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Showing posts with label Purkinje cells. Show all posts
Showing posts with label Purkinje cells. Show all posts

Thursday 6 June 2013

The Singing Statin, the BCL-2 Gene and Epigenetics

This post has something for both the casual reader and the scientists among you.  Today I will start with the science.

Epigenetics

Epigenetics are chemical markers that can appear on your DNA as the result of some environmental exposure, like diet or stress.  Methylation is a type of epigenetic change in which methyl groups are added to DNA and switch on or off the underlying gene.  This can have severe consequences depending on which gene is affected.

Identical Twins

It seems that if one identical twin has autism, there is a 70% chance that the other twin will be autistic.  In 30% of the cases the twin is neurotypical.  Researchers have very cleverly started to analyse pairs of twins from this 30% group and look for epigenetic marks.  This would highlight genetic causes of autism.

Apoptosis

Apoptosis is a tricky word to spell, for somebody like me, but is actually something quite simple; it is programmed cell death.  Apoptosis happens in all of us, all day long.  If it gets out of control, it becomes bad and something called atrophy will occur.  Too little apoptosis can result in irregular cell growth and cancer.

 
Candidate Genes

Using the epigenetics approach, in 2010 a study was published that identified two “candidate” genes linked to autism.  They were BCL-2 and RORA.

According to that study, BCL-2 is an anti-apoptotic protein located in the outer mitochondrial membrane that is important for cell survival under a variety of stressful conditions.  In other words BCL-2 inhibits cell death.

According to another source, BCL-2 is “one of the foremost anti-apoptotic molecules”.

A very recent study has identified more such genes, using the same approach.
 
If you are really interested in the genetics of autism, there is actually a database of all the indicated genes, maintained by the Simons Foundation.

  
BCL-2 and autism

Going back to 2001, researchers had already noted that the autistic brain was deficient in BCL-2 and they suggested that:-

“These results indicate for the first time that autistic cerebellum may be vulnerable to pro-apoptotic stimuli and to neuronal atrophy as a consequence of decreased BCL-2 levels.”


As we have already learned, in the autistic brain the important Purkinje Cells are reduced in number by half due to atrophy.  If BCL-2 can indeed reduce this excessive apoptosis, it should be a friend indeed.

 
Stimulating production of Bcl-2

Fortunately the clever people working with Professor Wood, at the University of Minnesota, have been studying cholesterol regulation in the brain for some time.  Here is what they have been up to:-

“The lab has recently made the novel discovery that statins both in vivo and in vitro stimulate gene expression and protein levels of one of the foremost anti-apoptotic molecules, Bcl-2. Currently, studies are focused on mechanisms of statin-induction of Bcl-2”

Or in plainer English, statin drugs increase your level of BCL-2 and so reduce cell death.
 

 
The Singing Statin

Now we have finished with the pure science and we move back to the practical world of applied science.

Monty, aged 9, has been taking atorvastatin for a few weeks.  After day one, he developed the urge to play the piano outside of lesson time.  Every day since, he has played more and more.  Now his piano teacher says she thinks he has absolute pitch.  It turns out that this is far more common in the autistic population and there is a great deal of research that has been done on this and music/autism in general.  Here is a short article on the subject.

Now in an earlier post we established the importance of the stress hormone cortisol and also the interesting finding that you can reduce it by singing.  Then I got people asking about, “what about just listening to music” or “what about playing an instrument”.  I did not do the research, but I think nothing works like a good sing.

So yesterday I was delighted to hear that Monty has started to sing spontaneously in his room.  He put on his Mozart CD and started to sing, with his own lyrics and not just in English, but also in his second language.

I have to thank Mr Pfizer and in fact Mr Bruce Roth for bringing us Atorvastatin (called Lipitor or Sortis, depending on where you live).  Mr Roth invented it in 1985.

Perhaps BCL-2 could be better named the Singing Gene?
 
 
 

Sunday 12 May 2013

Statins for Neuroprotection in Autism - Part 2

I suggest you start by reading Part 1.  Click here for Part 1



Choice of Statin
 
Some statins are soluble in fats/lipids (lipophilic) and some are more soluble in water.  In order to cross the blood brain barrier (BBB) to reach the cerebellum and the Purkinje Cell Layer (PCL) a lipophilic statin will be required.  There is a choice of three: - atorvastatin, lovastatin, and simvastatin.  These are also among the most commonly prescribed for cholesterol reduction and so are widely available and inexpensive.

I chose atorvastatin.  Some statins are derived from fungi, but atorvastatin is synthetic.  Lovastatin and simvastatin are pro-drugs, whereas atorvastatin is already in an active form straight out of the box. Absorption of atorvastatin decreases when taken with food.  Due to its long half-life, atorvastatin can be administered at any time of day.

