Single Drug Treatment for Alzheimer's, MS, TBI, and More

In a study published in the Journal of Neuroscience, a collaborative team of researchers led by Linda J. Van Eldik, director of the University of Kentucky Sanders-Brown Center on Aging, and D. Martin Watterson of the Northwestern University Feinberg School of Medicine, present results showing that a new central nervous system drug compound can reduce Alzheimer’s pathology in a mouse model of the disease.

The drug, called MW-151, is a selective suppressor of brain inflammation and overproduction of pro-inflammatory molecules from glial cells. The drug can be taken by mouth and readily enters the brain. The new study tested the hypothesis that intervention with drugs like MW-151 could be effective as a preventive measure, when administered at an early stage before Alzheimer's pathology appears, as well as after disease symptoms have begun to appear. _Source

The UK / Northwestern team has developed two drugs in this new class -- MW 151 and MW 189. This new class of drugs protects the brain by limiting production of and preventing the accumulation of pro-inflammatory cytokines in the brain. Inflammation in the brain can be particularly destructive in a wide range of infections, diseases, traumatic injuries, vascular insufficiencies, and more.

When too many of the cytokines are produced, the synapses of the brain begin to misfire. Eventually the entire organization of the brain falls into disarray, like a computer failing. The neurons lose their connections with each other and can eventually die. The resulting damage in the cortex and hippocampus can compromise memory and decision-making.

"In Alzheimer's disease, many people now view the progression from mild cognitive impairment to full-blown Alzheimer's as an indication of malfunctioning synapses, the pathways that allow neurons to talk to each other," said Watterson, the John G. Searle Professor of Molecular Biology and Biochemistry. "And high levels of proinflammatory cytokines can contribute to synaptic malfunction."

Because this harmful inflammatory mechanism also appears to be a major player in other neurodegenerative disorders in addition to Alzheimer's, the class of drugs represented by MW151 might hold bright potential as co-therapies for Parkinson's disease, frontotemporal dementia, amyotrophic lateral sclerosis, M.S. and the longer term complications of brain injury, Watterson said. _MedXpress

It is likely that this new class of drugs with its very broad spectrum of affects will find application in a wide range of conditions -- some not yet anticipated.

Regardless of neuro-inflammation’s exact role, a prevailing hypothesis is that targeting of pro-inflammatory cytokine overproduction in the brain might be a useful therapeutic strategy to add to the armamentarium of emerging interventions. The primary brain cell target for such a disease modifying strategy would be glia, cells in the brain that produce pro-inflammatory cytokines and other innate immunity responses to injury or disease progression. Glial cells normally cooperate with the nerve cells to keep the brain operating smoothly. When an injury or change in the brain occurs, the glial cells mount a beneficial inflammation response to fight off the insult and restore the brain to its proper functioning. This beneficial process sometimes gets out of balance and the inflammation becomes too strong or does not shut off on schedule. _SurfKy

Brain Rejuvenation Using Intravenous Cord Blood

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Researchers in Florida have managed to rejuvenate the brains of aging mice with a single injection of human cord blood cells in a peripheral vein. The single cord blood cell injection resulted in new progenitor stem cells in the mouse hippocampus, and new nerve cell formation.

Neurogenesis continues to occur throughout life but dramatically decreases with increasing age. This decrease is mostly related to a decline in proliferative activity as a result of an impoverishment of the microenvironment of the aged brain, including a reduction in trophic factors and increased inflammation.

We determined that human umbilical cord blood mononuclear cells (UCBMC) given peripherally, by an intravenous injection, could rejuvenate the proliferative activity of the aged neural stem/progenitor cells. This increase in proliferation lasted for at least 15 days after the delivery of the UCBMC. Along with the increase in proliferation following UCBMC treatment, an increase in neurogenesis was also found in the aged animals. The increase in neurogenesis as a result of UCBMC treatment seemed to be due to a decrease in inflammation, as a decrease in the number of activated microglia was found and this decrease correlated with the increase in neurogenesis.

The results demonstrate that a single intravenous injection of UCBMC in aged rats can significantly improve the microenvironment of the aged hippocampus and rejuvenate the aged neural stem/progenitor cells. Our results raise the possibility of a peripherally administered cell therapy as an effective approach to improve the microenvironment of the aged brain.

...Not only do the results of this study provide novel insight into the state of the aged stem cell niche, the ability of the UCBMC to exert their effects while being administered minimally invasively may make translation to the clinical setting more likely. For this reason it will be important in future studies to determine the most efficacious dose and dosing regimen. Nevertheless, this is the first time that a systemic injection of hematopoietic cells has been shown to restore the regenerative potential of the aged brain, providing a novel insight into how the regenerative potential of the aged stem cell niches could be restored.

