'Sleep Hormone' Discovery Leads To Novel Melatonin Drug With Potential To Treat Insomnia

Main Category: Sleep / Sleep Disorders / Insomnia
Also Included In: Endocrinology;  Depression
Article Date: 15 Dec 2011 - 0:00 PST

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A team from the Research Institute of the McGill University Health Centre (RI-MUHC) and McGill University has made a major breakthrough by unraveling the inner workings of melatonin, also known as the "sleep hormone." The research, conducted in collaboration with scientists in Italy, reveals the key role played by the melatonin receptor in the brain that promotes deep, restorative sleep. This discovery led the researchers to develop a novel drug called UCM765, which selectively activates this receptor. The results, published in The Journal of Neuroscience, may pave the way for the development of new and promising treatments for insomnia, a common public health problem that affects millions of people worldwide.

"We've spent many years develop medications that act selectively on a single melatonin receptor to specifically promote deep sleep, which we believe is the key to curing insomnia," says Dr. Gabriella Gobbi, a researcher in psychiatry at the RI-MUHC and the study's principal investigator. "Deep sleep has significant restorative effects, as well as the ability to increase memory and boost metabolism, while lowering blood pressure and slowing the heart rate." To date most treatments for insomnia, such as benzodiazepines, have not been selective for deep sleep, and can lead to dependence and cognitive impairment.

The researchers became interested in melatonin because of its effect on cerebral activity, and its involvement in sleep, depression and anxiety. Melatonin is a critical hormone produced by the pineal gland (located in the brain) in the absence of light stimulation. This hormone, present throughout the animal kingdom, is responsible for regulating sleep and circadian rhythms.

The research team discovered that two principal melatonin receptors, known as MT1 and MT2, played opposite roles in sleep regulation. "We discovered that MT1 receptors act on rapid eye movement (REM) sleep and block non-REM sleep, while MT2 receptors favour non-REM sleep, also known as deep sleep," explains Dr. Gobbi, who is also an associate professor of psychiatry in the Faculty of Medicine at McGill. "Specifying the role of MT2 receptors in melatonin represent a major scientific breakthrough that may designate them as a promising novel target for future treatments of insomnia. This discovery also explains the modest hypnotic effect of the over-the-counter melatonin pills, which act on both conflicting receptors."

Using a drug called UCM765, developed in collaboration with a group of chemists, under the leadership of Professor Tarzia in Urbino and Professor Mor in Parma, Italy which selectively binds to the MT2 receptor, the researchers observed an increase in the phases of deep sleep in rats and mice. Most importantly, UCM765 acts in a brain area called the reticular thalamus, which is the main driver of deep sleep. "This new molecule, contrary to traditional treatments for insomnia, increases deep sleep without destroying the "architecture" of sleep. In other words, it increases the duration of deep sleep while keeping the REM sleep episodes the same," says Dr. Gobbi.

"The development of this pharmacology by means of targeting deep sleep receptors to treat insomnia represents a major advancement in our ability to deal with this common health problem that affects people worldwide," concludes Dr. Vassilios Papadopoulos, Director of the Research Institute of the MUHC.

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our sleep / sleep disorders / insomnia section for the latest news on this subject. About the study
This paper was co-authored by Rafael Ochoa-Sanchez, Stefano Comai, Francis Rodriguez Bambico and Sergio Dominguez-Lopez, Gabriella Gobbi (Dept. of Psychiatry, McGill University and Research Institute of the MUHC); Baptiste Lacoste, Laurent Descarries (Depts. of Pathology, Cell Biology, Physiology, Université de Montréal); Annalida Bedini, Gilberto Spadoni, Giorgio Tarzia (Institute of Medicinal Chemistry, University of Urbino, Italy); Marco Mor, Silvia Rivara (University of Parma, Italy); Debora Angeloni (Scuola Superiore Sant'Anna, Pisa, Italy), Franco Fraschini (Dept.of Pharmacology, Chemiotherapy and Medical Toxicology, University of Milan, Italy).
This work was supported by grants from the Fonds de la recherche en Santé du Québec (FRSQ), by the Canadian Institutes of Health Research (CIHR), by the Canadian Foundation for Innovation (CFI), MSBi Valorisation, the McGill University Health Centre (MUHC), and the Quebec Ministry of Economic Development, Innovation and Exportation (MDEIE).
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posted by Ann Jorn, Ph.D. on 15 Dec 2011 at 8:23 am

This breakthrough in understanding deep sleep and the role of the melatonin hormone provides great hope for the chronically sleep deprived chronic pain sufferer. Sleep is not simply disturbed by pain but when sleep does happen restorative sleep is minimal. This is especially true for those that suffer from fibromyalgia.

