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3-substituted indolones as novel therapeutic compounds for neurodegenerative conditions
October 29, 2008Neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS), disrupt the quality of life for patients, put a tremendous burden on family caregivers, and cost society billions of dollars annually. The most consistent risk factor for developing neurodegenerative disease is aging. Because of the dramatic increase in life expectancy, the incidence of individuals afflicted with the aging-associated disorders is on the rise representing a major health problem. A commonality shared among this diverse set of disorders is the progressive and relentless loss of certain populations of neurons. Current medications for neurodegenerative diseases alleviate only the symptoms associated with these diseases but do not affect the underlying cause - degeneration of neurons. Because neuronal loss continues unabated, such palliative treatments have no effect on disease progression. The identification of small-molecule inhibitors of neuronal death is thus of urgent and critical importance.
In the November issue of EBM, researchers at the University of Texas at Dallas and Southern Methodist University have identified a class of compounds, 3-substituted indolones, that can protect neurons from degeneration. Furthermore, the group has conducted a structure-activity relationship study to identify substituent groups that are important for neuroprotective efficacy. A previous study by the same group demonstrated that one of these 3-substituted indolones, called GW5074, prevents neurodegeneration and improves behavioral outcome in a mouse model of neurodegeneration. The senior author, Dr. Santosh D'Mello said "More recent but unpublished work by our group and Doris Kretzschmar, a collaborator at the Oregon Health and Science University, found that GW5074 and other related 3-substituted indolones are also protective in a fly model of Alzheimer's disease. " The current study identifies several compounds that are more efficacious than GW5074 and that display no cytotoxicity even when used at high doses. These 3-substituted indolones are thus novel and promising candidate therapeutic agents for pre-clinical testing against human neurodegenerative conditions. According to Dr. D'Mello, "Studies into the mechanisms underlying neuronal apoptosis has identified several molecules that can be targeted in developing drugs to treat neurodegenerative diseases. Some of these have been tested in human clinical studies but have not proven to be effective at reducing neurodegeneration in patients. Our study has identified some 3-substituted indolones that might be suitable for development as therapeutic agents. The structure-activity relationship analysis we have described in our report, although not exhaustive, also provides useful information on which other efficacious 3-substituted indolones can be synthesized and tested in pre-clinical and clinical studies".
Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine, said "The work by D'Mello and colleagues has provided the basis for testing new versions of 3-substituted indolones for efficacy in the treatment of Alzheimer's disease and other neurodegenerative disorders. These drugs provide promising new therapeutic approaches to deal with the underlying cause of these disorders: neuronal cell death."
Society for Experimental Biology and Medicine
Society for Experimental Biology and Medicine
Neurodegenerative Disease Current Events and Neurodegenerative Disease News RSSNovel mouse gene reduces major pathologies associated with Alzheimer's disease
A new study reveals that a previously undiscovered mouse gene reduces the two major pathological perturbations commonly associated with Alzheimer's disease (AD).
Mouse gene suppresses Alzheimer's plaques and tangles
Investigators at Burnham Institute for Medical Research (Burnham) and colleagues have identified a novel mouse gene (Rps23r1) that reduces the accumulation of two toxic proteins that are major players in Alzheimer's disease: amyloid beta and tau.
Widely used cholesterol-lowering drug may prevent progression
Simvastatin, a commonly used, cholesterol-lowering drug, may prevent Parkinson's disease from progressing further. Neurological researchers at Rush University Medical Center conducted a study examining the use of the FDA-approved medication in mice with Parkinson's disease and found that the drug successfully reverses the biochemical, cellular and anatomical changes caused by the disease.
Member of NFL Hall of Fame diagnosed with degenerative brain disease
The Center for the Study of Traumatic Encephalopathy (CSTE) at Boston University School of Medicine (BUSM) announced today that a recently deceased member of the NFL Hall of Fame suffered from the degenerative brain disease Chronic Traumatic Encephalopathy (CTE) when he died, becoming the 10th former NFL player diagnosed with the disease.
First former college football player diagnosed with CTE
The Center for the Study of Traumatic Encephalopathy (CSTE) at Boston University School of Medicine (BUSM) announced today that a deceased former college football player who died at age 42 was already suffering from the degenerative brain disease, Chronic Traumatic Encephalopathy (CTE).
Natural compounds, chemotherapeutic drugs may become partners in cancer therapy
Research in the Linus Pauling Institute at Oregon State University suggests that some natural food compounds, which previously have been studied for their ability to prevent cancer, may be able to play a more significant role in treating it - working side-by-side with the conventional drugs that are now used in chemotherapy.
August 10, 2009 New Class of Compounds Discovered for Potential Alzheimer's Disease Drug, Penn Study Finds
A new class of molecules capable of blocking the formation of specific protein clumps that are believed to contribute to the dementia of Alzheimer's disease (AD) patients has been discovered by researchers at the University of Pennsylvania School of Medicine.
