In earlier
posts we learned about two kinds of stress:-
Oxidative stress is a biological stress that is measurable (GSH redox) and has been shown to be present in most autistic people.
Psychological stress is a feeling we experience in
difficult situations and is measurable by sampling the level of the hormone cortisol
in saliva.
It would
appear that both types of stress are interrelated.
We have
already established that oxidative stress in autism can be successfully be treated
with NAC. NAC acts both as an
anti-oxidant in its own right and as a precursor chemical to form GSH, the
body’s own antioxidant. NAC is cheap and
widely available.
The
scientific literature regarding autism includes many references to inflammation
of the brain, or neuroinflammation. It turns out that this inflammation is
also measurable. When samples of
cerebrospinal fluid (CSF) are taken, elevated levels of chemicals called
cytokines are found. Certain cytokines
are markers for neuroinflammation, such as TGF-ß1 and MCP-1.
In studies at Johns Hopkins, a leading teaching hospital in the US, they have tested all
their autistic research subjects for neuroinflammation and they all tested
positive. It also appears that this is
the result of on-going damage to the brain, not residual damage from the
pre-natal or early post natal period.
Such damage was exhibited in autistic subjects of all ages. These researchers were also able to locate
the part of the brain most affected by neuroinflammation.
“Our
study showed the cerebellum exhibited the most prominent neuroglial responses.
The marked neuroglial activity in the cerebellum is consistent with previous
observations that the cerebellum is a major focus of pathological abnormalities
in microscopic and neuroimaging studies of patients with autism. Based on our
observations, selective processes of neuronal degeneration and neuroglial
activation appear to occur predominantly in the Purkinje cell layer (PCL) and
granular cell layer (GCL) areas of the cerebellum in autistic subjects. These
findings are consistent with an active and on-going postnatal process of
neurodegeneration and neuroinflammation.”
There are
numerous other researchers who concur with these findings; the problem is that
they do not take the logical next step of finding how to reduce this
inflammation. Indeed John’s Hopkins go
as far as to tell us
“At
present, THERE IS NO indication for using anti-inflammatory medications in
patients with autism. Immunomodulatory or anti-inflammatory medications such as
steroids (e.g. prednisone or methylprednisolone), immunosupressants (e.g.
Azathioprine, methotrexate, cyclophosphamide) or modulators of immune reactions
(e.g. intravenous immunoglobulins, IVIG) WOULD NOT HAVE a significant effect on
neuroglial activation because these drugs work mostly on adaptive immunity by
reducing the production of immunoglobulins, decreasing the production of T
cells and limiting the infiltration of inflammatory cells into areas of tissue
injury. Our study demonstrated NO EVIDENCE at all for these types of immune
reactions. There are on-going experimental studies to examine the effect of
drugs that limit the activation of microglia and astrocytes, but their use in
humans must await further evidence of their efficacy and safety”
Here the researchers were experimenting with various
chemical including NAC as an antioxidant.
“Activation of microglia has been
implicated in the pathogenesis of a variety of neurodegenerative diseases,
including Alzheimer's disease (AD), Parkinson's disease (PD), Creutzfeld-Jacob
disease, HIV-associated dementia (HAD), stroke, and multiple sclerosis (MS) .
It has been found that activated microglia accumulate at sites of injury or plaques
in neurodegenerative CNS. Although activated microglia scavenge dead cells from
the CNS and secrete different neurotropic factors for neuronal survival, it is
believed that severe activation causes inflammatory responses leading to neuronal
death and brain injury. During activation, microglia secretes various
neurotoxic molecules and express different proteins and surface markers.
Although microglia populate only 2
to 3% of total brain cells in a healthy human being, the number increases up to
12 to 15% during different neurodegenerative diseases. Microglial activation is
always associated with neuronal inflammation and ultimately neuronal apoptosis.
Although microglial activation may not be always bad as it has an important
repairing function as well, once microglia become activated in
neurodegenerating microenvironment, it always goes beyond control and
eventually detrimental effects override beneficial effects. Therefore, microglial
activation is a hallmark of different neurodegenerative diseases and
understanding underlying mechanisms for microglial activation is an important
area of study. “
Another piece of research that looked at activated
microglia in a neurological condition (this time Alzheimer’s disease) also used NAC as an antioxidant and
anti-inflammatory agent.
Now,
to better understand the terminology and the science, a little bit of biology
would be useful. If you wish to skip
this part, you can go forward a few pages to the part where I look at practical
steps that seem likely to reduce neuroinflammation.
Here
are the key words we need to understand:-
- Neurons
- Neurotransmitters
- Glial cells
- Microglia
- Astrocytes or astroglia
- Cytokenes
Thanks to Wikipedia I have
presented a summary.
