On this blog I have been writing about stem cells, hyperbaric oxygen (HBOT), and some incredible new observations related to reversing brain inflammation. All of the diseases I listed above and a whole bunch more are tied to persistent inflammation. Inflammation itself is very important to the body. In a healthy person it doesn’t persist. It comes in response injury or infection – cleans that up – then stem cells communicate the need to stop the inflammation and heal. To that extent, these chronic – persistent inflammatory conditions are the result of a failure of stem cells to do their job to counter inflammation. I will explain what is keeping them out of the process below and in future posts.
As this following picture demonstrates, the balance of inflammation regulation in the brain is complicated, intricate and precarious. But science has reached a point where we understand a large portion of the regulatory pathways.
[Frontiers in Bioscience 14, 5291-5338, June 1, 2009]
Caption: Microglia are the primary recipients of peripheral inflammatory signals as they reach the brain. Activated microglia initiate an inflammatory cascade by releasing cytokines, chemokines, prostaglandins and reactive nitrogen and oxygen species (RNS and ROS, respectively). Bi-directional exchanges between microglia and astroglia amplify inflammatory signals within the central nervous system (CNS). Cytokines including interleukin (IL)-1, IL-6, tumor necrosis (TNF)-alpha and interferon (IFN)-gamma induce indoleamine 2,3 dioxygenase (IDO), the enzyme responsible for degrading tryptophan, the primary precursor of serotonin (5-HT), into kynurenine, which is eventually metabolized into quinolinic acid (QUIN), a potent NMDA agonist and stimulator of glutamate (Glu) release. Multiple astrocytic functions are compromised due to the excessive exposure to cytokines, prostaglandins, QUIN and RNS/ROS, ultimately leading to downregulation of glutamate transporters, impaired glutamate reuptake, excessive glutamate release and compromised synthesis and release of neurotrophic factors. Oligodendroglia suffer damage due to toxic overexposure to cytokines such as TNF-alpha, and diminished neurotrophic support, both of which promote apoptosis and demyelination. Copious amounts of glutamate are released from astrocytes in the vicinity of extrasynaptic NMDA receptors, whose activation leads to inhibition of BDNF synthesis. Excessive NMDA activation, caused by QUIN and D-serine, is compounded by diminished glutamate reuptake by astrocytes and oligodendroglia. NMDA-mediated excitotoxicity, combined with a consequent decline in neurotrophic support, and an increase in oxidative stress, synergistically disrupts neural plasticity and induces apoptosis (cell death).
So it doesn’t matter if we are talking about autism, post-stroke inflammation, Alzheimer’s, HIV dementia; the central mechanism is largely the same.
Now this is important to understand: if we have persistent inflammation in the brain, what is driving that signal? The immune system has lots of regulatory steps designed to keep it in balance, but despite all the intrinsic safeguards in the system – it has lost control. Why?
Some perspective: About 5 years ago I was sitting on a bus with Professor Thayne Sweeten. We were on our way to dinner to relax after a full day of brainstorming as a group of researchers interested in autism. Thayne is a bright guy. His PhD dissertation was Immune Activation and Autoimmunity in Autism. He explained from everything he had seen regarding the immune system of autism; the CSF observations, the increase in neopterin, etc,, that at least a significant subgroup of children had the immunological footprint of a persistent viral pathogen.
I agreed – and I still do agree – especially after 5 years of discoveries. And it doesn’t have to be a virus: many other pathogenic bacteria and fungi could cause the same response. But for simplicity let’s just say virus.
We don’t have to agree about which virus is persistent in autism, it actually doesn’t matter that much. I am surprised to hear myself say that, but after what I have learned in the last few months, I don’t think the actual virus is that important. That is because most do not have a specific anti-viral drug (apart from HIV and some Herpes viruses). Even in those cases the drugs are inadequate and something else is needed.
THE IMMUNE SYSTEM IS BLINDED
The picture depicts the blind miraculously being given sight. I would love to see a miracle of immune unblinding in autism, or any of these other disorders. Absent that we need to give it sight medically.
If you read my blog about this last night I spoke about the problem. We have a raging immune response just like we would expect with a viral infection, except it doesn’t go away. Why? The immune cells (particularly macrophages) seem to be blind and cannot find the enemy they are looking for. So while they stumble around, unable to find the viral enemies, the entire system stays turned on. And it will stay turned on until either stem cells say enough – its time to heal, or until the virus is eliminated.
The evidence is we don’t generate enough stem cell response to regulate this type of immune response – presumably because the viruses are still present. Therefore, extra stem cells may help cool the immune fires. BUT, and it is an important but, do we want to down-regulate the immune system if a virus is still present? My belief is – no.
What we want is to make the virus go away and with that have the immune response naturally calm down.
To do that we have to give sight to the blind and help the macrophages find their targets.
To do this we are working with some of the finest biotech labs in Europe and we believe we have the solution. More on that to come.
A brief but helpful discussion about TNF alpha is on wikipedia. http://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha