Scientists successfully test anti-alcoholism drug in animal models

Scientists at The University of Texas at Austin have successfully tested in animals a drug that, they say, may one day help block the withdrawal symptoms and cravings that incessantly coax people with alcoholism to drink. If eventually brought to market, it could help the more than 15 million Americans, and many more around the world who suffer from alcoholism stay sober.

If what has been shown to work in worms and rats addicted to alcohol can eventually be demonstrated to work in humans with minimal side effects, it would be a true breakthrough. Scientists point out, however, that the drug has more hoops to go through before that happens.

There are already drugs on the market prescribed to help people break their addiction to alcohol, but for many patients, they are not very effective and have negative side effects. The new drug, called JVW-1034, targets a different molecular pathway in the body and so far, in animal models, has no obvious side effects.

"There's clearly a huge need for something different and better," said James Sahn, research scientist in chemistry at UT Austin and co-first author of a new paper. "That's where our approach shines. It's modulating a pathway that doesn't seem to be associated with any of the other drugs that are available."

The researchers reported their findings in the journal Neuropsychopharmacology and have filed a patent on the drug.

The paper's other co-first authors are Luisa Scott, a research associate in neuroscience at UT Austin; and Antonio Ferragud, a postdoctoral associate at Boston University School of Medicine (BUSM). Senior authors are Stephen Martin, professor of chemistry, and Jonathan Pierce, associate professor of neuroscience, both at UT Austin; and Valentina Sabino, associate professor of pharmacology and psychiatry at BUSM.

While the drug is promising, the researchers plan to optimize its chemical properties to have a better chance of being effective in humans. They envision a pill that could one day be taken to block alcohol withdrawal symptoms and cravings, helping people avoid relapsing. But it isn't clear whether such a drug could actually cure alcoholism. That's because there are genetic and regulatory underpinnings to the disorder that researchers don't fully understand yet and that may not be permanently altered by this drug. But even a drug that could be taken chronically or in times of stress could have a huge benefit for people suffering from alcoholism.

"If we could achieve a medication that is effective for more people and doesn't have the negative side effects that some of these drugs have, that would be game-changing," said Martin.

It might also make a dent in the $250 billion annual cost of alcohol misuse in the U.S., as estimated by a 2015 study.

This work was supported by The Robert A. Welch Foundation, the Dell Medical School's Texas Health Catalyst program, donations from individuals including Tom Calhoon and June Waggoner through a crowdfunding program called Hornraiser, and the National Institute on Alcohol Abuse and Alcoholism.

Screening in Worm and Rat Models

The drug JVW-1034 was named in honor of James Virgil Waggoner, a UT Austin alumnus, businessman and philanthropist who donated funds to establish the university's Waggoner Center for Alcohol and Addiction Research.

It was one of many potential compounds developed in the lab by chemists Stephen Martin and James Sahn, which they suspected would interact with a cell receptor found throughout the central nervous systems of animals, called sigma 2. Other researchers had shown that that receptor was involved in cocaine addiction. So Martin and Sahn wondered whether it might also be involved in alcoholism.

To screen their compounds, their colleague Luisa Scott created hungover worms. She exposed C. elegans worms to alcohol for a day and then took it away. She could tell they were hungover because when she placed a tasty-smelling substance on the other side of their petri dish, they sluggishly meandered over.

"It smells like movie theater popcorn," Scott said. "Normal worms are quite speedy, but withdrawal worms go very slowly."

When she administered JVW-1034 to the hungover worms, they once again raced across the dish just like worms that had never been exposed to alcohol.

In follow-up experiments, Scott demonstrated that the receptor sigma 2 was in fact the target of JVW-1034. This also demonstrated for the first time that sigma 2 is involved in alcohol addiction. She noted that it can be difficult to identify which parts of an animal's cells a drug interacts with. In fact, scientists still don't know the targets of many drugs that have been in use for many years.

"So for me, being able to show that this really is the target it binds to, that's a big deal," she said.

Finally, a group of collaborators led by Valentina Sabino tested JVW-1034 in alcoholic rats. Alcoholic rats that could freely access alcohol and were then given JVW-1034 dramatically reduced their alcohol consumption.

The researchers are developing several other promising drugs that target the sigma 2 receptor to treat other neurological disorders, including traumatic brain injury, neuropathic pain and Alzheimer's disease.

Compound prevents neurological damage, shows cognitive benefits in mouse model of Alzheimer’s disease

The supplement nicotinamide riboside (NR) – a form of vitamin B3 – prevented neurological damage and improved cognitive and physical function in a new mouse model of Alzheimer’s disease. The results of the study, conducted by researchers at the National Institute on Aging (NIA) part of the National Institutes of Health, suggest a potential new target for treating Alzheimer’s disease. The findings appear in the Feb. 5, 2018, issue of Proceedings of the National Academy of Sciences.

NR acts on the brain by normalizing levels of nicotinamide adenine dinucleotide (NAD+), a metabolite vital to cellular energy, stem cell self-renewal, resistance to neuronal stress and DNA repair. In Alzheimer’s disease, the brain’s usual DNA repair activity is impaired, leading to mitochondrial dysfunction, lower neuron production, and increased neuronal dysfunction and inflammation.