Caffeine reverses memory impairment in Alzheimer's mice
Coffee drinkers may have another reason to pour that extra cup. When aged mice bred to develop symptoms of Alzheimer's disease were given caffeine - the equivalent of five cups of coffee a day - their memory impairment was reversed.
Huntington's disease deciphered
Researchers at the University of Illinois at Chicago College of Medicine have discovered how the mutated huntingtin gene acts on the nervous system to create the devastation of Huntington's disease.
What separates dangerous blood vessel plaques from benign ones
Researchers say they have evidence to explain what separates your average blood vessel plaque from those that are at high risk for triggering the development of dangerous-even fatal-blood clots.
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Neurodegenerative Diseases and Metal Ions: Metal Ions in Life Sciences by Astrid Sigel (Editor), Helmut Sigel (Editor), Roland K. O. Sigel (Editor) About the Series... Metal Ions in Life Sciences links coordination chemistry and biochemistry in their widest sense and thus increases our understanding of the relationship between the chemistry of metals and life processes. The series reflects the interdisciplinary nature of Biological Inorganic Chemistry and coordinates the efforts of scientists in fields like biochemistry, inorganic chemistry, coordination chemistry, molecular and structural biology, enzymology, environmental chemistry, physiology, toxicology, biophysics, pharmacy, and medicine. Consequently, the volumes are an essential source for researchers active in these and related fields as well as teachers preparing courses, e.g., in Bioinorganic Chemistry. About this Book... Volume 1, devoted... |
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Fatal Attractions: Protein Aggregates in Neurodegenerative Disorders (Research and Perspectives in Alzheimer's Disease) by V.M.-Y. Lee (Editor), J.Q. Trojanowski (Editor), L. Buee (Editor), Y. Christen (Editor) In this volume are contributions based on a meeting arranged by the WHO and the Fondation IPSEN. The scientists focus on neurodegenerative disorders like Alzheimer's Disease, Chromosome 17-Linked Dementia, Parkinson's Disease and disorders with tauopathies. |
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Glutamine Repeats and Neurodegenerative Diseases: Molecular Aspects by Peter S. Harper (Editor), Max Perutz (Editor) (The Royal Society) Univ. of Wales, Cardiff, UK. Molecular biology text focuses on the discovery of a common pathogenic basis for a group of genetically inherited disorders, including Huntington's Disease. Discusses how these diseases share certain molecular similarities, what causes neurodegeneration to begin, and other important discoveries. For researchers and clinicians. |
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So Much So Fast Starring: Stephen Heywood, Jamie Heywood Directed By: Steven Ascher;Jeanne Jordan What would you do if you were 29 and found you may only have a few years to live? So Much So Fast is about the remarkable events set in motion when Stephen Heywood discovers he has ALS (Lou Gehrig's disease) and his brother Jamie becomes obsessed with finding a cure. |
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Molecular Mechanisms of Neurodegenerative Diseases (Contemporary Clinical Neuroscience) by Marie-Francoise Chesselet (Editor) Univ. of California, Los Angeles. First volume in this series. Synthesizes novel ideas and concepts emerging to create a fresh understanding of neurodegenerative disorders, details mechanistic similarities in Alzheimer's, Parkinson's, and related diseases. DNLM: Neurodegenerative Diseases--genetics. |
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Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection (Heat Shock Proteins) by Alexzander A.A. Asea (Author), Alexzander A.A. Asea (Editor), Ian R. Brown (Editor) With the prevalence of neurodegenerative diseases on the rise as average life expectancy increases, the hunt for effective treatments and preventive measures for these disorders is a pressing challenge. Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis have been termed 'protein misfolding disorders' that are characterized by the neural accumulation of protein aggregates. Manipulation of the cellular stress response involving the induction of heat shock proteins offers a therapeutic strategy to counter conformational changes in neural proteins that trigger pathogenic cascades resulting in neurodegenerative diseases. Heat shock proteins are protein repair agents that provide a line of defense against misfolded,... |
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Intracellular Traffic and Neurodegenerative Disorders (Research and Perspectives in Alzheimer's Disease) by Peter H. St.George-Hyslop (Editor), William C. Mobley (Editor), Yves Christen (Editor) This book explores the role of sub-cellular trafficking in the pathogenesis, treatment and prevention of neurodegenerative diseases. Recent findings point to faulty trafficking as contributing to the dysfunction and degeneration of neurons and neural circuits. Increasingly, research is targeting the mechanisms responsible and means to address them therapeutically. This book investigates the ways in which sub-cellular trafficking pathways play a role both in the pathological accumulation of these misfolded proteins and in attempts to clear them. Because subcellular protein trafficking has an important role in the biology of neuronal function and survival, this also addresses how trophic factors maintain cell, including cell interactions and how the underlying mechanisms may be compromised... |
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