New small-molecule drug restores brain function, memory in mouse model of Alzheimer's disease

In continuation of my update  on canola oil

An international team of researchers has shown that a new small-molecule drug can restore brain function and memory in a mouse model of Alzheimer's disease. The drug works by stopping toxic ion flow in the brain that is known to trigger nerve cell death. Scientists envision that this drug could be used to treat Alzheimer's and other neurodegenerative diseases such as Parkinson's and ALS.

"This is the first drug molecule that can regulate memory loss by directly blocking ions from leaking through nerve cell membranes," said Ratnesh Lal, a professor of bioengineering at the University of California San Diego and co-senior author of the study.

Various studies have linked Alzheimer's disease to the accumulation of two particular proteins in the brain called amyloid-beta and tau. One theory is that these protein clusters create pores in nerve cell membranes that allow ions to travel in and out uncontrollably. This would alter ion levels inside the cells and in turn trigger neuronal dysfunction and cell death.

The new drug, a small molecule called anle138b, blocks these pores from moving ions in and out of nerve cells. Anle138b attaches to both amyloid-beta and tau protein clusters and deactivates the pores created by these clusters.

Researchers administered anle138b to mice with a genetic predisposition for developing an Alzheimer's-like condition. The mice had symptoms such as abnormal brain function, impaired memory and high levels of either amyloid-beta or tau proteins in the brain. Treatment with anle138b normalized brain activity and improved learning ability in mice.

The study was led by the German Center for Neurodegenerative Diseases, the University Medical Center Göttingen, the Braunschweig University of Technology, the Max Planck Institute for Biophysical Chemistry, the Center for Nanoscale Microscopy and Molecular Physiology of the Brain in Göttingen, Germany, and the University of California San Diego. Researchers published their findings on Dec. 5 in EMBO Molecular Medicine.

Christian Griesinger, a professor at the Max Planck Institute for Biophysical Chemistry and co-senior author of the study, noted, "The drug is able to reach the brain when taken orally. Therefore, it is easy to administer, and we are currently performing toxicology studies to eventually be able to apply anle138b to humans."

The team cautions that since the drug has so far only been tested in mice, it is unclear how well it would perform in humans. "I would like to emphasize that none of the current animal models fully recapitulate the symptoms seen in Alzheimer's patients. Thus, care has to be taken when interpreting such data. However, our study offers evidence that anle138b has potential for neuroprotection," said André Fischer, a senior researcher at the German Center for Neurodegenerative Diseases and the University Medical Center Göttingen, who is also a co-senior author of the study.

While collaborators in Germany will be pursuing clinical studies in human patients with neurodegenerative diseases, Lal and his research group at the UC San Diego Jacobs School of Engineering are particularly interested in testing anle138b on a variety of other diseases that are linked to toxic ion flow caused by amyloid proteins, including diabetes, tuberculosis and certain types of cancer. Lal's group has performed extensive research on amyloid ion channels and their roles in these diseases. "Blocking the ion leakiness of amyloid channels using anle138b could be an effective therapy for various diseases," Lal said.

Lal serves as co-director for the Center of Excellence for Nanomedicine and Engineering, a subcenter of the Institute of Engineering in Medicine at UC San Diego. His research group will also work on targeted delivery of the drug using their patent pending "nanobowls," which are magnetically guided nanoparticles that can be packed with drugs and diagnostic molecules, deliver them to particular sites in the body and release them on demand. Future studies will focus on using these nanobowls to deliver anle138b to the brain, as well as other diseased tissues and organs affected by toxic amyloid-beta ion channels.

http://ucsdnews.ucsd.edu/pressrelease/experimental_drug_block_toxic_ion_flow_linked_to_alzheimers_disease

New small-molecule drug restores brain function, memory in mouse model of Alzheimer's disease

Study finds no beneficial effect of cancer medication on Alzheimer's disease

Bexarotene (brand name: Targretin) is an antineoplastic (anti-cancer) agent approved by the U.S.Food and Drug Administration (FDA) (in late 1999) and the European Medicines Agency (EMA) (early 2001) for use as a treatment for cutaneous T cell lymphoma (CTCL). It is a third-generation retinoid.