“The pursuit of interventions to prevent or delay Alzheimer’s and related dementias is an important national priority,” said Richard J. Hodes, M.D., director of the NIA. “We are encouraging the testing of a variety of new approaches, and this study’s positive results suggest one avenue to pursue further.”

The international team of scientists was led by Vilhelm A. Bohr, M.D., Ph.D., senior investigator and chief of the Laboratory of Molecular Gerontology of the NIA’s Intramural Research Program, with Dr. Yujun Hou, a postdoctoral investigator in the laboratory.

Based on their studies in human postmortem brain, they developed a new strain of mice mimicking major features of human Alzheimer’s such as tau pathology, failing synapses, neuronal death and cognitive impairment. Using this animal model, the researchers tested the effects of an NR supplement by adding it to the drinking water of the mice. Over a three-month period, researchers found that mice who received NR showed reduced tau in their brains, but no change in amyloid-beta.

The NR-treated mice also had less DNA damage, higher neuroplasticity (activity and reorganization of brain cells associated with learning or memory), increased production of new neurons from neuronal stem cells, and lower levels of neuronal damage and death. In the hippocampus area of the brain – in which damage and loss of volume is found in people with dementia – NR seemed to either clear existing DNA damage or prevent it from spreading further.

The NR-treated mice also performed better than control mice on multiple behavioral and memory tests, such as water mazes and object recognition. NR mice also showed better muscular and grip strength, higher endurance, and improved gait compared to their control counterparts. The research team believes that these physical and cognitive benefits are due to a rejuvenating effect NR had on stem cells in both muscle and brain tissue.

“We are encouraged by these findings that see an effect in this Alzheimer’s disease model,” said Dr. Bohr. “We are looking forward to further testing of how NR or similar compounds might be pursued for their possible therapeutic benefit for people with dementia.”

Next steps for the research team include further studies on the underlying mechanisms and preparations towards intervention in humans.

The team’s work also included contributions from researchers at the Danish Aging Research Center at the University of Aarhus, and the Center for Healthy Aging at the University of Copenhagen. The Bohr lab has a Cooperative Research and Development Agreement -- which allows NIH investigators to join colleagues from industry and academia to pursue common research goals -- with ChromaDex Corp.

Compound prevents neurological damage, shows cognitive benefits in mouse model of Alzheimer’s disease

Diabetes drug holds promise of being developed into new treatment for Alzheimer's

A drug developed for diabetes could be used to treat Alzheimer's after scientists found it "significantly reversed memory loss" in mice through a triple method of action.

The research, published in Brain Research, could bring substantial improvements in the treatment of Alzheimer's disease through the use of a drug originally created to treat type 2 diabetes.

Lead researcher Professor Christian Holscher of Lancaster University in the UK said the novel treatment "holds clear promise of being developed into a new treatment for chronic neurodegenerative disorders such as Alzheimer's disease."

Alzheimer's disease is the most common cause of dementia and the numbers are expected to rise to two million people in the UK by 2051 according to Alzheimer's Society, who part- funded the research.

Dr Doug Brown, Director of Research and Development at Alzheimer's Society, said: ""With no new treatments in nearly 15 years, we need to find new ways of tackling Alzheimer's. It's imperative that we explore whether drugs developed to treat other conditions can benefit people with Alzheimer's and other forms of dementia. This approach to research could make it much quicker to get promising new drugs to the people who need them."

Although the benefits of these 'triple agonist' drugs have so far only been found in mice, other studies with existing diabetes drugs such as liraglutide have shown real promise for people with Alzheimer's, so further development of this work is crucial."

This is the first time that a triple receptor drug has been used which acts in multiple ways to protect the brain from degeneration. It combines GLP-1, GIP and Glucagon which are all growth factors. Problems with growth factor signaling have been shown to be impaired in the brains of Alzheimer's patients.

The study used APP/PS1 mice, which are transgenic mice that express human mutated genes that cause Alzheimer's. Those genes have been found in people who have a form of Alzheimer's that can be inherited. Aged transgenic mice in the advanced stages of neurodegeneration were treated.

In a maze test, learning and memory formation were much improved by the drug which also:-

• enhanced levels of a brain growth factor which protects nerve cell functioning
• reduced the amount of amyloid plaques in the brain linked with Alzheimer's
• reduced both chronic inflammation and oxidative stress
• slowed down the rate of nerve cell loss

Professor Holscher said: "These very promising outcomes demonstrate the efficacy of these novel multiple receptor drugs that originally were developed to treat type 2 diabetes but have shown consistent neuro- protective effects in several studies."

"Clinical studies with an older version of this drug type already showed very promising results in people with Alzheimer's disease or with mood disorders"

"Here we show that a novel triple receptor drug shows promise as a potential treatment for Alzheimer's but further dose-response tests and direct comparisons with other drugs have to be conducted in order to evaluate if this new drugs is superior to previous ones."

Type 2 diabetes is a risk factor for Alzheimer's and has been implicated in the progression of the disease. Impaired insulin has been linked to cerebral degenerative processes in type 2 diabetes and Alzheimer's disease. Insulin desensitisation has also been observed in the Alzheimer's disease brain. The desensitisation could play a role in the development of neurodegenerative disorders as insulin is a growth factor with neuroprotective properties.

