Reduced levels of an important neurotransmitter found in multiple sclerosis patients

ScienceDaily (Feb. 11, 2011) — Researchers at the University of Illinois at Chicago have shown for the first time that damage to a particular area of the brain and a consequent reduction in noradrenaline are associated with multiple sclerosis.

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The study is available online in the journal Brain.

The pathological processes in MS are not well understood, but an important contributor to its progression is the infiltration of white blood cells involved in immune defense through the blood-brain barrier.

Douglas Feinstein, research professor in anesthesiology at the UIC College of Medicine, and his colleagues previously showed that the neurotransmitter noradrenaline plays an important role as an immunosuppressant in the brain, preventing inflammation and stress to neurons. Noradrenaline is also known to help to preserve the integrity of the blood-brain barrier.

Because the major source of noradrenaline is neurons in an area of the brain called the locus coeruleus, the UIC researchers hypothesized that damage to the LC was responsible for lowered levels of noradrenaline in the brains of MS patients.

"There's a lot of evidence of damage to the LC in Alzheimer's and Parkinson's disease, but this is the first time that it has been demonstrated that there is stress involved to the neurons in the LC of MS patients, and that there is a reduction in brain noradrenaline levels," said Paul Polak, research specialist in the health sciences in anesthesiology and first author on the paper.

For the last 15 years, Feinstein and his colleagues have been studying the importance of noradrenaline to inflammatory processes in the brain.

"We have all the models for studying this problem, so in some ways it was a small step to look at this question in MS," said Polak.

The researchers found that LC damage and reduced levels of noradrenaline occur in a mouse model of MS and that similar changes could be found in the brains of MS patients.

The findings suggest that LC damage, accompanied by reduction in noradrenaline levels in the brain, may be a common feature of neurologic diseases, Polak said.

"There are a number of FDA-approved drugs that have been shown to raise levels of noradrenaline in the brain, and we believe that this type of therapeutic intervention could benefit patients with MS and other neurodegenerative diseases, and should be investigated," he said.

Sergey Kalinin, post-doctoral research associate in anesthesiology, also contributed to the study. This study was supported by grants from the Department of Veteran Affairs and Partners for Cures.

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Possible new target for treatment of multiple sclerosis

ScienceDaily (Mar. 28, 2011) — The immune system recognizes and neutralizes or destroys toxins and foreign pathogens that have gained access to the body. Autoimmune diseases result when the system attacks the body's own tissues instead. One of the most common examples is multiple sclerosis (MS). MS is a serious condition in which nerve-cell projections, or axons, in the brain and the spinal cord are destroyed as a result of misdirected inflammatory reactions. It is often characterized by an unpredictable course, with periods of remission being interrupted by episodes of relapse.

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A team of researchers led by LMU Munich Professor Martin Kerschensteiner of the Medical Center of the University of Munich and Professor Thomas Misgeld from the Technical University of Munich has now been able to explain how the damage is inflicted. Their results reveal that the inflammatory reaction can induce a previously unknown type of axonal degeneration, which they call "focal axonal degeneration" (FAD). In an animal model of MS, this process is reversible if it is recognized and treated early, so the researchers believe that it could serve as a potential target for therapeutic intervention. "Development of an effective treatment will be a long-term project," cautions Kerschensteiner. "As yet, we only have a superficial understanding of the underlying molecular mechanisms and, of course, finding effective therapies will require time-consuming screens and extensive trials of drug candidates."

Multiple sclerosis is a common and, in many cases seriously disabling, autoimmune disease that can lead to the disturbance or loss of sensory function, voluntary movement, vision and bladder control. Commonly, it is thought that the primary target of MS is the myelin sheath, an insulating membrane that enwraps axons, and increases the speed of signal transmission. However, damage to nerve fibers is also a central process, as whether autoimmune pathology ultimately leads to permanent disability depends largely on how many nerve fibers are damaged over the course of time.

The team led by Kerschensteiner and Misgeld set out to define precisely how the damage to the nerve axons occurs. As Misgeld explains, "We used an animal model in which a subset of axons is genetically marked with a fluorescent protein, allowing us to observe them directly by fluorescence microscopy." After inoculation with myelin, these mice begin to show MS-like symptoms. But the researchers found that many axons showing early signs of damage were still surrounded by an intact myelin sheath, suggesting that loss of myelin is not a prerequisite for axonal damage.