Study finds no beneficial effect of cancer medication on Alzheimer's disease: The cancer medication bexarotene, aka Targretin, made headlines when researchers reported that it quickly lowered Aβ in the brain, reduced amyloid plaques, and improved learning and memory in mice that mimic salient features of Alzheimer's disease (AD).

Olive ingredients may prevent Alzheimer's disease

It has long been proven that people who follow a Mediterranean diet and keep physically and mentally active are less likely to suffer from dementia. Olives in particular appear to play a key role in this regard. But just what are the substances contained in these small, oval fruit that are so valuable? This is what a Hessen-based group of researchers from the Goethe University Frankfurt, the Technical University (TU) of Darmstadt and Darmstadt company N-Zyme BioTec GmbH intends to find out. The three-year project "NeurOliv" has a project volume of 1.3 million Euros and is funded by the Federal Ministry of Education and Research as part of the high-tech initiative "KMU-innovativ Biochance".

This collaboration combines a number of approaches, the initiative of which came from N-Zyme BioTec GmbH. The aim is to use substances contained in olives to develop new functional food for the ageing society, which will protect against Alzheimer's disease. "We want to test whether olive polyphenols can even help to cure the disease. This is why we believe our products also relate to the pharmaceutical sector", says Dr. Joachim Tretzel, Managing Director of N-Zyme BioTec GmbH. The high-tech initiative of the German government was set up to fund small and medium-sized enterprises.

Olive oil : http://www.oliveoilsource.com/page/what-olive-oil

Olive ingredients may prevent Alzheimer's disease

Promising new natural treatment for Alzheimer's disease nears clinical trial

 

A promising new natural treatment for Alzheimer's disease is moving toward clinical trials. This will be a major step forward as there is nothing on the market that slows the progression of Alzheimer's.

Muraleedharan Nair, Michigan State University natural products chemist, has patented a botanical compound, withanamides. His spinoff company, Natural Therapeutics, will begin the trials as soon as funding is in place.

To date, none of the major pharmaceutical companies - Merck, Eli Lilly, Bristol-Myers Squibb - have been able to produce an effective treatment that passed human clinical trials, Nair said.

"This particular research has focused on Ashwagandha, an herbal remedy that's been used in Eastern medicines for centuries," he said. "Our compound withanamides may work to prevent Alzheimer's disease at the onset, and it also could prevent its progression."

While plants cannot be patented, compounds from it can. MSU holds the patent for withanamides, and earlier research revealed that the compound, found in the plants' seeds, proved to be a powerful anti-oxidant - double the strength of what's on today's market. The potent compound has shown that it can protect cells against damaging attacks by a rogue protein ¬- the earliest stage of Alzheimer's.

Alzheimer's begins when a specific protein starts breaking, or cleaving, at the wrong place to produce an unwanted fragment. This bad fragment, called BAP, stresses cells' membranes, sparks plaque formation and eventually kills the cells. This attack begins in the frontal lobe, erasing memories and continuing its unrelenting assault deeper into the brain.

A complicating factor is that the majority of protein cleaving is a natural, healthy process. Pharmaceutical companies, however, have focused their efforts on blocking the tiny faction of bad cleaving of the protein producing BAP.

Promising new natural treatment for Alzheimer's disease nears clinical trial

Study: Prostate cancer drug stabilizes memory loss for a year in women with Alzheimer's disease

Women with Alzheimer's disease showed stable cognition for a year when a drug that is more commonly used to treat advanced prostate cancer was added to their drug regimen, according to a new study from researchers at the University of Wisconsin-Madison.

"This is the first time any therapy has been shown to stabilize memory loss over a year," says Dr. Craig Atwood, co-lead author of the study and associate professor of medicine at the UW School of Medicine and Public Health.

 

The study was published today in the Journal of Alzheimer's Disease and is available here: http://iospress.metapress.com/content/n207096671247200.

