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Sunday, 5 May 2013

Stress, Neuroinflammation and Magnolia before bed

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.
 1.  Neurons
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.

 

2.  Neurotransmitters - interaction between neurons
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:
  1. To surround neurons and hold them in place,
  2. To supply nutrients and oxygen to neurons,
  3. To insulate one neuron from another,
  4. 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.

4.  Microglia
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.
5.  Astrocytes or astroglia,
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.
 
6.  Cytokines
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.
For a wider view of the medical properties of the magnolia family, there is an excellent paper from Korea that reviews the possible mechanisms. Therapeutic applications of compounds in the Magnolia family
 The proposed benefits are in the treatment of:- 
  • cancer
  • neuronal disease
  • inflammatory disease
  • cardiovascular disease 
The four active compounds are: 
  1. magnolol
  2. honokiol
  3. 4-O-methylhonokiol
  4. 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.

 

8 comments:

  1. Hi Peter, thanks for another very interesting piece. There certainly is a stack of exciting research out there regarding magnolia extracts and their effects on the human body, most especially including brain function. I thought I’d presume to alert your readers to two other relatively recent papers. These suggest that it’s not only obovatol that may exhibit neural anti-inflammatory or protective properties, but also honokiol and magnolol. I guess the next question is whether these compounds taken together will enhance or obstruct each other’s efficacy! Anyway, the papers are:

    “Therapeutic targeting of Krüppel-like factor 4 abrogates microglial activation” by Kaushik D et al in Journal of Neuroinflammation 2012, 9:57 (full text available online at: http://www.jneuroinflammation.com/content/9/1/57).

    “Neuroprotective effect of honokiol and magnolol, compounds from Magnolia officinalis, on beta-amyloid-induced toxicity in PC12 cells” by Hoi CP et al in Phytotherapy Research 2010 Oct; 24(10):1538-42.

    Ciao for now, Alexandria

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    1. Hi Alexandria, thank you very much for your comments and the link. I suppose when they started using Magnolia many hundreds of years ago they would not have been able to separate out obovatol, honokiol and magnolol and it seemed to work then, and so it should do now. Of course it would be best to separate them, but for now we do not have that option. The question remains how much you would need to have much effect. I have found with NAC that the dosage in supplements is far lower than you need to see the potential positive impact. In the recent Stanford trial the dose went up to 2.7 grams. The typical OTC NAC capsule has 0.6g ram and if you give that you will see no impact.

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  2. Hi Peter, Thank you for the very interesting article. I am a parent of 3 boys, all on the autism spectrum. I am considering the Magnolia extract and trying it on my younger son, but I'm curious to know if anyone else has and what their experience has been. Any feedback is welcomed. Thanks again.

    Sylvia

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    1. In the country I live nobody sells Magnolia extract and so I have not yet tried it. I certainly intend to, since it seems to be safe. The only problem is that you cannot be sure 100% what is in it and whether each pack will have the same proportion of magnolol, honokiol, methylhonokiol, obovatol.

      If you have a preference for "natural" therapies that have a scientific basis, another one that looks interesting is the mixture of natural flavenoids proposed by Dr Theoharides called NeuroProtek. It is available in the US, but they will not ship it to most other countries. It is not cheap, but at least each pill has the same contents.

      So far I have found that only synthetic drugs to be effective. I have friend with a very young son (under 3 years old) who is himself a doctor and gave his son NAC with great results. It seems to work well with all types of ASD and is cheap.

      Let me know you results with Magnolia Extract.

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    2. Thank you Peter. Great information! I am currently giving my younger sons "PharmaNac 900mg" which is an effervescent Tablet and the kids love it. I can't say I've seen improvements and unfortunately I've seen regressions in my youngest, thus my continued search to help him.

      The Magnolia extract I was considering are between these brands: “HonoPure” by Econugenics, “Magnolia Extract” by either Nutricology or Allergy Research Group. Only because these were recommended by Suzy Cohen (http://www.dearpharmacist.com/2012/09/04/magnolia-bark-is-a-natural-tranquilizer/) But looking closer at the ingredients not all four ingredients are included as you mentioned (magnolol, honokiol, methylhonokiol, obovatol). Would you consider any of these?

      Thank you so much for the additional information on Dr. Theoharides and since I live in the US I will be ordering NeuroProtek.

      Thanks again!

      - Sylvia

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    3. It looks like obovatol is the ingredient to look for, going by the Korean research.
      Since you are using NAC, did you see the research done on NAC in Stanford? They used a dosage rising to 3 x 900mg a day. If you read about NAC, it seems to take a certain amount before any effect is measurable. My son takes 2x600 mg NAC twice a day, so 2,400mg in total. Since your kids love the NAC, why not try a few days at the higher dosage and see if you notice a change. It should give a better mood, less obsessions and for us, much more spontaneous speech, everyone noticed it. The less expensive NAC works just as well, and you will need a lot of it, if you raise the dose.

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  3. Peter- I found this NACA compound- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387542/

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    1. N-acetylcysteine amide may indeed be better than NAC, because it better crosses the blood brain barrier. But you cannot but it, maybe one day that will change.

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