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joi, 15 decembrie 2011
'Sleep Hormone' Discovery Leads To Novel Melatonin Drug With Potential To Treat 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).
McGill University Health Centre Please use one of the following formats to cite this article in your essay, paper or report:
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15 Dec. 2011.
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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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vineri, 9 decembrie 2011
Deadliest Malaria Parasite Wiped Out By Novel Drug Leading To Starvation
Article Date: 09 Dec 2011 - 1:00 PST
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An antimalarial agent developed by researchers at Albert Einstein College of Medicine of Yeshiva University proved effective at clearing infections caused by the malaria parasite most lethal to humans - by literally starving the parasites to death. The novel research, carried out on a small number of non-human primates, could bolster efforts to develop more potent therapies against one of the world's leading killers. The study, published in the November 11, 2011 issue of PLoS ONE, was led by senior author Vern Schramm, Ph.D., professor and Ruth Merns Chair in Biochemistry at Einstein.
Malaria is a mosquito-borne disease caused by single-celled parasites belonging to the Plasmodium genus. The U.S. Centers for Disease Control and Prevention estimated that in 2008 (the latest year for which figures are available) between 190 million and 311 million cases of malaria occurred worldwide and between 708,000 and 1.003 million people died, most of them young children in sub-Saharan Africa. Plasmodium falciparum, the malaria species most likely to cause severe infections and death, is very common in many countries in Africa south of the Sahara desert.
The Einstein researchers exploited what is arguably P. falciparum's Achilles' heel: it can't synthesize purines, vital building blocks for making DNA. Instead, the parasite must make purines indirectly, by using an enzyme called purine nucleoside phosphorylase (PNP) to make a purine precursor called hypoxanthine. By inhibiting PNP, the drug BCX4945 kills the parasites by starving them of the purines they need to survive.
After BCX4945 showed potency against laboratory cultures of P. falciparum, owl monkeys were chosen as the non-human primate model for further testing of the drug. Three animals were infected with a strain of P. falciparum that is consistently lethal without antimalarial therapy. Orally administering BCX4945 twice a day for seven days cleared the infections from all the animals between the fourth and seventh day of treatment. The monkeys remained parasite-negative for up to nine days post-treatment. Parasitic infection eventually returned in all three monkeys after treatment ended, although a lower rate of parasitic growth was observed. No signs of toxicity were observed during the study period (30 days after the first dose).
BCX4945 belongs to a class of drugs known as transition state analogs that Dr. Schramm has been developing since 1994. Transition states form in every chemical change and whenever an enzyme does its job of converting one chemical (the substrate) into another (the product). The fleeting transition-state molecule is neither substrate nor product, but something in between - a ghostly intermediate to which the enzyme clings for just one billionth of a millionth of a second.
After figuring out the brief-lived transition-state structure for a particular enzyme, Dr. Schramm is able to design transition-state analogs to knock that enzyme out of action. The analogs closely resemble the actual transition-state structure but with one big difference: they powerfully inhibit the enzyme by binding to it and not letting go.
The transition-state analog BCX4945 was chosen for this study because of its high affinity for both P. falciparum PNP and human PNP (which the parasite obtains from the red blood cells it infects). Since PNP is abundant in mammalian red blood cells and those cells are constantly replaced, BCX4945 is toxic only to the parasite and not its mammalian hosts. (Two of Dr. Schramm's other PNP inhibitors - one for T-cell cancers, the other for gout - are being evaluated in clinical trials.)
"Inhibiting PNP differs from all other current approaches for treating malaria," said Dr. Schramm. "For that reason, BCX4945 fits well with the current World Health Organization protocols for malaria treatment, which call for using combination-therapy approaches against the disease."
Article adapted by Medical News Today from original press release. Click 'references' tab above for source.Visit our tropical diseases section for the latest news on this subject. The paper is titled "Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model." Other Einstein researchers involved in the study were Steven Almo, Ph.D., lead author Maria Cassera, Ph.D. (now at Virginia Polytechnic Institute and State University), Keith Hazleton, M.D./Ph.D. candidate, Emilio Merino (now at Virginia Polytechnic Institute and State University), Meng-Chiao Ho, Ph.D., (now at Academia Sinica), Andrew Murkin, Ph.D., (now at SUNY Buffalo), and Jemy Gutierrez, Ph.D., (now at Pfizer). This research was supported primarily by the National Institute of Allergy and Infectious Disease, part of the National Institutes of Health, and early aspects of the study were funded by Medicines for Malaria.
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A Novel Strategy For Fighting Cancer Targets Secondary Tumors
Article Date: 09 Dec 2011 - 0:00 PST
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The proliferation of metastases is often the main cause of complications and death from cancer. For the first time, researchers are looking very closely at the development of these metastases themselves, instead of focusing on the "primary" cancers from which they originated. In doing so, a team from the Swiss Center for Experimental Cancer Research (ISREC), at EPFL, was able to isolate a protein that plays a major role in metastasis development, and showed that the formation of secondary cancers could be prevented by blocking this protein. Their results were published December 7, 2011, in the advance online edition of the journal Nature and will open the door to new therapeutic options for treating late stage cancers.
A vital protein for metastases
The researchers already knew that cancer cells spread widely throughout the body once a malignant tumor is established. These cells don't always result in a secondary cancer, however. It turns out that all cancer cells aren't created equal: only some of them, known as "cancer stem cells," can initiate metastases. And in order to do this, they must settle into a spot - a niche - that is conducive for their development.
The ISREC team was able to show that several conditions are necessary for cancer to propagate. "In particular, we were able to isolate a protein, periostin, in the niches where metastases develop," explains Joerg Huelsken, holder of the EPFL Debiopharm Chair in Signal Transduction in Oncogenesis. "Without this protein, the cancer stem cell cannot initiate metastasis; instead, it disappears or remains dormant."
Minimal side effects in mice
Periostin exists naturally as part of the extracellular matrix, and has been shown to play a role in fetal development. In adults, it is only active in specific organs - the mammary glands, bones, skin and intestine. This research appears to prove that it plays an essential role in the environment that a cancer stem cell needs in order to develop a metastasis. Mice that were bred to lack this protein are resistant to metastasis formation. "We developed an antibody that adheres to this protein, making it inoperative, and we are hoping in this way to be able to block the process of metastasis formation," says Huelsken.
These experiments that blocked the periostin protein resulted in very few side effects in the mice. "This doesn't necessarily mean the same will hold true in humans," the researcher cautions. "We're not even sure that we'll be able to find an equivalent antibody that will work in humans."
This discovery is nonetheless very encouraging, especially since we now know that malignant tumors tend to spread more quickly than was previously believed. Preventing the development of metastases would thus appear to be an important therapeutic option that could limit the deleterious effects of cancers.
Article adapted by Medical News Today from original press release. Click 'references' tab above for source.Visit our cancer / oncology section for the latest news on this subject. Please use one of the following formats to cite this article in your essay, paper or report:
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9 Dec. 2011.
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