A neuron
is a cell that processes and transmits information through electrical and
chemical signals. A chemical signal occurs via a synapse a specialized
connection with other cells. Neurons connect to each other to form neural
networks. Neurons are the core components of the CNS (Central Nervous System),
which includes the brain and spinal cord. A number of specialized types of
neurons exist: sensory neurons respond to touch, sound, light and numerous
other stimuli affecting cells of the sensory organs that then send signals to
the spinal cord and brain. Motor neurons receive signals from the brain and
spinal cord, cause muscle contractions, and affect glansa. Interneurons connect
neurons to other neurons within the same region of the brain or spinal cord.
A neuron affects other neurons by releasing a
neurotransmitter that binds to chemical receptors. The effect upon the
postsynaptic neuron is determined not by the presynaptic neuron or by the
neurotransmitter, but by the type of receptor that is activated. A
neurotransmitter can be thought of as a key, and a receptor as a lock: the same
type of key can here be used to open many different types of locks. Receptors
can be classified broadly as excitatory (causing an increase in firing
rate), inhibitory (causing a decrease in firing rate), or modulatory
(causing long-lasting effects not directly related to firing rate).
The two most common neurotransmitters in the brain, and
GABA, have actions that are largely consistent. Glutamate acts on several
different types of receptors, and have effects that are excitatory at
ionotropic receptors and a modulatory effect at metabotropic receptors.
Similarly GABA acts on several different types of receptors, but all of them
have effects (in adult animals, at least) that are inhibitory. Because of this
consistency, it is common for neuroscientists to simplify the terminology by
referring to cells that release glutamate as "excitatory neurons,"
and cells that release GABA as "inhibitory neurons." Since over 90%
of the neurons in the brain release either glutamate or GABA, these labels
encompass the great majority of neurons.
GABA is very important
in autism and we will return to it in greater depth when we will look at the
three types of GABA receptors.
3. Glial cells
Glial cells are non-neuronal cells that maintain homeostasis
and provide support and protection for neurons in the brain, and for neurons in
other parts of the nervous system such as in the autonomic nervous system.
Four main functions of glial cells have been identified:
- To
surround neurons and hold them in place,
- To supply
nutrients and oxygen to neurons,
- To
insulate one neuron from another,
- To
destroy pathogens and remove dead neurons.
Glial cells do modulate neurotransmission, although the
mechanisms are not yet well understood.
Functions
Some glial cells function primarily as the physical
support for neurons. Others regulate the internal environment of the brain,
especially the fluid surrounding neurons and their synapses, and nutrify
neurons. During early embryogenesis glial cells direct the migration of neurons
and produce molecules that modify the growth of axons and dendrites. Recent research
indicates that glial cells of the hippocampus and cerebellum participate in
synaptic transmission, regulate the clearance of neurotransmitters from the
synaptic cleft, and release gliotransmitters such as ATP, which modulate
synaptic function.
Glial cells were not believed to have chemical synapses
or to release transmitters. They were considered to be the passive bystanders
of neural transmission. However, recent studies have shown this to be untrue. For example, astrocytes are crucial in clearance of
neurotransmitters from within the synaptic cleft, which provides distinction
between arrivals of action potentials and prevents toxic build-up of certain
neurotransmitters such as glutamate (excitotoxicity). It is also thought that
glia play a role in many neurological diseases, including Alzheimer’s disease.
Furthermore, at least in vitro, astrocytes can release gliotransmitter
glutamate in response to certain stimulation.
Glia have a role in the regulation of repair of neurons
after injury. In the CNA (Central Nervous System), glia suppress repair. Glial
cells known as astrocytes enlarge and proliferate to form a scar and produce
inhibitory molecules that inhibit regrowth of a damaged or severed axon. In the
PNS (Peripheral Nervous System), glial cells known as Schwann cells promote
repair. After axonal injury, Schwann cells regress to an earlier developmental
state to encourage regrowth of the axon. This difference between PNS and PNS
raises hopes for the regeneration of nervous tissue in the CNS. For example a
spinal cord may be able to be repaired following injury or severance.
Microglia are a type of glial cell that are the resident
macrophages of the brain and spinal cord, and thus act as the first and main
form of active immune defense in the CNS. Macrophages are highly specialized in
removal of dying or dead cells and cellular debris. This role is important in chronic inflammation, as the
early stages of inflammation are dominated by neutrophil granulocytes, which
are ingested by macrophages if they come of age.
Microglia constitute 20% of the total glial cell
population within the brain.]