Ref : http://www.research.lancs.ac.uk/portal/en/publications/-(ccd64550-72ab-4d4b-9e42-986da99f7b36).html

Diabetes drug holds promise of being developed into new treatment for Alzheimer's

FDA-approved drug to treat high blood pressure increases life span in worms

UT Southwestern Medical Center researchers find that an FDA-approved drug to treat high blood pressure seems to extend life span in worms via a cell signaling pathway that may mimic caloric restriction.

The drug, hydralazine, extended life span about 25 percent in two strains of C. elegans(roundworms), one a wild type and the other bred to generate high levels of a neurotoxic protein called tau that in humans is associated with Alzheimer's disease.

"This is the first report of hydralazine treatment activating the NRF2/SKN-1 signaling pathway. We found the drug extends the life span of worms as well as or better than other potential anti-aging compounds such as curcumin and metformin. The treatment also appeared to maintain their health as measured by tests of flexibility and wiggling speed," said Dr. Hamid Mirzaei, Assistant Professor of Biochemistry at UT Southwestern and senior author of the study, published today in Nature Communications.

The NRF2 pathway protects human cells from oxidative stress. The body's ability to protect itself against damaging oxygen free radicals diminishes with age, he said.

One of the hallmarks of aging and neurodegenerative diseases such as Alzheimer's and Parkinson's is oxidative stress, which is believed to result cumulatively from inflammatory and infectious illnesses throughout life, Dr. Mirzaei explained. SKN-1, a C. eleganstranscription factor, corresponds to NRF2 in humans. Both play a pivotal role in their respective species' responses to oxidative stress and life span, he said.

The UT Southwestern researchers were searching for a chemical probe they could use in experiments to identify proteins that get oxidized and become toxic during aging. Their screen for a substance that would cross the blood-brain barrier and be nontoxic led them to hydralazine.

"Age-related neurodegenerative diseases are devastating, and those conditions are on the rise due to the increase in the life span of humans. For that reason, it is important to develop treatments to maintain human health as long as possible," said Dr. Mirzaei, who is also an investigator in the Center for Alzheimer's and Neurodegenerative Diseases, part of the Peter O'Donnell Jr. Brain Institute at UT Southwestern.

http://www.utsouthwestern.edu/newsroom/articles/year-2017/hbp-drug.html

FDA-approved drug to treat high blood pressure increases life span in worms

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

Benzodiazepines linked to increased risk of death among Alzheimer’s disease patients

Benzodiazepine and related drug use is associated with a 40 per cent increase in mortality among persons with Alzheimer's disease, according to a new study from the University of Eastern Finland. The findings were published in the International Journal of Geriatric Psychiatry.

The study found that the risk of death was increased right from the initiation of benzodiazepine and related drug use. The increased risk of death may result from the adverse events of these drugs, including fall-related injuries, such as hip fractures, as well as pneumonia and stroke.

The study was based on the register-based MEDALZ (Medication Use and Alzheimer's Disease) cohort, which includes all persons diagnosed with Alzheimer's disease in Finland during 2005-2011. Persons who had used benzodiazepines and related drugs previously were excluded from this study, and therefore, the study population consisted of 10,380 new users of these drugs. They were compared with 20,760 persons who did not use these drugs.

Although several treatment guidelines state that non-pharmacological options are the first-line treatment of anxiety, agitation and insomnia in persons with dementia, benzodiazepines and related drugs are frequently used in the treatment of these symptoms. If benzodiazepine and related drug use is necessary, these drugs are recommended for short-term use only. These new results encourage more consideration for benzodiazepine and related drug use in persons with dementia.

Ref : https://www.uef.fi/en/-/bentsodiatsepiinit-lisaavat-kuolleisuutta-alzheimerin-tautia-sairastavilla

Benzodiazepines linked to increased risk of death among Alzheimer’s disease patients

Benzodiazepines linked to increased risk of death among Alzheimer’s disease patients

Benzodiazepine and related drug use is associated with a 40 per cent increase in mortality among persons with Alzheimer's disease, according to a new study from the University of Eastern Finland. The findings were published in the International Journal of Geriatric Psychiatry.

The study found that the risk of death was increased right from the initiation of benzodiazepine and related drug use. The increased risk of death may result from the adverse events of these drugs, including fall-related injuries, such as hip fractures, as well as pneumonia and stroke.

The study was based on the register-based MEDALZ (Medication Use and Alzheimer's Disease) cohort, which includes all persons diagnosed with Alzheimer's disease in Finland during 2005-2011. Persons who had used benzodiazepines and related drugs previously were excluded from this study, and therefore, the study population consisted of 10,380 new users of these drugs. They were compared with 20,760 persons who did not use these drugs.

Although several treatment guidelines state that non-pharmacological options are the first-line treatment of anxiety, agitation and insomnia in persons with dementia, benzodiazepines and related drugs are frequently used in the treatment of these symptoms. If benzodiazepine and related drug use is necessary, these drugs are recommended for short-term use only. These new results encourage more consideration for benzodiazepine and related drug use in persons with dementia.