Instead a previously unrecognized mechanism, termed focal axonal degeneration (FAD), is responsible for the primary damage. FAD can damage axons that are still wrapped in their protective myelin sheath. This process could also help explain some of the spontaneous remissions of symptoms that are characteristic of MS. "In its early stages, axonal damage is spontaneously reversible," says Kerschensteiner. "This finding gives us a better understanding of the disease, but it may also point to a new route to therapy, as processes that are in principle reversible should be more susceptible to treatment."

However, one must remember that it takes years to transform novel findings in basic research into effective therapies. First the process that leads to disease symptoms must be elucidated in molecular detail. In the case of MS it has already been suggested that reactive oxygen and nitrogen radicals play a significant role in facilitating the destruction of axons. These aggressive chemicals are produced by immune cells, and they disrupt and may ultimately destroy the mitochondria. Mitochondria are the cell's powerhouses, because they synthesize ATP, the universal energy source needed for the build-up and maintenance of cell structure and function.

"In our animal model, at least, we can neutralize these radicals and this allows acutely damaged axons to recover," says Kerschensteiner. The results of further studies on human tissues, carried out in collaboration with specialists based at the Universities of Göttingen and Geneva, are encouraging. The characteristic signs of the newly discovered process of degeneration can also be identified in brain tissue from patients with MS, suggesting that the basic principle of treatment used in the mouse model might also be effective in humans.

Even if this turns out to be the case, it would not mean that a new therapy would soon be at hand. The chemical agents used in the mouse experiments are not specific enough and not tolerated well enough to be of clinical use. "Before appropriate therapeutic strategies can be developed, we need to clarify exactly how the damage arises at the molecular level," says Kerschensteiner. "We also want to investigate whether similar mechanisms play a role in later chronic stages of multiple sclerosis ."

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Viagra could reduce multiple sclerosis symptoms, study suggests

ScienceDaily (May 19, 2011) — Universitat Autònoma de Barcelona researchers have discovered that Viagra®  (sildenafil) drastically reduces multiple sclerosis symptoms in animal models with the disease. The research, published in Acta Neuropathologica, demonstrates that a practically complete recovery occurs in 50% of the animals after eight days of treatment. Researchers are confident that clinical trials soon will be carried out in patients given that the drug is well tolerated and has been used to treat sexual dysfunction in some multiple sclerosis patients.

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Multiple sclerosis is the most common chronic inflammatory disease of the central nervous system and one of the main causes of disability among young adults. The disease is caused by the presence of multiple focuses of demyelination (loss of myelin sheaths around the axons, affecting the ability of neurons to communicate) and neurodegeneration in different areas of the central nervous system. There is currently no cure for the disease, although some drugs have proven effective in fighting symptoms and preventing it from progressing.

A research team from the UAB Institute of Biotechnology and Biomedicine directed by Dr Agustina García, in collaboration with the research team directed by Dr Juan Hidalgo from the UAB Institute of Neurosciences, has studied the effects of a treatment using sildenafil, sold as Viagra®, in an animal model of multiple sclerosis known as experimental autoimmune encephalomyelitis (EAE). Researchers demonstrated that a daily treatment with sildenafil after disease onset quickly reduced clinical signs, with a practically complete recovery in 50% of the cases after eight days of treatment. Scientists observed how the drug reduced the infiltration of inflammatory cells into the white matter of the spinal cord, thus reducing damage to the nerve cell's axon and facilitating myelin repair.

Sidenafil, together with tadalafil (Cialis®) and vardenafil (Levitra®), form part of a group of vasodilator drugs known as phosphodiesterase type 5 (PDE5) inhibitors, used in the treatment of erectile dysfunction and pulmonary arterial hypertension. Recent studies in animal models of central nervous system pathologies already pointed to the fact that in addition to vasodilation, these drugs could contain other neuroprotective actions and suggest their usefulness as possible treatments of both acute (cerebrovascular stroke) and chronic (Alzheimer's) neuropathologies.  Research published in 2010 in the Journal of Neurochemistry by the same research group from UAB demonstrated that one of these inhibitors reduced neuroinflammation and neuronal damage in animal models of traumatic brain injury.

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