The clinical trial, initiated by Dr. Richard Bowen at the former Voyager Pharmaceutical Corporation, followed 109 women with mild to moderate Alzheimer's disease. Some were treated with the drug leuprolide acetate (Lupron Depot first above structure), used to treat cancer in men and severe endometriosis in women, and with an acetylcholineesterase inhibitor such as Aricept (second below structure), which improves mood in people with the condition but does little to slow memory loss. Others taking an acetylcholineesterase inhibitor received low-dose Lupron alone or a placebo.

Study: Prostate cancer drug stabilizes memory loss for a year in women with Alzheimer's disease

Compound reverses symptoms of Alzheimer's disease in mice

"It reversed learning and memory deficits and brain inflammation in mice that are genetically engineered to model Alzheimer's disease," Farr said. "Our current findings suggest that the compound, which is called antisense oligonucleotide (OL-1), is a potential treatment for Alzheimer's disease."

Farr cautioned that the experiment was conducted in a mouse model. Like any drug, before an antisense compound could be tested in human clinical trials, toxicity tests need to be completed.

Antisense is a strand of molecules that bind to messenger RNA, launching a cascade of cellular events that turns off a certain gene.

In this case, OL-1 blocks the translation of RNA, which triggers a process that keeps excess amyloid beta protein from being produced. The specific antisense significantly decreased the over expression of a substance called amyloid beta protein precursor, which normalized the amount of amyloid beta protein in the body. Excess amyloid beta protein is believed to be partially responsible for the formation of plaque in
the brain of patients who have Alzheimer's disease.

Scientists tested OL-1 in a type of mouse that overexpresses a mutant form of the human amyloid beta precursor gene. Previously they had tested the substance in a mouse model that has a natural mutation causing it to overproduce mouse amyloid beta. Like people who have Alzheimer's disease, both types of mice have age-related impairments in learning and memory, elevated levels of amyloid beta protein that stay in the brain and increased inflammation and oxidative damage to the hippocampus  the part of the brain responsible for learning and memory.

"To be effective in humans, OL-1 would need to be effective at suppressing production of human amyloid beta protein," Farr said.

Scientists compared the mice that were genetically engineered to overproduce human amyloid beta protein with a wild strain, which served as the control. All of the wild strain received random antisense, while about half of the genetically engineered mice received random antisense and half received OL-1. 

The mice were given a series of tests designed to measure memory, learning and appropriate behavior, such as going through a maze, exploring an unfamiliar location and recognizing an object. 

Scientists found that learning and memory improved in the genetically engineered mice that received OL-1 compared to the genetically engineered mice that received random antisense. Learning and memory were the same among genetically engineered mice that received OL-1 and wild mice that received random antisense.

They also tested the effect of administering the drug through the central nervous system, so it crossed the blood brain barrier to enter the brain directly, and of giving it through a vein in the tail, so it circulated through the bloodstream in the body. They found where the drug was injected had little effect on learning and memory.

Ref http://iospress.metapress.com/content/px72758w0158103u/?issue=4&genre=article&spage=1005&issn=1387-2877&volume=40

1. 
   

1. 
   

Compound
reverses symptoms of Alzheimer's disease in mice  

'Peanut butter' test can help diagnose Alzheimer's disease, researchers find

A dollop of peanut butter and a ruler can be used to confirm a diagnosis of early stage Alzheimer's disease, University of Florida Health researchers have found...

Of the 24 patients tested who had mild cognitive impairment, which sometimes signals Alzheimer's disease and sometimes turns out to be something else, about 10 patients showed a left nostril impairment and 14 patients did not. The researchers said more studies must be conducted to fully understand the implications.

"At the moment, we can use this test to confirm diagnosis," Stamps said. "But we plan to study patients with mild cognitive impairment to see if this test might be used to predict which patients are going to get Alzheimer's disease."

Stamps and Heilman point out that this test could be used by clinics that don't have access to the personnel or equipment to run other, more elaborate tests required for a specific diagnosis, which can lead to targeted treatment. At UF Health, the peanut butter test will be one more tool to add to a full suite of clinical tests for neurological function in patients with memory disorders.