Ref : https://www.uef.fi/en/-/bentsodiatsepiinit-lisaavat-kuolleisuutta-alzheimerin-tautia-sairastavilla

Benzodiazepines linked to increased risk of death among Alzheimer’s disease patients

Moderate coffee consumption more likely to provide beneficial health outcomes

In continuation of my update on coffee

Drinking coffee is "more likely to benefit health than to harm it" for a range of health outcomes, say researchers in The BMJ today.

They bring together evidence from over 200 studies and find that drinking three to four cups of coffee a day is associated with a lower risk of death and getting heart disease compared with drinking no coffee. Coffee drinking is also associated with lower risk of some cancers, diabetes, liver disease and dementia.

However, they say drinking coffee in pregnancy may be associated with harms, and may be linked to a very small increased risk of fracture in women.

The included studies used mainly observational data, providing lower quality evidence, so no firm conclusions can be drawn about cause and effect, but their findings back up other recent reviews and studies of coffee intake. As such, they say, excluding pregnancy and women at risk of fracture, "coffee drinking appears safe within usual patterns of consumption" and they suggest that coffee could be safely tested in randomised trials.

Coffee is one of the most commonly consumed beverages worldwide and could have positive health benefits. But existing evidence is of lower quality from observational research and randomized controlled trials are needed to strengthen the evidence of benefits.

To better understand the effects of coffee consumption on health, a team led by Dr Robin Poole, Specialist Registrar in Public Health at the University of Southampton, with collaborators from the University of Edinburgh, carried out an umbrella review of 201 studies that had aggregated data from observational research and 17 studies that had aggregated data from clinical trials across all countries and all settings.

Umbrella reviews synthesize previous meta-analyses and provide a high-level summary of research on a particular topic

Drinking coffee was consistently associated with a lower risk of death from all causes and from heart disease, with the largest reduction in relative risk of death at three cups a day, compared with non-coffee drinkers. Increasing consumption to above three cups a day was not associated with harm, but the beneficial effect was less pronounced.

Coffee was also associated with a lower risk of several cancers, including prostate, endometrial, skin and liver cancer, as well as type 2 diabetes, gallstones and gout. The greatest benefit was seen for liver conditions, such as cirrhosis of the liver.

Finally, there seemed to be beneficial associations between coffee consumption and Parkinson's disease, depression and Alzheimer's disease.

There was less evidence for the effects of drinking decaffeinated coffee but it had similar benefits for a number of outcomes.

Many of the included studies may have adjusted for factors that may be associated with both the health outcome and with coffee drinking, such as smoking. This was not comprehensive and varied from study to study. The authors can therefore not rule out the effect of such factors on the apparent harmful or beneficial associations.

The authors conclude that coffee drinking "seems safe within usual patterns of consumption, except during pregnancy and in women at increased risk of fracture." And they call for robust randomized controlled trials "to understand whether the key observed associations are causal."

In a linked editorial, Eliseo Guallar at the Johns Hopkins Bloomberg School of Public Health says, although we can be reassured that coffee intake is generally safe, doctors should not recommend drinking coffee to prevent disease - and people should not start drinking coffee for health reasons.

As this study shows, some people may be at higher risk of adverse effects, he writes, and there is "substantial uncertainty" about the effects of higher levels of intake. Finally, coffee is often consumed with products rich in refined sugars and unhealthy fats, "and these may independently contribute to adverse health outcomes," he adds.

However, even with these caveats, "moderate coffee consumption seems remarkably safe, and it can be incorporated as part of a healthy diet by most of the adult population," he concludes.

Ref : http://www.bmj.com/content/359/bmj.j5356

Moderate coffee consumption more likely to provide beneficial health outcomes

Drug that stimulates neuron pruning promotes goal-directed behavior in mice

A drug that stimulates neuron pruning can nudge mice away from habit-driven behaviors when combined with retraining, neuroscientists have found.

The results were published online on November 30 by Nature Communications.

The drug fasudil, approved in Japan for cerebral vasospasm and stroke, inhibits an enzyme that stabilizes cells' internal skeletons. The researchers suggest that fasudil or similar compounds could be effective tools for facilitating the treatment of drug abuse and preventing relapse.

A large fraction of the actions people perform each day come from habits, not from deliberate decision making. Going on auto-pilot can free up attention for new things, but it can also be detrimental, in the case of drug abuse and drug-seeking behavior, says lead author Shannon Gourley, PhD, assistant professor of pediatrics, psychiatry and behavioral sciences at Emory University School of Medicine and Yerkes National Primate Research Center.

"Some habits are adaptive - for example, turning off a light when you exit a room - but others can be maladaptive, for example in the case of habitual drug use. We wanted to try to figure out a way to help 'break' habits, particularly those related to the highly-addictive drug cocaine," says Gourley.

Gourley and former graduate students Andrew Swanson, PhD and Lauren Depoy, PhD tested fasudil in situations where they had trained mice to poke their noses in two chambers, based on rewards of both food and cocaine. Then the researchers changed the rules of the game. The mice had to learn something new, in terms of where to poke their noses to get the reward.