Microglia (and astrocytes) are distributed in large non-overlapping regions
throughout the brain and spinal cord. Microglia are constantly scavenging the CNS
for plaques, damaged neurons and infectious agents. The brain and spinal cord
are considered "immune privileged" organs in that they are separated
from the rest of the body by a series of endothelial cells known as the blood
brain barrier (BBB), which prevents most infections from reaching the
vulnerable nervous tissue. In the case where infectious agents are directly
introduced to the brain or cross the blood–brain barrier, microglial cells must
react quickly to decrease inflammation and destroy the infectious agents before
they damage the sensitive neural tissue. Due to the unavailability of
antibodies from the rest of the body (few antibodies are small enough to cross
the blood brain barrier), microglia must be able to recognize foreign bodies,
swallow them, and act as antigen presenting cells activating T-cells. Since
this process must be done quickly to prevent potentially fatal damage,
microglia are extremely sensitive to even small pathological changes in the
CNS. They achieve this sensitivity in part by having unique
potassium channels that respond to even small changes in extracellular
potassium.
Astrocytes or astroglia are characteristic star-shaped
glial cells in the brain and spinal cord. They are the most abundant cell of
the human brain. They perform many functions, including biochemical support of
endothelial cells that form the blood-brain barrier, provision of nutrients to
the nervous tissue, maintenance of extracellular ion balance, and a role in the
repair and scarring process of the brain and spinal cord following traumatic
injuries.
Research since the mid-1990s has shown that astrocytes
propagate intercellular Ca2+- waves over long distances in response
to stimulation, and, similar to neurons, release transmitters (called
gliotransmitters) in a Ca2+-dependent manner. Data suggest that
astrocytes also signal to neurons through Ca2+-dependent release of
glutamate. Such discoveries have made astrocytes an important area of research
within the field of neuroscience..
Previously in medical science, the neuronal network was
considered the only important one, and astrocytes were looked upon as gap
fillers. More recently, the function of astrocytes has been reconsidered,
and are now thought to play a number of active roles in the brain, including
the secretion or absorption of neural transmitters and maintenance of the blood–brain
barrier. Following on this idea the
concept of a "tripartite synapse" has been proposed, referring to the
tight relationship occurring at synapses among a presynaptic element, a
postsynaptic element and a glial element.
- Structural:
They are involved in the physical structuring of the brain. Astrocytes get
their name because they are "star-shaped". They are the most
abundant glial cells in the brain that are closely associated with
neuronal synapses. They regulate the transmission of electrical impulses
within the brain.
- Glycogen
fuel reserve buffer: Astrocytes contain glycogen and are capable of
glycogenesis. The astrocytes next to neurons in the frontal cortex and
hippocampus store and release glycogen. Thus, Astrocytes can fuel neurons
with glucose during periods of high rate of glucose consumption and
glucose shortage. Recent research suggests there may be a connection
between this activity and exercise.
- Metabolic
support: They provide neurons with nutrients such as
lactate.
- Blood-brain barrier:
The astrocyte end-feet encircling endothelial cells were thought to aid in
the maintenance of the blood–brain barrier, but recent research indicates
that they do not play a substantial role; instead, it is the tight
junctions and basal lamina of the cerebral endothelial cells that play the
most substantial role in maintaining the barrier. However, it has recently
been shown that astrocyte activity is linked to blood flow in the brain,
and that this is what is actually being measured in fMRI.
- Transmitter
uptake and release: Astrocytes express plasma membrane transporters
such as glutamate transporters for several neurotransmitters, including
glutamate, ATP, and GABA. More recently, astrocytes were shown to release
glutamate or ATP in a vesicular, Ca2+-dependent manner.
- Regulation of ion
concentration in the extracellular space Astrocytes express potassium channels at a
high density. When neurons are active, they release potassium, increasing
the local extracellular concentration. Because astrocytes are highly
permeable to potassium, they rapidly clear the excess accumulation in the
extracellular space. If this function is interfered with, the
extracellular concentration of potassium will rise, leading to neuronal
depolarization by the Goldman equation. Abnormal accumulation of
extracellular potassium is well known to result in epileptic neuronal
activity.
- Vasomodulation:
Astrocytes may serve as intermediaries in neuronal regulation of blood
flow.
- Nervous
system repair: Upon injury to nerve cells within the central
nervous system, astrocytes fill up the space to form a glial scar,
repairing the area and replacing the CNS cells that cannot regenerate.
- Long-term
potentiation: Scientists continue to argue back and forth as to
whether or not astrocytes integrate learning and memory in the
hippocampus. It is known that glial cells are included in neuronal
synapses, but many of the LTP studies are performed on slices, so
scientists disagree on whether or not astrocytes have a direct role of
modulating synaptic plasticity.
Cytokines are small signaling molecules used for cell
signaling. The term cytokine encompasses
a large and diverse family of regulators produced throughout the body by cells
of diverse embryological origin.
