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New peptides prevent brain damage
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MOLECULAR MEDICINE TODAY, JULY 1999 (VOL. 5)
New peptides prevent brain damage American scientists have discovered a class of neuropeptides that prevent damage caused by alcohol in the developing fetal brain. Their findings, which were presented at FASEB’s Experimental Biology ’99 conference*, provide a model for the role of these proteins in protecting against oxidative stress, and could have implications for the treatment of a variety of neurodegenerative diseases. Fetal Alcohol Syndrome (FAS) affects 12 000 babies in the USA every year. Stunted growth, reduced brain weight and mental deficiency characterize it, with sufferers typically showing an IQ of ~70. After genetic causes, maternal alcohol consumption is the most common cause of mental retardation, and consuming more than three units of alcohol a week can double the risk of miscarriage. Exposure to alcohol causes cell death in the embryonic neuroepithelium – the outer layer of the developing neural tube – and FAS has been associated with oxidative stress and an increase in the production of free radicals. Catherine Spong and co-workers in Douglas Brenneman’s lab (National Institutes of Health, Bethesda, MD, USA), and their collaborators in Illana Gozes’ group (Tel Aviv University, Tel Aviv, Israel), thought the condition might make a good model for testing a protein that they suspected of having antioxidant, neuroprotective properties. The protein, vasoactive intestinal peptide (VIP), has been the object of intense scrutiny in Brenneman’s lab for almost two decades now. Despite its name, it is found in the brain and is known to regulate early embryonic growth in the mouse. Receptors for VIP are found in the floorplate of the embryonic neural tube, where their action is mediated by several other proteins, including activity dependent neurotrophic factor (ADNF) and another similar molecule called activity dependent neurotrophic protein (ADNP). Both ADNF and ADNP are secreted by glial cells in the neuroepithelium, and Brenneman’s team has extracted from them their active components, known as SAL and NAP (named after the first three amino acids of each fragment), respectively. The purpose of these most recent experiments was to see if these two protein fragments could prevent the symptoms of alcohol exposure in a mouse model of FAS. The researchers treated pregnant mice with NAP, SAL, or a combination of both, 30 minutes before injecting them with alcohol. They chose the eighth day of embryogenesis to do so because 282
that is the gestational stage when the neural tube is closing and the embryo is most vulnerable to oxidative stress. After ten days, they measured the number of miscarriages and the weights of surviving fetuses in each group. And they found a dramatic effect. In mice treated with alcohol alone, 36% of the fetuses had been miscarried compared with 4% of the untreated controls. But in mice pre-treated with NAP, or both NAP and SAL, the death rate decreased to control levels. Alcohol alone caused a reduction in both fetal brain and body weight but the NAP–SAL combination also brought these back to control levels. In a further experiment, Spong’s team found that pre-treatment with NAP and SAL prevented the decline in VIP mRNA seen in the alcohol-treated mice. ‘This stuff is doing something extraordinary to an oxidatively stressed developing animal’, says Brenneman. In the mouse, embryogenesis day eight is associated with the highest incidence of fetal abnormalities and deaths. It corresponds to the end of the first month of pregnancy in humans – as Spong points out, ‘before you even know you’re pregnant.’ So the findings have serious implications for the prevention of FAS and, potentially, other conditions caused by oxidative stress. NAP is completely conserved between mice and humans. And the fact that it is found in the cortex, cerebellum and hippocampus, areas known to be important in learning and memory, means that it could also play a role in neurodegenerative diseases such as Alzheimer’s. According to Brenneman, there is already research to show that when a new born rat is treated with NAP, its ability to learn reflexes improves. But the most exciting thing of all is that these peptides are working at minute, femtomolar concentrations. ‘That’s extremely unusual’, he says. ‘It means that they are literally effective at the molecular level.’ And in his opinion, it suggests that they are operating by a different mechanism from other neuroprotective agents, such as nerve growth factor. ‘NAP is a thousand times more potent than any growth factor.’ Laura Spinney Freelance science writer *For more news from FASEB’s Experimental Biology ’99 conference, check out BioMedNews at: http://www.biomednet.com/biomednews/ 1999/FASEB