In particular, the mice could now only get a reward from one chamber instead of both. Fasudil helped the mice adjust and display "goal-directed" behavior, rather than their previous habit-based behavior.

In addition, the researchers trained the mice to supply themselves a sweet cocaine solution. Then they changed the nature of that experience: the cocaine was paired with lithium chloride, which made the mice feel sick. Fasudil treatment nudged the mice to give themselves less cocaine afterwards, rather than continuing to respond habitually. The scientists envision this as modeling negative experiences associated with cocaine use in humans.

"Humans may seek treatment due to the negative consequences of cocaine abuse, but many people still relapse. We're trying to strengthen the goal of abstaining from drug taking," says Gourley.

The researchers conducted additional experiments that revealed that fasudil didn't make cocaine itself less pleasurable, but was specifically modifying the habit process. Also, fasudil did not affect other forms of decision making.

Un-learning of habits involves remodeling connections made by cells in the brain. In the mouse retraining experiments, the way that fasudil seems to work is that it promotes the pruning of dendritic spines. Dendritic spines are structures that help neurons communicate and embody the strength of connections between them.

Fasudil inhibits Rho kinase, which stabilizes F-actin, a major component of cells' internal skeletons. Thus, it loosens up cell structures. And in mice, fasudil appears to slightly reduce the density of dendritic spines in a region of the brain that is important for learning new behaviors.

"In this context, we imagine that fasudil is optimizing signal-to-noise, so to speak, allowing this brain region to efficiently guide decision making," says Gourley.

When fasudil is given to the mice a day after training, no changes in spine density are seen, indicating that it must be paired with new learning to have that effect.

Some caution is order, because overactive synaptic pruning is proposed to play roles in Alzheimer's disease and schizophrenia. In their paper, the authors conclude:

Pairing Rho kinase inhibitors with cognitive behavioral therapy in humans could be an effective pharmacological adjunct to reduce the rate of relapse... Given its favorable safety profile and our evidence that it can mitigate cocaine self-administration, fasudil is a strong candidate, with the caveats that we envision it administered as an adjunct to behavioral therapy and potentially during early phases of drug withdrawal.

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Drug that stimulates neuron pruning promotes goal-directed behavior in mice

Two research studies on new molecules could potentially treat Alzheimer's disease

This year, results have been published of two significant research studies about molecules that could potentially treat Alzheimer's disease. The chief researcher in both studies was the head of the Laboratory of Medical Chemistry and Bioinformatics at MIPT Yan Ivanenkov. Papers on the two new molecules were published in Molecular Pharmaceutics and Current Alyheimer Research. Mark Veselov, another MIPT employee, also participated in the second study.

Both papers cover the study of neuroprotectors - antagonists to the 5-HT6R receptor. The latest research confirms that this target has a high therapeutic potential in the treatment of Alzheimer's disease. Preclinical studies on lab animals have shown that the compounds have a high selectivity.

Alzheimer's is one of the most widespread diseases in elderly people. People over the age of 60 are at the greatest risk of developing the disease, but it can also occur at a younger age. Patients suffer from loss of memory and cognitive functions; they become socially detached and lose their independence, and the body can no longer function properly, which inevitably leads to death. According to medical statistics, Alzheimer's is the cause of two out of every three cases of dementia in the elderly and it is a huge economic problem in developed countries - the financial impact in the US, for example, is higher than for cancer or cardiovascular diseases.

Scientists have not yet succeeded in finding an effective cure for Alzheimer's. Despite the fact that we know how the disease develops, we cannot say that we are even close to a solution. Pharmaceutical studies are still being conducted in order to be able to reduce the symptoms of the disease.

In the first paper, specialists Alexander Ivashenko and Yan Lavrovsky from Alla Chem LLC, Avineuro Pharmaceuticals Inc. and R-Pharm Overseas Inc. (all US companies), in collaboration with MIPT's Yan Ivanenkov, worked on a 5-HT6R activity blocking compound. A similar task was investigated in Yan and Alexander's second study with another MIPT employee, Mark Veselov. 5-HT6R receptors were chosen because they are integrated into nerve cell membranes and are capable of reacting to certain external signals, which is why scientists consider them as targets for AD treatment. The antagonists to the receptor are able to ease the symptoms of the disease in a clinical environment.

Studying AVN-211

Scientists studied the pharmacokinetic features, activity, efficiency, and also the toxicity profile of AVN-211. First, a screening test was performed using recombinant human cells containing 5-HT6R to make sure that AVN-211 really is an antagonist. Another series of experiments with cell cultures demonstrated its ability to spread in a tissue and provided preliminary data about its state in the human body - metabolism, biochemical interactions, etc.

Tests were then performed on lab animals - mice, rats and monkeys to obtain the pharmacokinetic profile of a drug candidate in a real body. Observing concentration changes in the animals' blood after intake provided information about the compound's pharmacodynamics.

Memory disorder stress tests have shown that AVN-211 might be able to improve memory function. Rats and mice were taught to find an exit from a maze, while their cognition was imaired by drugs provoking memory loss. Animals who were given the drug demonstrated better results. In addition, healthy animals who received the new drug were better learners and could be trained more efficiently.