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Changing The Locks: HIV Discovery Could Allow Scientists To Block Virus's Entry Into Cell Nucleus

Main Category: HIV / AIDS
Article Date: 11 Dec 2011 - 0:00 PST

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Scientists have found the 'key' that HIV uses to enter our cells' nuclei, allowing it to disable the immune system and cause AIDS The finding, published today in the open access journal PLoS Pathogens, provides a potential new target for anti-AIDS drugs that could be more effective against drug-resistant strains of the virus.

HIV is transmitted through bodily fluids, primarily infected blood or semen. Once inside the bloodstream, the virus infects key components of the immune system including cells known as macrophages. It works its way into the nucleus of the macrophages, where it integrates itself into the cell's DNA, allowing it to replicate and spread throughout the body.

To access the DNA, the HIV must pass through the Nuclear Pore Complex, a gateway into the nucleus. Until now, the mechanism that allows the virus to pass through this gateway was unknown. Now, a team of scientists from UCL (University College London), the University of Pennsylvania School of Medicine and the Laboratory of Molecular Biology in Cambridge, has identified a vital component of this mechanism. A part of the HIV virus called the capsid protein, acting like a key, binds to Nup358, a protein on the nuclear pore complex, unlocking the gateway and granting the virus access to the DNA.

Professor Greg Towers, a Wellcome Trust Senior Research Fellow at UCL, who led the research, says: "It's thirty years since the first cases of AIDS were reported and whilst great progress has been made in developing and improving antiretroviral drugs for treating HIV infection, the virus often develops resistance against these drugs making it very difficult to treat. It's very important that we stay one step ahead with new therapeutic strategies.

"In our research, we have found the 'lock and key' that allow HIV to enter a cell's nucleus. Once inside, the virus can begin to replicate itself, spreading almost unchecked throughout the body. If we were able to block this entry with a drug - in effect, to change the locks - then we could stop this spread."

Targeting proteins in the host, rather than in the virus itself, has added benefits, explains first author Dr Torsten Schaller.

"Almost all HIV treatments target the virus itself," he explains. "We know that HIV can easily evolve and change, which means that the virus can become immune to the effects of the drugs, rendering them ineffective. But if we can develop drugs which target proteins in the infected person's body, the virus will struggle to evolve to get around this."

According to the World Health Organization, 33.3 million people were living with HIV in 2009, of which 2.6 million were newly infected. Without treatment, the virus causes potentially fatal damage to the immune system, leading to opportune infections. Deaths from AIDS-related illnesses are the third most common cause of death in low-income countries, killing around 1.8 million people a year worldwide.

The research was funded by the Wellcome Trust, the National Institute of Health Research and the Medical Research Council in the UK, and the National Institutes of Health, the University of Pennsylvania Center for AIDS Research, and the Pennsylvania Department of Health in the US.

Professor Danny Altmann, Head of Pathogens, Immunology and Population Health at the Wellcome Trust, said: "This is exciting work into somewhat uncharted territory. Professor Towers and colleagues have taken a big step towards modelling how HIV enters and integrates itself into the cell's DNA and then uses it to replicate. It offers the prospect of novel ways to try and combat HIV infection."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
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New Discovery Bonds To Anthrax Spores, Not Just Anthrax Bacteria

Main Category: Biology / Biochemistry
Also Included In: Infectious Diseases / Bacteria / Viruses
Article Date: 08 Dec 2011 - 1:00 PST

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A new study has shown previously unseen details of an anthrax bacteriophage - a virus that infects anthrax bacteria - revealing for the first time how it infects its host, and providing an initial blueprint for how the phage might someday be modified into a tool for the detection and destruction of anthrax and other potential bioterror agents.

The bacteriophage, known as Bacillus anthracis spore-binding phage 8a (or SBP8a, for short), is too small to be seen with a conventional light microscope. To create a portrait of the virus, researchers employed cryo-electron tomography, using an electron microscope to image a flash-frozen sample from many different viewing angles. With the help of computers, the scientists then recombined these views to produce three-dimensional renderings of the phage.

One of the surprising initial results was that the samples imaged contained SBP8a in four distinctly different configurations. While all four states are generally similar, with globular "heads" and linear "tails," significant differences can be seen that the researchers believe correspond to different steps in the viral infection process.

"The images we made from these four major populations clearly show in three dimensions exactly how these remarkable nanodevices are able to penetrate the anthrax cell, release their DNA from the bacteriophage's head and ultimately control its flow through the phage tail and into the cell," said University of Texas Medical Branch at Galveston assistant professor Marc Morais, senior author of a paper on the study now online in Virology.

Each of SBP8a's different states is marked by four key substructures: a hockey-puck-shaped "baseplate" at the opposite end of the tail from the head; a hollow tube running from the head to the baseplate; a sheath formed by six strands that wind around the hollow tube; and SBP8a's neck, which lies at the intersection of the bacteriophage's tail and its DNA-containing head and which is connected to the baseplate by the six-stranded helical sheath.