...The effects of UCBMC have been attributed to changes in the microenvironment of the brain, through the release of trophic factors or by reducing inflammation, and not by a direct replacement of cells [21-23]. UCBMC contains a number of cell types including B-Cells and T-Cells, as well as, mesenchymal and endothelial progenitor cells. UCBMC is also a rich source of CD34⁺ hematopoietic stem cells [24-26]. It was recently demonstrated that a systemic injection of UCBMC cells could suppress inflammation in the brain following stroke. Moreover, the effects of UCBMC cells seemed to shift the cytokine expression from a Th1 response to a Th2 response [20,23,27]. In addition to the immune modulatory effects, UCBMC cells also produce a number of trophic factors including, but not limited to, VEGF, nerve growth factor, and cytokine colony stimulating factor-1, thrombopoietin, and IL11 [20,28,29]. ___BiomedCentral__via_madscience__via__TechnutNews

It is important to understand that the cells that were injected into the peripheral veins of mice were human umbilical cord blood mononuclear cells (HUCBMCs). The results are somewhat startling, given that the injected cells were not neural stem cells, the cells were not injected directly into the brain, and the cells were given in a single dose only. It will be important for the researchers to tease out the important cellular and trophic factors present in the UCBMC's that may have led to the rejuvenatory effects.

This is a line of research that I am interested in following further.

Enbrel: Etanercept -- A New Conceptual Approach for Treating Alzheimer's and Other Diseases

Enbrel (Etanercept) is a Tumour Necrosis Factor (TNF) blocker originally developed to treat arthritis (RA and JRA). Its use has been enlarged to treat psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis. Even more astounding, Etanercept has shown efficacy in treating forms of diabetes, advanced heart failure, and most recently, Alzheimer's Disease.

Of particular relevance to intersections between neuroinflammation and neurodegeneration is the ability of TNF to increase expression of interleukin-1 (IL-1), which in turn increases production of the precursors necessary for formation of amyloid plaques, neurofibrillary tangles, and Lewy bodies. More recent data have revealed that TNF, one of the few gliotransmitters, has strikingly acute effects on synaptic physiology. These complex influences on neural health suggest that manipulation of this cytokine might have important impacts on diseases characterized by glial activation, cytokine-mediated neuroinflammation, and synaptic dysfunction. Toward such manipulation in Alzheimer's disease, a six-month study was conducted with 15 probable-Alzheimer patients who were treated weekly with perispinal injection of Etanercept, an FDA-approved TNF inhibitor that is now widely used for treatment of rheumatoid arthritis and other systemic diseases associated with inflammation. The results demonstrated that perispinal administration of etanercept could provide sustained improvement in cognitive function for Alzheimer patients. Additionally, the authors were impressed by the striking rapidity with which these improvements occurred in the study patients.

How rapid were these improvements? Would you believe, for some patients, "in minutes?"

The drug, called Enbrel, is injected into the spine where it blocks a chemical responsible for damaging the brain and other organs.

A pilot study carried out by U.S. researchers found one patient had his symptoms reversed "in minutes".

Other patients have shown some improvements in symptoms such as forgetfulness and confusion after weekly injections over six months.

The study of 15 patients with moderate to severe Alzheimer's has just been published in the Journal of Neuroinflammation by online publishers Biomed Central.

... Sue Griffin, a researcher at the University of Arkansas for Medical Sciences, said: 'It is unprecedented to see cognitive and behavioural improvement in a patient with established dementia within minutes of therapeutic intervention.

'This gives all of us in Alzheimer research a tremendous new clue about new avenues of research.' Enbrel is not approved for treating Alzheimer's in the U.S. or the UK and is regarded as highly experimental, said Dr Griffin.

Source

There is also evidence that Etanercept can normalize mitochondrial function in some conditions. Clearly, TNF-mediated inflammation plays a significant role in a very broad array of disease processes.

While the vast majority of such research findings take place in the western world, the benefits from their discovery will quickly disseminate to the far corners of the entire world. This is one dimension of the "seed effect" of a freer intellectual environment within the west. What a shame to ever lose that.

To watch a fascinating animation of TNF and Etanercept at work, go here.

HSP90, Cancer, and Sepsis

HSP90 is a heat shock protein--proteins in the cell that become more concentrated in reaction to cellular stresses, including heat. HSP90 also has normal, non-stress functions in the cell--particularly chaperone functions. As a chaperone, HSP90 helps to keep proteins from folding in aberrant and dysfunctional conformations.

HSP90 inhibitors have recently come into play for the treatment of malignancies. HSP90 tends to reduce (through re-folding and other pro-degradation processes) the concentration of apoptotic products coming from early cancer cells--allowing the cells to grow longer and become more difficult to treat with conventional cancer treatments. Inhibiting HSP90 leads to more apoptosis of cancer cells, and more effective cancer treatment.Researchers have recently begun to look at HSP90 inhibitors for treating sepsis and other conditions of extreme inflammation in the body.

Studies in an animal model of sepsis, a major cause of ICU patient death, indicate HSP 90 inhibitors help degrade proteins perpetuating inflammation, says Dr. John D. Catravas, director of the Medical College of Georgia Vascular Biology Center.

Results include restored lung function, reduced blood vessel leakage, which can lead to dangerous swelling in the lungs, and fewer byproducts of inflammation such as white blood cells, MCG researchers report in the American Journal of Respiratory and Critical Care Medicine, a journal of the American Thoracic Society.