Atorvastatin is approved for use in children as young as 10 and in the US is prescribed to children as young as 5.

Atorvastatin, originally made by Pfizer under name Lipitor, is the best-selling drug in the history of the pharmaceutical industry.  It came off patent recently and so the price has collapsed to a very reasonable level.

In some countries the low dose forms are available over the counter, without a prescription.

 

More Related Research

The research effort into degenerative conditions like Alzheimer’s disease (AD) is far more prolific than into autism.  The closest research to my hypothesis that statins will “perk up the Purkinje cells” is this study:-


  

Fragile X syndrome

Fragile X syndrome is a genetic syndrome that leads to autistic behaviours.  About 5% of the cases defined as autism are due to this genetic flaw.  It also results in certain physical differences, namely:-
  • Large, protruding ears (one or both)
  • Long face (vertical maxillary excess)
  • High-arched palate (related to the above)
  • Hyper extensible finger joints
  • Hyper extensible ('Double-jointed') thumbs
  • Flat feet
  • Soft skin
  • Hypotonia (low muscle tone)
  • single palm crease (crease goes across entire palm)

 At MIT researchers have found that the statin Lovastatin “can correct Fragile X syndrome”.
 
I presume what is actually happening, is that in Fragile X there is also neuroinflammation and this has been reduced by the statin, rather than correcting the syndrome.
  

Retts Syndrome

Retts syndrome is another genetic disorder that causes regression and autism-like behaviours.  It affects mainly girls, because male fetuses with the disorder rarely survive to term.  The prognosis is not good.

Research is underway with statins and currently shows that statins improve symptoms of Rett syndrome in mice.

 
Statins and depression

A large study of patients with heart disease examined the difference between those on statins and those not.  Very interesting was the finding that those on statins had better mental health (i.e. less depression).


Statins: Mechanisms of neuroprotection

A very thorough presentation of the effect of statins and their possible mechanisms along with a review of their use in Alzheimer’s, Parkinson’s, Multiple Sclerosis and strokes, is in the excellent paper:-  Statins: Mechanisms of neuroprotection


 The anti-oxidant effect of statins

A study called The anti-oxidant effect of statins, looks very interesting, but only the abstract is freely available.  Here is the summary:-  

"A number of recent reports have shown that statins may also have important anti-inflammatory effects, in addition to their effects on plasma lipids. Since inflammation is closely linked to the production of reactive oxygen species (ROS), the molecular basis of the observed anti-inflammatory effects of statins may relate to their ability block the production and/or activity of ROS. In this review, we will discuss both the inhibition of ROS generation by statins, through interference with NAD(P)H oxidase expression and activity, and the actions of statins that serve to blunt the damaging effects of these radicals, including effects on antioxidant enzymes, lipid peroxidation, LDL cholesterol oxidation and nitric oxide synthase. These antioxidant effects of statins likely contribute to their clinical efficacy in treating cardiovascular disease as well as other chronic conditions associated with increased oxidative stress in humans."

 
Conclusion
 
Given the minimal side effects, that was more than enough evidence for me to start some primary research of my own. Step one was to try atorvastatin myself. 

My hypothesis is that atorvastatin will reduce autistic behaviours and that the mechanism is the reduction of neuroinflammation in the cerebellum and particularly in the Purkinje Cell Layer (PCL).  I believe that this will be valid regardless of the type of autism. 

The beneficial secondary effect will be reduction in LDL cholesterol, which is typically elevated in cases of autism.

 
Click here for  -  Statins Part 3



 

Wednesday 8 May 2013

Neurogenesis & Neuroplasticity


Today we have two new N- words and we finally get to the bottom of what autism is and what it is not.   There is nothing revolutionary here, it can all be found in the research and indeed most of it can be found in just one book, but then who would read my blog?
We will start with the bad news and finish with the good news.

Neurogenesis
Neurogenesis sounds like a good thing; it is the birth of neurons in the brain.  This is substantially completed in the pre-natal period, but it can continue in certain parts of the brain throughout life.  After a head injury, or trauma, neurogenesis can take place.

In the case of autism the potential benefit exists, but seems likely to be minimal.
Many studies have already established the pattern of deformities in the autistic brain.  One researcher in particular, Eric Courchesne, seems to have chosen to make this his life’s work.  He has carried out repeated studies over many years focused on examination of brain growth, and overgrowth, in autism using post-mortem brains and later MRI (magnetic resonance imaging).
His findings are unequivocal, and in line with those of his peers.  In his autistic subjects, the brain grows much faster in the first couple of years than typical subjects and then the process slows right down and in later life the autistic brain starts to shrink.  His and other studies show that in later life the brain does seem to try to compensate for its defective development; this is seen as ineffective (but how can anyone possibly know?).

