FROM BLOOD TO BRAIN, NEW STUDIES CROSS BARRIERS TO TREATMENTS


ATLANTA, October 17, 2006 - Recent discoveries about blood flow in the brain are bringing scientists closer to developing new and more effective treatments for a wide variety of neurological disorders, including stroke, Alzheimer's disease, Parkinson's disease, epilepsy, and spinal cord injury.

"Brain cells need the constant nourishment of blood," says Berislav Zlokovic, MD, PhD, of the University of Rochester. "When the regulation of that blood flow goes awry, the results can be devastating." Low blood flow to the brain is now believed, for example, to play a significant role in the development of certain dementias, including those related to Alzheimer's and Parkinson's diseases. Zlokovic is the scientific founder of Socratech, a start-up biotechnology company with a goal to develop neuroprotection strategies for the aging brain and against neurodegenerative diseases such as stroke.

Peter Carmeliet of the University of Leuven and the Flanders Interuniversity Institute of Biotechnology in Belgium, will give a Presidential Special Lecture on "The Emerging Importance of the Neuro-Vascular Link in Health and Disease." His work shows how the interplay between clinical and basic science can lead to new therapies. His research team started with the mouse gene, then went to human genetics, and then back to the mouse and the rat to evaluate therapeutic potential.

Five years ago, Carmeliet and his colleagues found that mutations in a gene known for triggering new blood vessel growth -- vascular endothelial growth factor, or VEGF -- were linked to symptoms, including progressively weaker muscles and spinal cord injury, much like amyotropic lateral sclerosis (ALS) in lab animals. Studies of some 2,000 people found three slightly different versions of the gene that appeared to cause lowered levels of VEGF protein in the body. What's more, the low VEGF levels corresponded with a higher risk of developing ALS.

Recently, Carmeliet has shown that VEGF is critical to nervous system development. He is now exploring the possibility of VEGF gene therapy for ALS. Preclinical animal studies have shown that this therapy can slow the onset of disease and increase life expectancy by 30 percent. Clinical trials are expected to start within a year.

At the University of California, Los Angeles, William Pardridge, MD, reports a new "Trojan horse" approach to transporting large molecule therapeutics across the blood-brain barrier (BBB). The BBB is a complex "security system" that alters the permeability of brain capillaries in a way that severely limits the passage of substances -- including helpful drugs -- from blood to brain cells. The new research promises to open the door to new and more effective treatments for many neurological disorders.

"Only a small class of drugs -- those that are small molecules with high lipid solubility and a low molecular mass -- can cross the blood-brain barrier, and only a few diseases, such as depression, affective disorders, epilepsy, and chronic pain, respond to these drugs," says Pardridge.

None of the large molecule drugs that have shown promise in animal studies for treating brain disorders -- protein drugs, monoclonal antibody drugs, RNA interference drugs, and gene therapies -- are able to make that crossing, Pardridge adds. "That's why the study of the blood-brain barrier is so crucial," he says. "Any new therapy that is going to be widely used in humans must be able to get past that barrier."

The molecular Trojan horses being studied by Pardridge are endogenous peptides -- or monoclonal antibodies that mimic endogenous peptides -- that cross the blood-brain barrier on specific receptor/transport systems. "By reformulating a large molecule drug or gene so that it attaches to one of these molecular Trojan horses, we can deliver the therapeutic through the blood-brain barrier and into the brain," he says.

In studies with rats, Pardridge and his colleagues have been successful in tricking receptors for transferrin, a protein critical for delivering iron to the brain, into carrying an unusual shipment across the blood-brain barrier: brain-derived neurotrophic factor (BDNF), a protein that supports the survival of brain cells and encourages them to grow. This stealth delivery has been shown to reduce the number of cerebral cortex brain cells killed by a simulated stroke by up to 70 percent when given within 2 hours of the stroke. Recently, Pardridge reported that animals that received the intravenous administration of the neurotrophin following the experimental stroke showed greater recovery of their motor skills than animals that didn't receive the treatment.

Pardridge and his team have also developed a large molecule delivery system based on the insulin receptor; this system is even more effective than the transferrin receptor method. Primate tests have shown that the insulin receptor Trojan horse delivers either recombinant proteins, or nonviral gene therapeutics, to all parts of the brain following intravenous administration. The insulin receptor delivery system has been genetically engineered to make it usable in humans.

"The Trojan horse technique has been shown to be effective in carrying large molecule therapeutics from the blood to the brain in experimental models for a number of brain disorders, including stroke, brain cancer, Parkinson's disease, and Alzheimer's disease," says Pardridge. "These findings are very promising, as any progress for the development of new drugs for brain disorders cannot take place without solving the blood-brain barrier drug delivery problem."