...These manmade HSP 90 inhibitors work by attaching where the protein pair's energy source, called ATP, should be. The body appears to have an endogenous version, ADP, which has one less phosphate than ATP and binds at the same site, also opening the protein claws and sending the client protein toward degradation.

Source

Getting down to the level of folding and re-folding of proteins is an important step for pharmacologists and protein scientists. This is where the rubber meets the road in cellular function. It should not go unsaid that there are important lessons here for nanotechnologists as well.

By understanding how to lock, unlock, and modify active sites of proteins--and controlling their energetics and shape--protein scientists are in essence bio-nanotechnologists.

Alzheimer's Disease and Microglia Triggered Inflammation

A recent posting at Developing Intelligence blog discussed the vital role of glial cells in the activity of neurons, including the effect of inflammation triggered by glia. Now U Penn Medical School researchers have shown that microglial activation leads to formation of neural tangles of tau protein. These tangles cause more inflammation and so on . . .

Researchers at the University of Pennsylvania School of Medicine have shown that impaired function and loss of synapses in the hippocampus of a mouse form of Alzheimer’s disease (AD) is related to the activation of immune cells called microglia, which cause inflammation. These events precede the formation of tangles – twisted fibers of tau protein that build up inside nerve cells – a hallmark of advanced AD. The researchers report their findings in the February 1 issue of Neuron.

“Abolishing the inflammation caused by the accumulation of the tau protein might be a new therapy for treating neurodegenerative disorders,” says senior author Virginia Lee, PhD, Director of the Center for Neurodegenerative Disease Research. “This work points the way to a new class of drugs for these diseases.”

In addition, the immunosuppressant FK506 diminishes neuron loss and extends the life span of the transgenic Alzheimer’s mice. Normally only 20 percent of these mice survive by one year. With FK506, 60 percent of the mice were alive by one year.

Source.

Glial cells perform housekeeping functions for neurons, but in some situations can trigger inflammation that leads to neuron death. Learning how to intervene in such situations before irreversible damage is done to neurons may postpone the loss of mental function in senescent individuals.

Cancer Targets Part I: NF Kappa B

Treatments for cancer can end up killing the patient, or at least killing large parts of the patient which the patient needed. More selective, better targeted treatments are needed, that will kill the cancer cells but leave normal cells alone. Researchers have spent a great deal of time identifiying crucial differences between cancer cells and normal cells, in order to find specific therapeutic targets in the cancer.

In the context of cancer therapy, NF-kappa B (NF-kB) has been found to protect several cancer types from apoptosis, programmed cell suicide. Since much of cancer treatment involves trying to induce apoptosis in the cancer, NF-kB is standing in the way of treatment. It makes sense to try to disable the active NF-kB, so the cancer cell can commit suicide.

This Eurekalert newsrelease looks at three cancer targets. Today, I will discuss the first target in the newsrelease, NF-kappa B. NF-kappa B is a transcription factor that activates genes involved in protecting cells from apoptosis, and several other cellular actions.

In their study, the NCI researchers set out to determine the role of NF-kB in reversing the apoptotic (or programmed cell death) effect of selective estrogen receptor modulators (SERMs) in brain cancer, as well as potential therapies that can be used either alone or in combination to block the protein. High levels of NF-kB are activated and present in transplanted glioma cells and glioma tumor samples, but not in normal brain tissue cells.

SERMs have shown some value in inducing cell death in brain cancers by a previously unknown method. They are designed to deliver the benefits of estrogen without its negative side effects, although gliomas do not generally express the estrogen receptor. However, previous studies have shown that NF-kB protects glioma cells from breaking down, therefore reversing the effect of SERM therapies.

Researchers looked at 203 glioma samples and determined that NF-KB was activated. They also noticed that the level of activation was related to the grade of the tumor, suggesting that NF-KB is related to tumor progression.

....IkB-alpha is one of a series of inhibitory proteins that controls the activation of NF-kB, preventing it from binding to DNA in the nucleus. Bortezomib not only stops the degradation of IkB-alpha, it also suppresses the activation of NF-kB, thus stopping cell growth.

"By interfering with the function of IkB-alpha proteins, bortezomib was shown to induce glioma cell degradation and enhance anti-cancer effects of SERMs," said Ai-Min Hui, M.D., Ph.D., research fellow at the National Cancer Institute and lead investigator on this trial.

Read more here.

NF-kB will be central to many future treatments of cancer, and inflammatory disease--such as rheumatoid arthritis. That is because NF-kB is central to the transcription of mRNAs for proteins involved in inflammation, the cell growth cycle, and protecting cancer from apoptosis.

For more information on this important cell signal transduction pathway, consult these references:

http://people.bu.edu/gilmore/nf-kb/

http://www.jci.org/cgi/content/full/107/2/135

MIT World Video--David Baltimore: "The Many Faces of NF-Kappa B"

It would be impossible to exaggerate the key importance of this transcription factor, for research into cancer, immunology, rheumatology, ageing, and other important areas of biomedicine. More on cancer targets 2 and 3 later.