He finds a wide pattern of abnormalities, including the expected presence of a reduced number of Purkinje cells.  He goes on to argue that his evidence shows that this damage was done in the pre-natal period, so he will not be popular with the vaccine damage theorists.

“Thus, given the resulting tight bond between the olivary neurons and the Purkinje cells after this time, loss or damage to the cerebellar Purkinje cells results in an obligatory retrograde loss of olivary neurons. Since, in the autistic brain, the number of the olivary neurons is preserved, it is likely that whatever event resulted in the reduction of the Purkinje cells in these cases has to have occurred before this tight bond has been  established, and thus before 28–30 weeks gestation.”
 
“In addition, microscopic observations of enlarged cells in some brain regions in autistic children and small pale cells that are reduced in number in these same areas in adults strongly indicate changes with age. Clinically and pathologically, this process does not appear to a degenerative one and may reflect the brain’s attempt to compensate for its atypical circuitry over time.”

“This early cessation of growth results in a 2–4 year old autistic brain size that is not different from a normal adolescent or adult in the majority of cases. Thus, at the age of typical clinical diagnosis of the disorder (i.e. 3–4 years), the period of pathological growth and arrest has likely already passed, leaving clinicians and researchers with an outcome, rather than process, of pathology for study and treatment intervention.”

Here are three of Eric’s studies, which include graphs showing autistic brain development vs. the control group at various ages throughout life.


Neuroplasticity
If neurogenesis was the bad news then neuroplasticity is certainly the good news. I think that Eric needs to read up on this subject and perk himself up.  It seems even a deformed brain can do some pretty clever stuff.

Neuroplasticity, also known as brain plasticity, refers to changes in neural pathways and synapses which are due to changes in behavior, environment and neural processes, as well as changes resulting from bodily injury.  Neuroplasticity has replaced the formerly-held position that the brain is a physiologically static organ, and explores how - and in which ways - the brain changes throughout life.
In the field of neuroplasticity we have some pioneering work from  Michael Merzenich is a neuroscientist. He has made some of "the most ambitious claims for the field - that brain exercises may be as useful as drugs to treat diseases as severe as schizophrenia - that plasticity exists from cradle to the grave, and that radical improvements in cognitive functioning - how we learn, think, perceive, and remember are possible even in the elderly."  Merzenich’s work was affected by a crucial discovery made by Hubel and Wiesel in their work with kittens. The experiment involved sewing one eye shut and recording the cortical brain maps. Hubel and Wiesel saw that the portion of the kitten’s brain associated with the shut eye was not idle, as expected. Instead, it processed visual information from the open eye. It was"… as though the brain didn’t want to waste any ‘cortical real estate’ and had found a way to rewire itself.
Merzenich created a plasticity-based computer aided learning programme called FastForWord, which  offers seven brain exercises to help with the language and learning deficits of dyslexia.

ABA and neuroplasticity.  Then of course, I started thinking about Monty’s  6 years of ABA and endless hours on his computer based learning programmes.  This of course is the link between neuroscience and ABA - the fuzzy science of neuroplasticity; otherwise known as making the most of what you’ve got. 
 
Conclusion
We have established that autistic behaviours are likely caused by stress and inflammation in the cerebellum, and in particular in the region of the Purkinje Cell Layer (PCL).

We have seen that in classic autism this stress and inflammation is associated with physical brain growth abnormalities that occurred in the pre-natal and early post natal period.  The oxidative stress and inflammation is ongoing throughout adulthood.
We have seen that stress and inflammation in the cerebellum can be caused by entirely different causes, that take effect later in life, such as Tuberous Sclerosis Complex (TSC).  There is another truly horrible one called Childhood Disintegrative Disorder (CDD).

With the availability of noninvasive MRI scans, it would be interesting and highly possible to ascertain the level of brain deformity in milder cases of autism and Asperger’s syndrome. 
Given that by the time autistic behaviors are exhibited, the damage to the brain  has already run its course, our main ally would seem to be neuroplasticity and of course to halt the ongoing oxidative stress and inflammation.

In addition, we need to consider countering the apparent ion-channel disfunction, and maybe give the damaged hippocampus a lesson or two about hormone production.

 

 

 

Tuesday 7 May 2013

Pep up those Purkinje cells

In the previous post we established that both oxidative stress and neuroinflammation can be measured.  We learned from the clever people at Johns Hopkins that the site of the greatest inflammation is in the  cerebelleum; as they put it:-

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.