Rapid update When grafts don’t fight back Bone marrow transplants carry not only a risk of the recipient rejecting the graft but also of the graft rejecting the recipient – a phenomenon known as graft-versus-host disease (GvHD). A study by Eva C. Guinan and colleagues at the Dana-Farber Cancer Institute and Harvard Medical School (Boston, MA, USA), published in the 3 June issue of the New England Journal of Medicine, reports the transplantation of histoincompatible bone marrow into 12 patients. A state of anergy was induced in the donor cells before transplantation by incubating them with the recipients’ peripheral-blood lymphocytes and CTLA-4-Ig, an agent that inhibits T-cell co-stimulation by blocking B7–CD28 interactions. Although seven of the patients have since died of causes unrelated to GvHD, five are in remission and free of GvHD up to 31 months after their operations. It is hoped that this work will open the door to a universal pool of transplant donors. Australians rate medical research above the Olympics In a poll commissioned by the Australian Society for Medical Research and the Australian pharmaceutical Company AMRAD, most Australians considered medical research funding to be more important than funding for the next Olympic Games, and 70% said that they would pay more tax to fund Australian Medical Research. Shifting genes by flexing muscles Mutations in mitochondrial DNA are a common cause of mitochondrial myopathy in adults, but in most cases a mixture of normal and mutant mitochondria coexist (heteroplasmy). Owing to selection, the satellite cells that give rise to myofibers tend to have mostly normal mitochondria, whereas the myofibers themselves, which are postmitotic, tend to have mostly mutant mitochondria. Tanja Taivassalo and colleagues at the Montreal Neurological Institute (McGill University, Montreal, Canada) managed to shift the genotype of the muscle in a patient with mitochondrial myopathy, using concentric resistance exercise training. This caused the satellite cells to re-enter the cell cycle and fuse with myofibers, thereby providing them with a dose of normal mitochondria. The results of this study are published in the June issue of Human Molecular Genetics. Catherine Brooksbank Molecular Medicine Today
1357-4310/99/$ - see front matter © 1999 Elsevier Science. All rights reserved.
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MOLECULAR MEDICINE TODAY, JULY 1999 (VOL. 5)
New peptides prevent brain damage American scientists have discovered a class of neuropeptides that prevent damage caused by alcohol in the developing fetal brain. Their findings, which were presented at FASEB’s Experimental Biology ’99 conference*, provide a model for the role of these proteins in protecting against oxidative stress, and could have implications for the treatment of a variety of neurodegenerative diseases. Fetal Alcohol Syndrome (FAS) affects 12 000 babies in the USA every year. Stunted growth, reduced brain weight and mental deficiency characterize it, with sufferers typically showing an IQ of ~70. After genetic causes, maternal alcohol consumption is the most common cause of mental retardation, and consuming more than three units of alcohol a week can double the risk of miscarriage. Exposure to alcohol causes cell death in the embryonic neuroepithelium – the outer layer of the developing neural tube – and FAS has been associated with oxidative stress and an increase in the production of free radicals. Catherine Spong and co-workers in Douglas Brenneman’s lab (National Institutes of Health, Bethesda, MD, USA), and their collaborators in Illana Gozes’ group (Tel Aviv University, Tel Aviv, Israel), thought the condition might make a good model for testing a protein that they suspected of having antioxidant, neuroprotective properties. The protein, vasoactive intestinal peptide (VIP), has been the object of intense scrutiny in Brenneman’s lab for almost two decades now. Despite its name, it is found in the brain and is known to regulate early embryonic growth in the mouse. Receptors for VIP are found in the floorplate of the embryonic neural tube, where their action is mediated by several other proteins, including activity dependent neurotrophic factor (ADNF) and another similar molecule called activity dependent neurotrophic protein (ADNP). Both ADNF and ADNP are secreted by glial cells in the neuroepithelium, and Brenneman’s team has extracted from them their active components, known as SAL and NAP (named after the first three amino acids of each fragment), respectively. The purpose of these most recent experiments was to see if these two protein fragments could prevent the symptoms of alcohol exposure in a mouse model of FAS. The researchers treated pregnant mice with NAP, SAL, or a combination of both, 30 minutes before injecting them with alcohol. They chose the eighth day of embryogenesis to do so because 282