These results led the researchers to believe that AVN-211 will be able to combat cognitive dysfunction caused by AD.

Scientists also think that this compound can be used to treat certain mental disorders. Tests with chemicals that produce the same symptoms as psychosis have shown a possible antipsychotic and anxiolytic (reducing anxiety) effect. Such effects are used in treating schizophrenia and depression. It was also noticed that AVN has a comparable effect to haloperidol - a common antipsychotic drug.

In vitro studies revealed that this compound affects the 5-HT6R receptor more effectively and selectively compared to all other drugs, including those currently in clinical trials. Studies on lab animals showed that AVN-211 has low toxicity.

Studying AVN-322

The same tests were performed for AVN-322. Screening with the 5-HT6R receptor on human cell culture proved that the molecule is a highly effective antagonist. In vivo tests were performed on mice: the animals were taught how to get out of a maze and had to remember that a section of the floor was electrified. The results showed that mice that received low levels of AVN-322 performed better than after any existing neuroleptic drugs.

The pharmacokinetics of AVN-322 were analyzed in mice, rats, dogs and monkeys. During a 30-day intake monkeys did not have any toxic after-effects. A possible danger was noticed after a 180-day intake in rats - the substance can cause brachycardia and hypotension. However the exact after-effects are less serious than all other existing drugs. Pre-clinical data proves that AVN-322 also has a good pharmacokinetic profile - it is very digestible and passes well through the blood-brain barrier.

In conclusion, we can say that both compounds have a high pharmaceutical potential and low toxicity. The positive results of the studies mean that researchers can move on to clinical trials in order to verify the safety and effectiveness of a drug that could potentially treat one of the most serious diseases of our time.

Moderate coffee consumption may offer protection against age-related cognitive decline

A new report from the Institute for Scientific Information on Coffee (ISIC), a not-for-profit organisation devoted to the study and disclosure of science related to coffee and health, highlights the potential role of coffee consumption in reducing the risk of cognitive decline. The report concludes that a moderate intake of coffee (3-5 cups per day) may provide protection against age-related cognitive decline and other neurodegenerative diseases such as Alzheimer's and Parkinson's.

The report provides a summary of the research presented at ISIC's symposium, titled 'Nutrition, Coffee and Age-Related Cognitive Decline', held during the European Union Geriatric Medicine Society's 2016 Congress in Lisbon, Portugal. The findings are particularly relevant given Europe's ageing population: the number of people aged 60 years or over is projected to rise to 217.2 million by 2030, therefore understanding and communicating diet and lifestyle factors that may limit age-related cognitive decline will help to improve the quality of life for this growing demographic.

The symposium speakers whose insights and research contributed to ISIC's report were:

• Professor Lisette de Groot, Professor of Nutrition and Ageing, Division of Human Nutrition at Wageningen University (The Netherlands)
• Professor Rodrigo A. Cunha, Professor at the Faculty of Medicine of the University of Coimbra and Principal Investigator at the Centre for Neuroscience and Cell Biology of the University of Coimbra (CNC) (Portugal)
• Dr Elisabet Rothenberg, Associate Professor of Nutrition at Kristianstad University (Sweden)

Key highlights about coffee from the report include:

• Research published in 2016 suggests that moderate coffee consumption can reduce the risk of developing Alzheimer's by up to 27%. Research has suggested that it is regular, long-term coffee drinking that is key to helping to reduce the risk of Alzheimer's Disease.
• The association between coffee consumption and cognitive decline is illustrated by a 'U-shaped' pattern in recent meta-analyses, with the greatest protection seen at an intake of approximately 3-5 cups of coffee per day.
• Although the precise mechanisms of action behind the suggested association between coffee and age-related cognitive decline are unknown, caffeine is likely to be involved. There are many other compounds in coffee, such as antioxidants and anti-inflammatory agents, which may also play a role. Caffeic acid, for example, is a polyphenol (antioxidant) found in coffee, and research suggests that these may be associated with improved cognitive function.

Professor Rodrigo A. Cunha, Professor at the Faculty of Medicine of the University of Coimbra and Principal Investigator at the Centre for Neuroscience and Cell Biology of the University of Coimbra (CNC), Portugal, commented:

"Healthcare professionals have an important part to play in providing patients with accurate research-based information, to help them to follow a healthy diet and lifestyle, and in turn, reduce their risk of age-related cognitive decline. Moderate coffee consumption could play a significant role in reducing cognitive decline which would impact health outcomes and healthcare spending across Europe."

In its Scientific Opinion on the safety of caffeine, the European Food Safety Authority (EFSA) concluded that intakes of up to 400mg of caffeine (the equivalent of up to 5 cups of coffee per day), from all sources, do not raise any concerns for healthy adults. One cup of coffee provides approximately 75-100mg caffeine.

New drug appears to decrease inflammation in the brain linked to Alzheimer's disease

An experimental drug shows promise in treating Alzheimer's disease by preventing inflammation and removing abnormal protein clumps in the brain that are associated with the disease, suggests a study in mice presented at the ANESTHESIOLOGY® 2016 annual meeting.

