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

Micro-Electronic Brain Implant Supervises Brain Re-Wiring

When the human brain is damaged from trauma, stroke, infection, or tumour etc., the damaged tissue does not re-grow itself spontaneously. Instead, the person must learn to compensate for the loss of function. Some brain plasticity may occur, as undamaged parts of the brain take responsibility for some of the functions which the destroyed parts previously carried out. But damaged brain does not heal.

Researchers at Case Western Reserve University intend to change that, by using implanted electronics devices which can help teach the brain how to re-wire itself to allow disconnected parts of the brain to become connected -- and functional -- again.

Pedram Mohseni, a professor of electrical engineering and computer science at Case Western Reserve University, and Randolph J. Nudo, a professor of molecular and integrative physiology at Kansas University Medical Center, believe repeated communications between distant neurons in the weeks after injury may spark long-reaching axons to form and connect.

Their work is inspired by the traumatic brain injuries suffered by ground troops in Afghanistan and Iraq.

...Mohseni has been building a multichannel microelectronic device to bypass the gap left by injury. The device, which he calls a brain-machine-brain interface, includes a microchip on a circuit board smaller than a quarter. The microchip amplifies signals, called neural action potentials, produced by the neurons in one part of the brain and uses an algorithm to separate these signals – brain spike activity - from noise and other artifacts. Upon spike discrimination, the microchip sends a current pulse to stimulate neurons in another part of the brain, artificially connecting the two brain regions.

...During the next four years, they expect to understand the ability to rewire the brain in a rat model and to determine whether the technology is safe enough to test in non-human primates. If tests show the treatment is successful in helping recovery from traumatic brain injury, the researchers foresee the possibility of using the approach in patients 10 years from now. _Eurekalert

Here is an abstract of a paper published by Mohseni in an IEEE publication from 2008:

This paper reports on the design, implementation, and performance characterization of a high-output-impedance current microstimulator fabricated using the TSMC 0.35 mum 2P/4M n-well CMOS process as part of a fully integrated neural implant for reshaping long-range intracortical connectivity patterns in an injured brain. It can deliver a maximum current of 94.5 muA to the target cortical tissue with current efficiency of 86% and voltage compliance of 4.7 V with a 5-V power supply. The stimulus current can be programmed via a 6-bit DAC with an accuracy better than 0.47 LSB. Stimulator functionality is also verified with in vitro experiments in saline using a silicon microelectrode with iridium oxide (IrO) stimulation sites. _IEEEXplore

The technology for such interventions is in the early stages. The researchers are also working on devices which can be used for a broad range of neurological and psychiatric conditions, and in conjunction with neurosurgery and standard post-surgical rehabilitation.

Eventually such devices will probably be implanted into a damaged area of brain, along with an artificial matrix seeded with a person's own stem cells and growth factors. The devices will be wired to "bridge" from healthy brain on one side of the lesion to healthy brain on other sides of the lesion (corresponding to interrupted pathways). The electronic signals will not only help guide a re-wiring of the brain, but they should also guide the re-growth of new replacement brain tissue of specific replacement types.

Anyone who has read the science fiction novel "Old Man's War" by John Scalzi, should recognise some of the intent behind the early stage, rudimentary devices being developed at Case Western -- and to see where the technology may be heading.

More on a related topic from Brian Wang

Transgenic Brain Cell Transplants: Rat Brain or Mouse Brain?

Researchers in Bangalore destroyed neurons in the subiculum (inferior hippocampus) of 48 adult rats. Half the 48 rats were then given fluorescent protein-tagged transplants of hippocampal cells from neonatal mice, the other half were kept as controls. 

Two months later, the scientists measured how well both the transplant and non-transplant rats learned and remembered, using two well-established maze tests of spatial learning. The rats given cell transplants had recovered completely: On both mazes, they performed as well as those rats which had not had their subiculums damaged. The rats without transplants did not recover: They had many problems learning their way through the mazes.


After studying behavior, the scientists examined what happened in the brain. Under the microscope, it appeared that the transplanted cells had settled mainly in a sub-area of the hippocampus called the dentate gyrus. There, the transplants appeared to promote the secretion of two types of growth factors, namely brain-derived neurotrophic factor and fibroblast growth factor, which boost the growth and survival of the cells that give rise to neurons. In the hippocampi of rats with cell transplants, the expression of brain-derived growth factor went up threefold.


It is significant that transplants can provide more neural growth factors in the hippocampus, because the formation of new neurons there may be critical for cognitive function. _ScienceDaily

One can easily imagine storing cultures of immature neurons for just that purpose -- to replace damaged neurons in more mature animals.   There is good reason to hope that damage from many types of brain trauma, tumour, infection, and neurodegeneration will be reversed by timely transplatation of tissue-banked immature neural cells.

