first free-form of L-arginine
was identified, produced, and patented by Japanese scientists
(Momose et al.1982). The race to find an appropriate
Blind Amino Acid™ Rider was similar to the race
for the Double Helix.
American
arginine scientists won the race in 1997, when they
perfected the extraction process for plant glycosides
that became the first working version of a Blind Amino
Acid Rider. The arginine scientists received a full
patent and filed three additional patents *, naming
their Blind Amino Acid™ Rider “Trutina Dulcem
®.”
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Cleverly,
the scientists did not reveal the 32-step extraction process for
producing Trutina Dulcem® in their patents, and that trade secret
is still proprietary.
Manufacturing
at the nanoscale involves the industrial application of nanotechnologies
in manufacturing Nanosize particles. Nanoparticles have been prohibitively
expensive to produce until recently, due to advances in the science
of nanotechnology. Trutina Dulcem® is manufactured at the nanoscale
under a process that defies reverse-engineering. It is currently
impossible to “copy” or duplicate a product based on
Nanotechnology due to the minuscule size of the components used
in the manufacturing process.
Blind
Amino Acid™ Riders perform biochemically like carrier-mediated
transporters, utilizing Nanoparticle biostrategy to allow transport
across the blood-brain-barrier (BBB). Other methodologies for BBB
transport include receptor-mediated transcytosis for insulin or
transferrin; and blocking of active efflux transporters such as
p-glycoprotein.
Nanoparticles possess a diameter small enough to penetrate through
diminutive capillaries into the cell's internal machinery (3) and
create a pre-programmed response. This technology was compared by
scientists to computer chips in electronics, which then coined the
term Edible Computer Chip (www.EdibleComputerChips.com).
BBB PATHS OF ENTRY
There
are only four distinct paths of entry that allow Nanoparticles to
enter the human body. The four entry routes for nanoparticles into
the body are:
1)
Inhaled
2) Swallowed (oral entry)
3) Absorbed through skin
4) Deliberately injected during medical procedures (or released
from implants)
Once within the body, nanoparticles are highly mobile, which allows
scientists to bioengineer agents that can cross the blood-brain
barrier (BBB) without negative incidence.
The
blood-brain barrier (BBB), also known as the blood-cerebrospinal
fluid barrier, is a membrane that controls the passage of substances
from the blood into the central nervous system. The BBB is a physical
barrier between the local blood vessels and most parts of the central
nervous system itself, and stops many substances from traveling
across it (2).
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Throughout
the body, the walls of the capillaries (the smallest
of the blood vessels) are made up of endothelial cells
separated by small gaps. These gaps allow soluble chemicals
within tissues to pass into the blood stream, where
they can be carried throughout the body, and subsequently
pass out of the blood into different tissues. In the
brain, these endothelial cells are packed more tightly
together, due to the existence of zonulae occludentes
(tight junctions) between them, blocking the passage
of most molecules (2).
The
blood-brain barrier blocks all molecules except those
that cross cell membranes by means of lipid solubility
(such as oxygen, carbon dioxide, ethanol, and steroid
hormones) and those that are allowed in by specific
transport systems (such as some amino acids).
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With
new methodologies heretofore unavailable to scientists, nanoparticles
will now take their respective place in the medical and science
fields, particularly in the field of chemotherapy drug delivery.
In the field of nutrition and Nutraceuticals, nanoparticles are
capable of improving utilization of a nutrient, vitamin, or mineral
by 30-40 %. This makes a significant contribution in micro-nutrient
delivery, such as chromium.
PHARMACEUTICAL
NANO DRUGS
Strategies
for BBB drug delivery include intracerebral implantation and convection-enhanced
distribution. Substances with a molecular weight higher than 500
daltons (AMUs) generally cannot cross the blood-brain barrier, while
smaller molecules often can, thus elucidating the complexity of
creating a nanoparticle that can cross the BBB.
Many
drugs are unable to pass the barrier, since 98 percent of them are
heavier than 500 daltons. In addition, the endothelial cells metabolize
certain molecules to prevent their entry into the central nervous
system; the most-studied example of this is L-DOPA (2).
The
blood-brain barrier protects the brain from the many chemicals flowing
around the body. Many bodily functions are controlled by hormones,
which are detected by receptors on the plasma membranes of targeted
cells throughout the body.
The
secretion of many hormones are controlled by the brain, but these
hormones generally do not penetrate the brain from the blood, so
in order to control the rate of hormone secretion effectively, there
are specialized sites where neurons can "sample" the composition
of the circulating blood. At these sites, the blood-brain barrier
is 'leaky'; these sites include three important 'circumventricular
organs', the subfornical organ, the area postrema and the organum
vasculosum of the lamina terminalis (OVLT) (2).
As
a neuro-watchdog, the blood-brain barrier functions to hinder the
delivery of many potentially important diagnostic and therapeutic
agents to the brain (a)(b)(c)(d). Therapeutic molecules and genes
that might otherwise be effective in diagnosis and therapy do not
cross the BBB in adequate amounts.
Mechanisms
for drug targeting in the brain involve going either "through"
or "behind" the BBB. Modalities for drug delivery through
the BBB entail disruption of the BBB by osmotic means, biochemically
by the use of vasoactive substances such as bradykinin, or even
by localized exposure to ultrasound. The potential for using BBB
opening to target specific agents to brain tumors has just begun
to be explored (2).
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