A key characteristic of Alzheimer's disease is the development of abnormal protein clumps called amyloid plaques and tangled bundles of fibers in the brain. These changes cause inflammation in the brain and damage to the neurons. This progressive damage leads to memory loss, confusion and dementia. The new drug, known as NTRX-07, appears to decrease this inflammation in the brain, while preserving neurons and regenerative cells in the brain.

"This drug may reduce inflammation in the brain, which is linked to Alzheimer's disease," said lead researcher Mohamed Naguib, M.D., a physician anesthesiologist in the Department of General Anesthesiology at the Cleveland Clinic and professor of anesthesiology at the Cleveland Clinic Lerner College of Medicine. "NTRX-07 uses a different mechanism than many other Alzheimer's drugs currently available, as it targets the cause of the disease, not just the symptoms."

The authors discovered NTRX -07's memory-restoring abilities while studying the drug's potential to treat a complex, chronic pain condition called neuropathic pain. "Patients who have neuropathic pain have chronic neuroinflammation," said Dr. Naguib. "This is a compound that blunts that inflammation."

Researchers tested NTRX -07 on mice bred to have similar brain neurodegenerative issues as seen in Alzheimer's. They found that inflammation produced in response to the disease caused changes in the brain's microglia cells - immune cells that typically remove dangerous amyloid plaques (protein clumps) in the brain. As the amyloid plaques accumulated in the mice, the microglia (immune cells) were unable to remove them, leading to inflammation and damage to nerve cells, which caused decreased cognitive ability.

Microglia cells have receptors on the surface called CB2 receptors, which when activated can produce an anti-inflammatory response. NTRX -07 targets CB2 receptors, which leads to decreased inflammation and prevents damage to the brain tissue. The new drug improved removal of abnormal amyloid plaques and improved memory performance and other cognitive skills.

The drug also increased levels of a protein called SOX2, which has been shown to help new brain cells develop and protect the brain in people with Alzheimer's disease. The study found in mice treated with NTRX-07, the levels of SOX2 were restored to normal levels. In contrast, mice treated with a placebo showed decreased levels of SOX2, active inflammation in the brain, poor removal of amyloid plaques, and poor memory performance.

Study shows how caffeine counteracts age-related cognitive deficits in animals

A study published in the journal Scientific Reports from Nature publishing group, describes the mechanism by which caffeine counteracts age-related cognitive deficits in animals.

The study coordinated by Portuguese researchers from Instituto de Medicina Molecular (iMM Lisboa) and collaborators from Inserm in Lille, France, along with teams from Germany and United States, showed that the abnormalexpression of a particular receptor - the adenosine A2A, target for caffeine - in the brain of rats induces an aging-like profile namely memory impairments linked to the loss of stress controlling mechanisms.

"This is part of a larger study initiated 4 years ago in which we identified the role of this receptor in stress, but we did not know whether its activation would be sufficient to trigger all the changes. We now found that by altering the amount of this receptor alone in neurons from hippocampus and cortex - memory related areas - is sufficient to induce a profile that we designate as 'early-aging' combining the memory loss and an increase in stress hormones in plasma (cortisol)" - explains Luisa Lopes, Group Leader at iMM Lisboa and the coordinator of the study.

When the same animals were treated with a caffeine analogue, which blocks the action of adenosine A2A receptors, both memory and stress related deficits were normalized.

David Blum, from Inserm research director, adds: "In elderly people, we know there is an increase of stress hormones that have an impact on memory. Our work supports the view that the procognitive effects of A2AR antagonists, namely caffeine, observed in Alzheimer's and age-related cognitive impairments may rely on this ability to counteract the loss of stress controlling mechanisms that occurs upon aging"

This is important not only to understand the fundamental changes that occur upon aging, but it also identifies the dysfunctions of the adenosine A2A receptor as a key player in triggering these changes. And a very appealing therapeutic target" - concludes Luisa Lopes.

Study shows how caffeine counteracts age-related cognitive deficits in animals: A study published in the journal Scientific Reports from Nature publishing group, describes the mechanism by which caffeine counteracts age-related cognitive deficits in animals.

Drugs designed to target nervous system could control inflammation in the gut, study shows

There's a reason it's called a gut feeling. The brain and the gut are connected by intricate neural networks that signal hunger and satiety, love and fear, even safety and danger. These networks employ myriad chemical signals that include dopamine, a powerful neurotransmitter most famous for its role in reward and addiction.

Duke University researchers have shown that manipulating dopamine signaling in the nervous system of the nematode worm C. elegans can control inflammation in the gut.

The study, which appears Aug. 12 in Current Biology, provides a proof of principle that the immune system can be controlled using drugs originally designed to target the nervous system, such as antipsychotics.

"We are talking about an existing set of drugs and drug targets that could open up the spectrum of potential therapeutic applications by targeting pathways that fine-tune the inflammatory response," said Alejandro Aballay, Ph.D., a professor of molecular genetics and microbiology at Duke School of Medicine.

"It is a big leap from worms to humans, but the idea of targeting the nervous system to control the immune system could potentially be used to treat conditions such as rheumatoid arthritis, autoimmune disease, cancer, inflammatory bowel disease, and Crohn's disease," Aballay said.