Now, you may recall that I recommended an excellent book called "Autism: Oxidative Stress, Inflammation and Immune Abnormalities".  The book is from 2010, and since then the authors have been busy.  In 2012 they published a study called:   Brain Region-Specific Glutathione Redox Imbalance in Autism
This study tells us which parts of the brain are most affected by oxidative stress.  The abnormal level of GSH redox (the marker for oxidative stress) was highest in the cerebellum and in the temporal cortex.
This is good to hear, since I have assumed that oxidative stress and neuroinflammation are essentially part of the same process and that what halts one, will likely halt the other.
 

Purkinje Cells
Purkinje cells are a class of GABAergic (controlled by the neurotransmitter GABA) located in the cerebellum.
Purkinje cells are some of the largest neurons in the human brain, perhaps this makes them target of stress and inflammation.
Purkinje cells send inhibitory projections to the deep cerebellar nuclei, and constitute the sole output of all motor coordination (and maybe more?) from the cerebellum.

In humans, Purkinje cells are affected in a variety of diseases ranging from toxic exposure (alcohol, lithium), to autoimmune diseases and to genetic mutations (spinocerebellar ataxias, Unverricht-Lundborg disease and autism) and neurodegenerative diseases that are not thought to have a known genetic basis (cerebellar type of multiple system atrophy, sporadic ataxias).

Purkinje Damage in Autism
It has been shown that there is a 35 to 50% reduction in the number of Purkinje cells in the autistic cerebellum when compared with a normal cerebellum.  (this comes from a paper on glutamate neuro-transmitter abnormalities)

Here is an excellent and  very readable study all about Purkinje damage in autism, from 10 years ago:-
 Purkinje cell vulnerability and autism: a possible etiological connection

It is proposed that the cell death in the Purkinje cell layer produces the autistic-like behaviours.

Functions of the and temporal lobe and cerebellum
(where the oxidative stress was measured to be highest)

The temporal lobe seem very much related to the problematic areas of autistim, namely:-
·         Processing sensory input

·         Language comprehension
It also contains the hippocampus.  The hippocampus has made an earlier appearance on this blog since one of its main functions is the realease of hormones including TRH (thyrotropin releasing hormone) CRH (Corticotropin releasing hormone) GHRH (growth hormone releasing hormone).  Disfunction of the hippocampus is known to occur in epilepsy (often comorbid with autism).
If you want to read all about the temporal lobe, try this : Anatomy of the temporal lobe.

The cerebellum is commonly associated with motor control function, but it may have a role in cognitive function, such as language.  Damage to the cerebellum is known to causes disorders in fine movement (sloppy handwriting in autism?)
So it would appear at first glance that inflammation in the temporal lobe and cerebellum could indeed account for many autistic-like behaviors.  

 
Pep up those Purkinje cells  -  Indirect or direct action?
As is often the case, there is the direct approach and the indirect approach.  I usually favour the subtle indirect approach; this would be to work on reducing the oxidation and inflammation. 

There may also a direct approach, using a drug developed as an anti-fungal agent, that turned out to be a potent immunosuppressant.    It prevents activation of T cells and B cells by inhibiting their response to interleukin (IL-2). 

Since nothing in neuroscience is clear cut, there is of course a far more complicated alternative explanation of what is going on.  It could be a genetic disorder that is causing the failure in the Purkinje cells.  Take a look:-

Tuberous sclerosis complex (TSC) is a dominant tumour suppressor disorder caused by mutations in either TSC1 or TSC2. TSC causes substantial neuropathology, often leading to autism spectrum disorders (ASDs) in up to 60% of patients. The anatomic and neurophysiologic links between these two disorders are not well understood…. These studies provide compelling evidence that Purkinje cell loss and/or dysfunction may be an important link between TSC and ASD as well as a general anatomic phenomenon that contributes to the ASD phenotype.


The good news is that TSC already has a viable therapy (in mice at least, and in clinical trials), with a drug called rapamycin/sirolimus.  If you look on the web, you will find people experimenting with it.
There have been several studies using mutant mice. 

Autism in mice

In a study of sirolimus as a treatment for TSC, researchers observed a major improvement regarding effects related to autism. The researchers discovered sirolimus regulates one of the same proteins the TSC gene does, but in different parts of the body. They decided to treat mice three to six months old (adulthood in mice lifespans); this increased the autistic mice's intellect to about that of normal mice in as little as three days.

Here are two studies:- 


Before heading down to the pharmacy to ask about Rapamycin, click on this to see a warning or two.  Also TSC is a genetic condition that usually leads to autism.  This does not mean that if you have autism you also have TSC.  It does mean that better understanding TSC may help to better undertand autism.


It looks like the indirect approach is best again.  Just keep taking the NAC !!