that is the gestational stage when the neural tube is closing and the embryo is most vulnerable to oxidative stress. After ten days, they measured the number of miscarriages and the weights of surviving fetuses in each group. And they found a dramatic effect. In mice treated with alcohol alone, 36% of the fetuses had been miscarried compared with 4% of the untreated controls. But in mice pre-treated with NAP, or both NAP and SAL, the death rate decreased to control levels. Alcohol alone caused a reduction in both fetal brain and body weight but the NAP–SAL combination also brought these back to control levels. In a further experiment, Spong’s team found that pre-treatment with NAP and SAL prevented the decline in VIP mRNA seen in the alcohol-treated mice. ‘This stuff is doing something extraordinary to an oxidatively stressed developing animal’, says Brenneman. In the mouse, embryogenesis day eight is associated with the highest incidence of fetal abnormalities and deaths. It corresponds to the end of the first month of pregnancy in humans – as Spong points out, ‘before you even know you’re pregnant.’ So the findings have serious implications for the prevention of FAS and, potentially, other conditions caused by oxidative stress. NAP is completely conserved between mice and humans. And the fact that it is found in the cortex, cerebellum and hippocampus, areas known to be important in learning and memory, means that it could also play a role in neurodegenerative diseases such as Alzheimer’s. According to Brenneman, there is already research to show that when a new born rat is treated with NAP, its ability to learn reflexes improves. But the most exciting thing of all is that these peptides are working at minute, femtomolar concentrations. ‘That’s extremely unusual’, he says. ‘It means that they are literally effective at the molecular level.’ And in his opinion, it suggests that they are operating by a different mechanism from other neuroprotective agents, such as nerve growth factor. ‘NAP is a thousand times more potent than any growth factor.’ Laura Spinney Freelance science writer *For more news from FASEB’s Experimental Biology ’99 conference, check out BioMedNews at: http://www.biomednet.com/biomednews/ 1999/FASEB
Rapid update When grafts don’t fight back Bone marrow transplants carry not only a risk of the recipient rejecting the graft but also of the graft rejecting the recipient – a phenomenon known as graft-versus-host disease (GvHD). A study by Eva C. Guinan and colleagues at the Dana-Farber Cancer Institute and Harvard Medical School (Boston, MA, USA), published in the 3 June issue of the New England Journal of Medicine, reports the transplantation of histoincompatible bone marrow into 12 patients. A state of anergy was induced in the donor cells before transplantation by incubating them with the recipients’ peripheral-blood lymphocytes and CTLA-4-Ig, an agent that inhibits T-cell co-stimulation by blocking B7–CD28 interactions. Although seven of the patients have since died of causes unrelated to GvHD, five are in remission and free of GvHD up to 31 months after their operations. It is hoped that this work will open the door to a universal pool of transplant donors. Australians rate medical research above the Olympics In a poll commissioned by the Australian Society for Medical Research and the Australian pharmaceutical Company AMRAD, most Australians considered medical research funding to be more important than funding for the next Olympic Games, and 70% said that they would pay more tax to fund Australian Medical Research. Shifting genes by flexing muscles Mutations in mitochondrial DNA are a common cause of mitochondrial myopathy in adults, but in most cases a mixture of normal and mutant mitochondria coexist (heteroplasmy). Owing to selection, the satellite cells that give rise to myofibers tend to have mostly normal mitochondria, whereas the myofibers themselves, which are postmitotic, tend to have mostly mutant mitochondria. Tanja Taivassalo and colleagues at the Montreal Neurological Institute (McGill University, Montreal, Canada) managed to shift the genotype of the muscle in a patient with mitochondrial myopathy, using concentric resistance exercise training. This caused the satellite cells to re-enter the cell cycle and fuse with myofibers, thereby providing them with a dose of normal mitochondria. The results of this study are published in the June issue of Human Molecular Genetics. Catherine Brooksbank Molecular Medicine Today
1357-4310/99/$ - see front matter © 1999 Elsevier Science. All rights reserved.