But the transgenic nature of the experiment is also intriguing.  The transplanted rat brains contained functioning rat neurons and functioning mouse neurons.  Imagine expanding the experiment step by step, adding more and more mouse neurons to replace rat neurons that had been destroyed.  At what point does the rat begin thinking and acting more like a mouse?

Or consider the use of neonatal monkey neurons transplanted to damaged area of brain in adult humans.   As one transplants into larger and larger volumes of damaged tissue, when does the adult human begin behaving like a monkey -- perhaps a juvenile monkey?

No, I am not attempting to explain the behaviour of the current US Congress, or the delegates to the Copenhagen climate conference.   The neural transplant therapies I describe reside in the future.  But as a thought experiment, it does call up images "The Island of Dr. Moreau."  Brain cells from different animal sources might very well lead to different behaviours by human recipients.

Realistically, induced pluripotent cells from the patient herself, would more likely be used in such therapies of the future.  Signs are encouraging that many types of damage, disease, and degeneration can be at least partially reversed.  We may well be on the verge of a cascading biosingularity.  Stay tuned.

Rebuilding a Damaged Brain and More

After strokes and other types of brain damage, entire areas of brain can die and be replaced by fluid filled cavities or depressions. Scientists at Kings College London are experimenting with a biodegradable polymer matrix that may someday re-build the damaged brain after strokes, abscesses, and other types of brain damage.

Scientists say that the key to the advance, published today in the journal Biomaterials, is the use of a biodegradable polymer called PLGA, which ensures that the stem cells remain in the area of stroke damage and establish connections with surrounding brain tissue. By reducing the number of stray stem cells, the system is likely to be safer as well as more effective than other methods, the researchers add.

...The researchers injected particles of the PLGA polymer loaded with neural stem cells directly into the stroke cavities. Once inside the brain, the particles link up to form complex scaffolds. Modo's team used MRI scans to pinpoint where the stem-cell injections were needed and to monitor the development of new brain tissue. "Over a few days we can see cells migrating along the scaffold particles and forming a primitive brain tissue that interacts with the host brain," says Modo. "Gradually, the particles biodegrade, leaving more gaps and conduits for tissue, fibers, and blood vessels to move into." The next step, he says, will be to add the growth factor VEGF, which should encourage blood vessels to enter the new tissue and speed its development into mature tissue.

...The key to the advance was the ability of the new polymer to encourage the growth and differentiation of the neural stem cells at three different scales, says Modo's colleague Kevin Shakesheff, a tissue engineer at Nottingham University. "At the large scale, it enables the void formed by the injury to get new blood vessels very quickly, which is vital if the new tissue is to survive. At the cellular level, the scaffold surface allows stem-cell receptors to attach to it. And at the molecular level, it will allow cells to mix with the right growth factors." _TechnologyReview

Another fascinating area of brain research involves the use of ultra-short electrical pulses to affect nanopores in the nuclear membranes of neurons, while leaving the nanopores of the cell membrane intact. This specificity appears to have interesting effects on the behaviour of neurons individually and as a group.

When an electric field is applied to a cell, a charge starts to build up on the cell membranes. After a few microseconds, the charge is so high that holes (or "pores") start to form in the cell wall, an effect called electroporation. This allows material (in particular calcium ions) to pass through, affecting the function of the cell. With shorter pulses there is not enough time to affect the cell. But electroporation can affect the structures within the cell such as the nucleus, known as organelles.

"Because the organelles are much smaller than the cell itself... they reach their maximum charge much more quickly," Center founder Karl H. Schoenbach explains in an article. " Ending the pulse after the organelles are charged up, within a few hundred nanoseconds but before large pores appear in the cell’s own membrane, lets you focus the electric field’s effects on the organelles, such as the nucleus, while leaving the cell membrane relatively untouched. That, in turn, lets you do the complex and varied things medical science is interested in, such as killing tumor cells or triggering an immune system response."

So on the one hand ultra-short pulses can be used to selectively destroy cancerous cells. But they can also produce much more effective stunning effects.

A paper from the Center on Neuromuscular disruption with ultrashort electrical pulses compares 450-nanosecond pulses with multi-microsecond Taser pulses and found that the shorter pulses were more effective for suppressing voluntary movement, and used less energy. Another study found that even shorter, 60-nanosecond pulses could stun rats.

But the most significant is a paper which found that it was possible to incapacitate cells for a prolonged period -- "our study provides experimental evidence that even a single 60-ns pulse at 12 kV/cm can cause a profound and long-lasting (minutes) reduction of the cell membrane resistance (Rm), accompanied by the loss of the membrane potential." _Wired

I understand if a readers eyes fog up while reading fine print in italics dealing with scientific topics, particularly late at night when they really should be in bed asleep. But it might be worth one's time to contemplate the implications of research on ultra-short electrical pulses on neurons individually and in aggregate.