'Peanut butter' test can help diagnose Alzheimer's disease, researchers find

Ref : http://dx.doi.org/10.1016/j.jns.2013.06.033

Diabetes drug rosiglitazone, improves memory, study suggests

In continuation of my update on rosiglitazone 

Working with genetically engineered mice designed to serve as models for Alzheimer's, University of Texas Medical Branch at Galveston researchers found that treatment with the anti-insulin-resistance drug rosiglitazone enhanced learning and memory as well as normalized insulin resistance. The scientists believe that the drug produced the response by reducing the negative influence of Alzheimer's on the behavior of a key brain-signaling molecule.

"Using this drug appears to restore the neuronal signaling required for proper cognitive function," said UTMB professor Larry Denner, the lead author of a paper describing this work now online in the Journal of Neuroscience. "It gives us an opportunity to test several FDA-approved drugs to normalize insulin resistance in Alzheimer's patients and possibly also enhance memory, and it also gives us a remarkable tool to use in animal models to understand the molecular mechanisms that underlie cognitive issues in Alzheimer's."

Ref : http://www.utmb.edu/newsroom/article8071.aspx

Diabetes drug improves memory, study suggests

Scientists Discover Drug Candidate for Alzheimer’s, Huntington’s

Scientists at the Gladstone Institutes have identified a drug candidate that diminishes the effects of both Alzheimer's disease and Huntington's disease in animal models, offering new hope for patients who currently lack any medications to halt the progression of these two debilitating illnesses.

Gladstone Investigator Paul Muchowski, PhD, has identified a new compound called JM6 in experiments done in collaboration with an international team of researchers, and which are being published today in an online article in Cell. In laboratory tests involving mice genetically engineered to model one or the other of the two diseases, Dr. Muchowski's team found that JM6 blocks kynurenine 3-monooxygenase (KMO), an enzyme that has long been speculated to play a role in neurodegenerative diseases.

In mice modeling Alzheimer's disease, the novel compound prevented memory deficits and the loss of synaptic connections between brain cells—both of which are key features of the human disease. In mice modeling Huntington's disease, JM6 prevented brain inflammation and the loss of synaptic connections between brain cells, while also extending lifespan.

“This discovery has significant implications for two devastating diseases and suggests that the KMO enzyme is a good protein for us to target with medications in diverse neurodegenerative disorders,” said Lennart Mucke, MD, who oversees all neurological research at Gladstone and who won the prestigious Potamkin Prize last year for developing experimental strategies to make the brain more resistant to Alzheimer's. “With any luck, Dr. Muchowski and his colleagues could begin testing this drug in patients within the next two years.”

Remarkably, JM6 (see structure) does not penetrate into the brain, but works by inhibiting KMO in the blood. The blood cells then send a protective signal to the brain, to stabilize brain-cell function and prevent neurodegeneration. The fact that the compound does not pass the so-called blood-brain barrier will facilitate testing in patients, as JM6's potential impact could be confirmed with a simple blood test.

JM6 was named for Dr. Muchowski's father, Dr. Joseph Muchowski, PhD, a retired medicinal chemist who helped his son devise the novel KMO inhibitor. The study was carried out in collaboration with the laboratories of Dr. Robert Schwarcz, a University of Maryland School of Medicine professor who pioneered studies linking KMO and metabolically related enzymes to nerve-cell loss, and Professor Eliezer Masliah at the University of California, San Diego, an expert in neuropathology.

 Ref : www.cell.com/abstract/S0092-8674(11)00581-2

Magnesium supplement helps boost brainpower ....

Neuroscientists at MIT and Tsinghua University in Beijing show that increasing brain magnesium with a new compound enhanced learning abilities, working memory, and short- and long-term memory in rats. The dietary supplement also boosted older rats’ ability to perform a variety of learning tests.