Recent research suggests that the wiring between the gut and the brain is involved in many other maladies, including autism, anxiety, depression, Alzheimer's disease, and Parkinson's disease.

Aballay believes that C. elegans provides an excellent model for dissecting this complex cross-talk between the nervous system and the immune system. This tiny, transparent worm has a simple nervous system, consisting of only 302 neurons compared to the roughly 100 billion neurons in the human brain. Yet the worm also has a very basic, rudimentary immune system.

Aballay and his team first stumbled upon the gut-brain connection a few years ago when they were studying the immune system of C. elegans. The worms were subjected to a barrage of chemicals in search of immune activators that could protect against bacterial infections. Out of more than a thousand different chemical compounds, they identified 45 that turned on an immune pathway. Curiously, half of those were involved in the nervous system, and a handful blocked the activity of dopamine.

In this study, Aballay decided to examine the effects of dopamine and dopamine signaling pathways on immunity.

Graduate student Xiou Cao blocked dopamine by treating animals with chlorpromazine, a dopamine antagonist drug used to treat schizophrenia and manic depression in humans. He found that these worms were more resistant to infection by the common pathogen Pseudomonas aeruginosa than counterparts that hadn't received the drug.

When Cao then treated the animals with dopamine, it generated the opposite effect, rendering them more susceptible to infection.

The researchers believe their findings indicate that dopamine signaling acts by putting the brakes on the body's inflammatory response so it doesn't go too far.

"Worms have evolved mechanisms to deal with colonizing bacteria," Aballay said. "That is true for us as well. Humans have trillions of microorganisms in our guts, and we have to be careful when activating antimicrobial defenses so that we mainly target potentially harmful microbes, without damaging our good bacteria -- or even our own cells -- in the process."

"The nervous system appears to be the perfect system for integrating all these different physiological cues to keep the amount of damage in check," Aballay said.

Aballay plans continue his studies in C. elegans to identify the different cues involved in fine-tuning the immune response. He also thinks it is worth looking at different analogues or different doses of dopamine antagonists to see if their effects on psychosis can be separated from their effects on immunity.

Drugs designed to target nervous system could control inflammation in the gut, study shows

Commonly used anti-inflammatory drug shows potential to treat Alzheimer's disease

A research project has shown that an experimental model of Alzheimer's disease can be successfully treated with a commonly used anti-inflammatory drug.

A team led by Dr David Brough from The University of Manchester found that the anti-inflammatory drug completely reversed memory loss and brain inflammation in mice.

Nearly everybody will at some point in their lives take non-steroidal anti-inflammatory drugs; mefenamic acid, a common Non-Steroidal Anti Inflammatory Drug (NSAID), is routinely used for period pain.

The findings are published today in a paper authored by Dr Brough and colleagues, in the respected journal Nature Communications. Dr Brough and Dr Catherine Lawrence supervised PhD student Mike Daniels, and postdoc Dr Jack Rivers-Auty who conducted most of the experiments.

Though this is the first time a drug has been shown to target this inflammatory pathway, highlighting its importance in the disease model, Dr Brough cautions that more research is needed to identify its impact on humans, and the long-term implications of its use.

The research, funded by the Medical Research Council and the Alzheimer's Society, paves the way for human trials which the team hope to conduct in the future.

Around 500,000 people in the UK have Alzheimer's disease which gets worse over time, affecting many aspects of their lives, including the ability to remember, think and make decisions.

In the study transgenic mice that develop symptoms of Alzheimer's disease were used. One group of 10 mice was treated with mefenamic acid, and 10 mice were treated in the same way with a placebo.

The mice were treated at a time when they had developed memory problems and the drug was given to them by a mini-pump implanted under the skin for one month.

Memory loss was completely reversed back to the levels seen in mice without the disease.

Dr Brough said: "There is experimental evidence now to strongly suggest that inflammation in the brain makes Alzheimer's disease worse.

"Our research shows for the first time that mefenamic acid, a simple Non-Steroidal Anti Inflammatory Drug can target an important inflammatory pathway called the NLRP3 inflammasome , which damages brain cells."

He added: "Until now, no drug has been available to target this pathway, so we are very excited by this result.

"However, much more work needs to be done until we can say with certainty that it will tackle the disease in humans as mouse models don't always faithfully replicate the human disease."Because this drug is already available and the toxicity and pharmacokinetics of the drug is known, the time for it to reach patients should, in theory, be shorter than if we were developing completely new drugs.

"We are now preparing applications to perform early phase II trials to determine a proof-of-concept that the molecules have an effect on neuroinflammation in humans."

Dr Doug Brown, Director of Research and Development at Alzheimer's Society, said: "Testing drugs already in use for other conditions is a priority for Alzheimer's Society - it could allow us to shortcut the fifteen years or so needed to develop a new dementia drug from scratch.

"These promising lab results identify a class of existing drugs that have potential to treat Alzheimer's disease by blocking a particular part of the immune response. However, these drugs are not without side effects and should not be taken for Alzheimer's disease at this stage - studies in people are needed first."

Commonly used anti-inflammatory drug shows potential to treat Alzheimer's disease