I will come back to both of these topics in the future.

Saving the Brain and Spinal Cord With Silicon Nanoparticles + PEG + Hydralazine

Researchers at Purdue University have combined silicon nanoparticles with polyethylene glycol (PEG) and the antihypertensive drug hydralazine, seeking a way to preserve brain and spinal cord function after central nervous system injury and trauma.

A team led by Richard Borgens of the School of Veterinary Medicine's Center for Paralysis Research and Welden School of Biomedical Engineering coated silica nanoparticles with a polymer to target and repair injured guinea pig spinal cords. That research is being published in the October edition of the journal Small....The team then used the coated nanoparticles to deliver both the polymer and hydralazine to cells with secondary damage from a naturally produced toxin. That research was published in August by the journal Nanomedicine.

....In the first study, the researchers coated the nanoparticles with PEG to treat guinea pig spinal cord injuries. The treated spinal cord cells showed improved physiological functioning.

In the second study, the researchers added both PEG and hydralazine, an antihypertension drug, to mesoporous silica nanoparticles. These nanoparticles have pores that can hold the drug, which is later delivered to the damaged cells. The hydralazine was added to fight off secondary damage to cells that occurs after the initial injury.

"When cells are injured, they produce natural toxins," Borgens said. "Acrolein is the most poisonous of these toxins. It's an industrial hazard for which hydralazine is an antidote."

Borgens and his team introduced acrolein into cells and then treated the cells with different combinations of hydralazine and/or PEG delivered by the mesoporous silica nanoparticles....They found that the treatment restored disrupted cell function caused by acrolein.

The team concluded that the use of nanoparticles to deliver both PEG and hydralazine increased the effectiveness of earlier PEG-only treatment by controlling and concentrating release of the drug and the polymer, producing a dual treatment and prolonging the treatment's duration.

...."All ambulances should have PEG on board," he said. "It can probably save thousands of people from more severe head and spinal damage." _PO

As biomedical science develops better treatments for degenerative and infectious diseases, better means to prevent and treat cancer, and better ways to delay and reverse the aging process, more attention will turn to the treatment of traumatic injury. Brain injury is easier to prevent than to recuperate from. Even so, expect more and more uses of nanoscale treatment modalities combined with regenerative therapies in the natural human attempt to turn back the entropy of trauma, time, and life.

More on the use of PEG in head injury

Rapid Head Injury Treatment : Polyethylene Glycol

Polyethylene glycol (PEG; 2000 MW, 30% by volume) has been shown to mechanically repair damaged cellular membranes and reduce secondary axotomy after traumatic brain and spinal cord injury (TBI and SCI respectively). This repair is achieved following spontaneous reassembly of cell membranes made possible by the action of targeted hydrophilic polymers which first seal the compromised portion of the plasmalemma, and secondarily, allow the lipidic core of the compromised membranes to resolve into each other. _Source

Polyethylene Glycol (PEG) is a group of multi-use polymers of ethylene glycol, classified by molecular weight. Recently, PEG has achieved increasing use in pharmacology via the "PEGylation" process of attaching PEG to a pharmacologic agent to modify its retention time and binding properties to membranes and receptors. PEG also recently made the news as an experimental nano-cage (via Speculist via Will Brown) to hold hemoglobin as a form of artificial blood.

Now it has been discovered that injection of PEG 2000 MW, 30% by volume, if injected early after brain and spinal cord injury, can reduce long term neurologic deficits.

Treated animals received a single subcutaneous injection of PEG. When treated within 2 hours of the injury, injured PEG-treated rats showed statistically significant improvement in their exploratory behavior recorded in the activity box when compared to untreated but brain-injured controls.

A delay of 4 hours reduced this level of achievement, but a statistically significant improvement due to PEG injection was still clearly evident in most outcome measures compared at the various evaluation times. A further delay of 2 more hours, however, eradicated the beneficial effects of PEG injection as revealed using this behavioral assessment.

Thus, there appears to be a critical window of time in which PEG administration after TBI can provide neuroprotection resulting in an enhanced functional recovery. As is often seen in clinically applied acute treatments for trauma, the earlier the intervention can be applied, the better the outcome. __7thSpace

Closed head injury and spinal injury are common occurrences in developed societies, most commonly from motor vehicle accidents and sports injuries. Given the apparent safety and ease of a single subcutaneous injection of PEG, this treatment should considered for approval for use by first responders/EMS, emergency ward physicians, and sports event physicians and paramedics.

Author: Andrew O Koob, Julia M Colby and Richard B Borgens
Credits/Source: Journal of Biological Engineering 2008, 2:9