Magnesium, an essential element, is found in dark, leafy vegetables such as spinach and in some fruits. Those who get less than 400 milligrams daily are at risk for allergies, asthma and heart disease, among other conditions. In 2004, Guosong Liu and colleagues at MIT discovered that magnesium might have a positive influence on learning and memory. They followed up by developing a new magnesium compound — magnesium-L-threonate (see structure, MgT) — that is more effective than conventional oral supplements at boosting magnesium in the brain, and tested it on rats.  

“We found that elevation of brain magnesium led to significant enhancement of spatial and associative memory in both young and aged rats,” said Liu, now director of the Center for Learning and Memory at Tsinghua University. “ 

If MgT is shown to be safe and effective in humans, these results may have a significant impact on public health.” Liu is cofounder of Magceutics, a California-based company developing drugs for prevention and treatment of age-dependent memory decline and Alzheimer’s disease.

Magnesium supplement helps boost brainpower - MIT Media Relations

A Novel Neurotrophic Drug for Cognitive Enhancement and Alzheimer's Disease

A new drug candidate may be the first capable of halting the devastating mental decline of Alzheimer's disease.  The drug, known as J147 (above  structure), improved memory and prevented brain damage caused by the disease claims the researchers from Salk's Cellular Neurobiology Laboratory, lead by David Schubert. The new compound,  could be tested for treatment of the disease in humans in the near future.Researchers add that, J147 enhances memory in both normal and Alzheimer's mice and also protects the brain from the loss of synaptic connections.

Salk researchers went on to show that it prevented cognitive decline in animals with Alzheimer's and that mice and rats treated with the drug produced more of a protein called brain-derived neurotrophic factor (BDNF), a molecule that protects neurons from toxic insults, helps new neurons grow and connect with other brain cells, and is involved in memory formation.

Because of the broad ability of J147 to protect nerve cells, the researchers believe that it may also be effective for treating other neurological disorders, such as Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis (ALS), as well as stroke.

Although it is yet unknown whether the compound will prove safe and effective in humans, the Salk researchers' say their results suggest the drug may hold potential for treatment of people with Alzheimer's...

Ref : http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0027865

Salk scientists develop new drug that improves memory and prevents brain damage in mice

A new drug candidate may be the first capable of halting the devastating mental decline of Alzheimer's disease, based on the findings by a research group of Salk's Cellular Neurobiology Laboratory.

When given to mice with Alzheimer's, the drug, known as J147 (see structure), improved memory and prevented brain damage caused by the disease. The new compound, developed by scientists at the Salk Institute for Biological Studies, could be tested for treatment of the disease in humans in the near future.

"J147 enhances memory in both normal and Alzheimer's mice and also protects the brain from the loss of synaptic connections," says David Schubert, the head of Salk's Cellular Neurobiology Laboratory, whose team developed the new drug. "No drugs on the market for Alzheimer's have both of these properties."

Although it is yet unknown whether the compound will prove safe and effective in humans, the Salk researchers' say their results suggest the drug may hold potential for treatment of people with Alzheimer's.

More.....

New Alzheimer's Drug Shows Early Promise

An experimental Alzheimer's disease drug, gantenerumab, may help lower levels of amyloid plaque in the brains of people with the disease, an early clinical trial indicates. Researchers claims that, of 16 people with mild-to-moderate Alzheimer's disease, those who received two to seven infusions of the experimental drug every four weeks showed marked reductions in the amount of plaque in their brains via imaging tests that were conducted several months after their treatments.....

More...

Yale scientists synthesize huperzine A to combat Alzheimer's

Scientists at Yale University have developed the first practical method to create a compound called huperzine A  (see structure below) in the lab. Huperzine A is a naturally occurring sesquiterpene alkaloid compound found in the plant firmoss Huperzia serrata. Huperzine A is also an Acetylcholinesterase inhibitor, which has a mechanism of action similar to donepezil, rivastigmine, and galantamine. In the US, Huperzine A is sold as a dietary supplement for memory support. The botanical has been used in China for centuries for the treatment of swelling, fever and blood disorders. Clinical trials in China have shown it to be effective in the treatment of Alzheimer's disease and enhancing memory in students. 

More at : http://opac.yale.edu/news/article.aspx?id=8796