The term cytokine has been used to refer to the
immunomodulating agents, such as interleukins and interferons. Biochemists
disagree as to which molecules should be termed cytokines and which hormones.
As we learn more about each, anatomic and structural distinctions between the
two are fading. Classic protein hormones circulate in nanomolar (10-9M)
concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines
(such as IL-6) circulate in picomolar (10-12M) concentrations that
can increase up to 1,000-fold during trauma or infection. The widespread
distribution of cellular sources for cytokines may be a feature that
differentiates them from hormones. Virtually all nucleated cells, but
especially endo/epithelial cells and resident macrophages (many near the
interface with the external environment) are potent producers of IL-1, IL-6,
and TNF-a. In contrast, classic hormones, such as insulin, are secreted from
discrete glands (e.g., the pancreas). As
of 2008, the current terminology refers to cytokines as immunomodulating
agents. However, more research is needed in this area of defining cytokines and
hormones.
Part of the difficulty with distinguishing cytokines from
hormones is that some of the immunomodulating effects of cytokines are systemic
rather than local. Further, as molecules, cytokines are not limited to their
immunomodulatory role. For instance, cytokines are also involved in several
developmental processes during embyrogenesis.
Several inflammatory cytokines are induced by oxidant
stress. The fact that cytokines themselves trigger the release of other
cytokines and also lead to increased oxidant stress makes them important in
chronic inflammation, as well as other immunoresponses, such as fever and acute
phase proteins of the liver (IL-1,6,12, INF-a).
Practical Steps to reduce
neuroinflammation
Neuroscience
is both complex and an evolving science; much remains unknown and so often there
cannot be definite answers; rather judgements based on the balance of
probabilities.
What is clear
is that in autism we have oxidative stress and inflammation. There also appears to be a vicious circle
where the inflammation messenger itself makes that inflammation worse. In some cases, it is the oxidative stress
that triggers the inflammation; in other cases the inflammation may have other causes.
A more complex explanation relates to where
the signal to the microglia came from in the first place. Mast cells from the immune system are
proposed to be the source of this signal.
For the time
being let us focus on the simpler solution; that the anti-oxidant should also be
the anti-inflammatory agent. Surprise,
surprise, our friend NAC is being used in numerous studies as the anti-inflammatory
agent.
This is good
news for Monty; it may be that NAC is not just reducing his state of oxidative stress,
but gradually his neuroinflammation as well.
It certainly does seem to be doing him good. As indicated in the research, the effect of NAC seems to be highly dose dependent.
But not to
have all our eggs in one basket, it would be nice to have another
anti-neuroinflammatory agent. It seems
there is one at hand, but we have to look to the East to find it.
Obovatol
The bark of
the magnolia tree has been used in Korean, Chinese and Japanese medicine for more
than a thousand years. It seems that one
compound in particular within magnolia, obovatol, has powerful properties to
reduce neuroinflammation.
In another
paper
and another
This is all
experimental but it is clear that in theory at least, obovatol looks very
interesting.
The proposed benefits are in the treatment of:-
cancer
neuronal disease
inflammatory disease
cardiovascular disease
The four active compounds are:
magnolol
honokiol
4-O-methylhonokiol
obovatol
Also, anxiolytic-like effects of obovatol
appeared to be mediated by the GABA benzodiazepine receptor Cl− channel opening
and obovatol potentiated pentobarbital-induced sleeping time through GABA receptors/Cl−
channel activation.
This data suggest
that components of Magnolia could be used for treating anxiety, and its effect
may be linked to GABA receptor/Cl− channel activation.
Anti-inflammatory mechanisms of Magnolia have
been reported to be associated with the suppression of NO production, the
expression of iNOS, IL-1β, TNF-α and COX, the generation of prostaglandins, thromboxanes
and leukotrienes, and the activation of MAPKs, AP-1 and NF-κB.
Magnolia Bark Extract
Magnolia bark
extract is extensively produced in China and sold inexpensively by the
supplement industry. The individual
compounds could be separated, as in the Korean research, but the extract that is sold is
just a mixture of what happened to be in that batch of bark. If you read the reviews, it seems that many
people experience a reduction in cortisol allowing them to sleep better;
reduced anxiety is widely reported. It even seems to stop some people snoring, which I am certainly all in favour of.
So while it
is far from the scientific basis on which you could use NAC, it would seem that
Magnolia bark extract will unlikely do harm and just might do some good as an
anti-neuroinflammatory agent. In about
20 years, the research will show whether you were wasting your money, or whether
you were a pioneering early-adopter.
I think I
will do some primary research on this one and be a pioneer.
