Showing posts with label Sirolimus. Show all posts
Showing posts with label Sirolimus. Show all posts

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:-


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 !!