The process begins when the baseplate recognizes and binds to a suitable receptor on an anthrax bacterium. This binding causes the baseplate to immediately change its shape to a more open, clawlike structure, which in turn signals the sheath to contract to nearly half its length.

"When it contracts the tube has no choice but to be driven into the cell, much like a syringe," Morais said. "And in addition to contracting, the tail sheath is rotating, and that rotation exerts a torque on the neck protein, which opens the neck protein up so that DNA can now flow from the head into the tail, and then through the tail into the host cell's cytoplasm."

Morais' interest in SBP8a goes beyond the mechanics of its replication. He and his colleagues would like to take advantage of the fact that unlike other anthrax bacteriophages, SBP8a bonds to anthrax spores, not just anthrax bacteria. That gives it the potential to serve as the basis of a highly efficient detection system for the deadly agent.

"We want to push to high enough resolution where we can see secondary structure and make reliable models, and really rationally engineer these type of things," Morais said. "The genome has been sequenced now, and we're figuring out which parts can be removed and replaced with green fluorescent protein - the first step to endowing these bacteriophages with a reporter capacity and making them a detection tool.

"The great thing about our approach is that it is completely flexible. Every pathogenic bacterium has a phage associated with it. Thus, one could imagine tagging each pathogen-specific phage with a different colored signaling molecule such that you could make a cocktail of modified phages that glows a different color depending on which bacteria is present. Such a kit could be used to quickly identify a pathogen present in a bioterror attack."

Article adapted by Medical News Today from original press release. Click 'references' tab above for source.
Visit our biology / biochemistry section for the latest news on this subject. Morais' co-author on the Virology paper is assistant professor Jun Liu of the University of Texas Health Science Center at Houston. Other authors include postdoctoral fellow Xiaofeng Fu and assistant professor Angel Paredes of the University of Texas Health Science Center at Houston. The SBP8a phage was discovered and isolated by co-author Michael Walter, an associate professor at the University of Northern Iowa.
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Discovery Of New Tick-Borne Disease

Main Category: Infectious Diseases / Bacteria / Viruses
Also Included In: Immune System / Vaccines;  Vascular
Article Date: 08 Dec 2011 - 1:00 PST

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Researchers at the University of Gothenburg's Sahlgrenska Academy have discovered a brand new tick-borne infection. Since the discovery, eight cases have been described around the world, three of them in the Gothenburg area, Sweden.

In July 2009 a 77-year-old man from western Sweden was out kayaking when he went down with acute diarrhea, fever and temporary loss of consciousness. He was taken to hospital where it was found that he was also suffering with deep vein thrombosis (DVT). Following treatment with antibiotics, he was discharged some days later with an anticoagulant to thin his blood. However, the man - who had an impaired immune system - went down with a fever again.

Brand new infection

Over the following months the 77-year-old was admitted as an emergency case on several occasions, but despite repeated attempts to find a microbe, and repeated doses of antibiotics, the fever returned. Finally the patient's blood underwent special analysis to look for bacterial DNA - and that produced results. The findings matched a bacterium in an online gene bank and the results were a sensation: the man had contracted a brand new infection in humans which had never been described in the world before.

Never before seen in Sweden

Researchers at the University of Gothenburg's Sahlgrenska Academy have discovered a brand new tick-borne infection. Since the discovery, eight cases have been described around the world, three of them in the Gothenburg area, Sweden.

The man's blood contained DNA that derived with 100% certainty from the bacterium Neoehrlichia mikurensis. This bacterium was identified for the first time in Japan in 2004 in rats and ticks but had never before been seen in Sweden in ticks, rodents or humans.

Research published

Christine Wennerås, a doctor and researcher at the Department of Infectious Diseases and the Department of Haematology and Coagulation at the University of Gothenburg's Sahlgrenska Academy, has been studying the case since it first came to light. Last year she was able, for the first time, to describe the newly discovered disease in a scientific article published in the Journal of Clinical Microbiology. "Since our discovery the bacterium has been reported in eight cases around the world, three of them in Gothenburg," says Wennerås.

Causes DVT

All three of the Gothenburg cases involved patients with an impaired immune system, all of whom became ill during the summer months when ticks are most active.

"The nasty thing about this infection is that it causes DVT, at least in people with an impaired immune system," says Wennerås. "This can be life-threatening. Fortunately, the infection can be treated successfully with antibiotics.

Spreads from mammals

"If the newly discovered bacterium is similar to those we already know, it has presumably spread from wild mammals to people via ticks, and it is unlikely that it can be passed on from person to person."

The mikurensis in the bacterium's name comes from the Japanese island of Mikura, where it was first discovered.

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