In other work, scientists have recently identified the enzyme NADPH oxidase as a major source of vascular free radicals in the brains of animal models of hypertension and Alzheimer's disease. NADPH oxidase is a final common pathway for vascular oxidative stress that alters the delivery of blood flow during brain activity.

"Together, these findings stress how important neurovascular coupling is to the health of the normal brain and suggest a possible therapeutic target for treating brain disorders associated with cerebrovascular dysfunction and cognitive decline," says Costantino Iadecola, MD, of Weill-Cornell Medical College in New York City.

Iadecola and his colleagues are investigating how the disruption of the interaction between neural activity and cerebral blood vessels may contribute to brain dysfunction, including that seen in hypertension, stroke, and Alzheimer's disease.

"The brain needs a continuous supply of blood to function, and there are neurovascular control mechanisms in place that make sure the brain receives enough blood to meet its energy needs," says Iadecola.

When the brain is active, it needs more blood -- and needs that blood in the specific areas where the activity is occurring. This close temporal and spatial relationship between neural activity and cerebral blood flow, known as neurovascular coupling, forms the basis for modern brain imaging techniques, such as functional magnetic resonance imaging (fMRI).

Neurovascular coupling involves the coordinated interaction of neurons, glia, and vascular cells. The neurons and glia generate the signals that get the process going, but it's the vascular cells (endothelial cells, pericytes, and smooth muscle cells) that transduce those signals into an increased flow of blood to the activated area of the brain.

For reasons that are not yet understood, in hypertension, stroke, Alzheimer's disease, and other neurodegenerative brain ailments associated with oxidative stress (cell dysfunction and destruction caused by free radical molecules), the coupling between blood flow and neural activity becomes disturbed. As a result, the brain ceases to have enough blood to meet all its metabolic needs, wreaking havoc on its cells and leading to cognitive deficits and dementia.

At the University of Rochester, Maiken Nedergaard, MD, PhD, studies the role of once overlooked brain cells -- astrocytes -- in regulating blood flow in the brain. This research is challenging a basic assumption behind today's most sophisticated brain imaging techniques. It's also offering intriguing new insight into many neurological conditions, including epilepsy, spinal cord injury, and Alzheimer's.

Scientists used to believe that the star-shaped astrocytes, a category of glial cells, functioned mainly to nourish and maintain a healthy environment for neurons. But, as Nedergaard and her colleagues reported in a study published earlier this year, astrocytes play a direct role in controlling blood flow in the brain, often without any prompting from neurons. Specifically, the study showed that when brain activity increases, the astrocytes release calcium, which in turn signals other chemical messengers to cause blood vessels in the brain to expand, increasing blood flow.

"This means that when we measure blood flow, we may not be measuring the activity of neurons so much as that of astrocytes," says Nedegaard.

The study's finding calls into question the assumption behind functional MRI scans and other modern brain imaging techniques. When brain scans show a decrease in blood flow, it's assumed that neurons in that brain region have died. That assumption may still be true, Nedegaard says, but her findings also suggest the cause of the decrease may be the result of astrocyte activity.

Nedegaard's research has implications for Alzheimer's disease and other brain disorders characterized by plummeting blood flows to critical regions of the brain. The assumption has been that the decrease in demand for blood meant there were fewer neurons to feed.

"It may be that it's the astrocytes themselves that are damaged first," says Nedegaard. "For whatever reason, they're not doing their job properly, which causes blood flow to decrease. That may then cause the neurons to die, since neurons depend on astrocytes for their nourishment and survival."

This and other research suggests that astrocytes may make good targets for the treatment of Alzheimer's and other brain illnesses and injuries.

At the Scripps Research Institute, Gregory del Zoppo, MD, examines what happens to the complex relationship between neurons, the tiny blood vessels that supply them, and supportive cells (astrocytes, other glial cells, and resident inflammatory cells) during a stroke. Research into this "neurovascular unit" promises to lead to more effective neuroprotective drugs than those currently given to people immediately after an ischemic stroke.

Most of the agents currently in use have failed to show any beneficial activity in patients with stroke, primarily because scientists still do not sufficiently understand the evolution of ischemic injury in the brain, says del Zoppo. What is known is that ischemia disrupts the blood-brain barrier. The endothelial cells in the brain's microvessels detach from each other and from astrocytes, and the extracellular matrix breaks down. The result: Blood cells that produce inflammatory chemicals enter the brain and destroy brain cells.

Del Zoppo and his team are currently trying to see if agents that block the adhesion of granulocytes (a type of white blood cell) and other immune cells to endothelial cells can reduce the neuronal injury to stroke patients. They have identified proteases called matrix metalloprotease (MMPs) and other matrix proteases as potential targets for therapy and, in laboratory studies, are testing MMP inhibitors to determine if they prevent the degradation of the matrix.

"These studies are yielding new insights into neuron survival and neuron-microvessel communication," del Zoppo says

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