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.

FDA-approved blood pressure drug reduces cell damage linked to Alzheimer's disease

In laboratory neuronal cultures, an FDA-approved drug used to treat high blood pressure reduced cell damage often linked to Alzheimer's disease, say researchers at Georgetown University Medical Center (GUMC) and the National Institutes of Health.

They say their work, published online Jan. 28 in the journal Alzheimer's Research and Therapy, provides information supporting the potential effect of the drug candesartan -- as well as other Angiotensin receptor blockers (ARBs) for the early treatment of Alzheimer's disease.

"Our findings make sense in many ways," says the study's senior author Juan M. Saavedra, MD, from GUMC's Department of Pharmacology and Physiology. "Hypertension reduces blood flow throughout the body and brain and is a risk factor of Alzheimer's disease. Previous epidemiological studies found that Alzheimer's progression is delayed in hypertensive patients treated with ARBs."

Using neuronal cultures, the researchers explored the action of candesartan on the neurotoxic effects of exposure to excessive glutamate, a demonstrated injury factor in the early stages of Alzheimer's disease.

The scientists found that candesartan prevented glutamate-induced neuronal death. They conducted in-depth gene analyses of the laboratory results, demonstrating that candesartan prevented neuronal inflammation and many other pathological processes, including alterations in amyloid metabolism, a hallmark of Alzheimer's disease.

The study's first author, Abdel G. Elkahloun, PhD, from the Comparative Genomics and Cancer Genetics Branch of the National Human Genome Research Institute, then compared gene expression in the neuronal cultures with published gene databases of autopsy samples from Alzheimer's disease patients. "The correlations were impressive -- the expression of 471 genes that were altered by excess glutamate in our cultures were also altered in brain autopsy samples from patients who suffered from Alzheimer's disease. Candesartan normalized expression of these genes in our cultures," Elkahloun says.

"We hypothesize that candesartan, or other members of the ARB group, may not only slow progression of Alzheimer's but also prevent or delay its development," Saavedra says.

FDA-approved blood pressure drug reduces cell damage linked to Alzheimer's disease: In laboratory neuronal cultures, an FDA-approved drug used to treat high blood pressure reduced cell damage often linked to Alzheimer's disease, say researchers at Georgetown University Medical Center and the National Institutes of Health.

New heart failure drug may increase patients' risk of Alzheimer's disease, macular degeneration

In continuation of my update on sacubitril and Valsartan

Patients with mild heart failure stand to benefit from a new drug that can halt the progression of their disease and reduce their risk of cardiovascular-related death. But the drug -- a tablet that combines the agents valsartan and sacubitril, sold under the trade name Entresto by drugmaker Novartis -- may be too good to be true, according to Arthur M. Feldman, MD, PhD, Executive Dean of the Lewis Katz School of Medicine at Temple University (LKSOM), Chief Academic Officer of the Temple University Health System, and Laura H. Carnell Professor of Medicine at LKSOM.

In an article published online December 7th in the Journal of the American Medical Association, Dr. Feldman and colleagues at Thomas Jefferson University and the University of Florida warn that valsartan/sacubitril could theoretically increase patients' risk of Alzheimer's disease and macular degeneration, a blinding condition affecting the retina of the eye. The article raises these concerns about the drug, which was approved by the U.S. Food and Drug Administration in July 2015.

"Basic science data has caused us to speculate that off-target effects of valsartan/sacubitril may cause an exacerbation of Alzheimer's disease and could also exacerbate the course of macular degeneration," Dr. Feldman explained.

Dr. Feldman went on to note that "doctors are prescribing these drugs without knowledge of these theoretical risks."

Valsartan/sacubitril works by inhibiting an enzyme known as neprilysin, which normally plays a critical role in breaking down a wide array of peptides in cells. Among those substances are the so-called natriuretic peptides, which function in regulating scarring and cell growth in the heart when neprilysin is blocked. Because of those activities, valsartan/sacubitril can delay the progression of heart failure in some patients.

Neprilysin, however, also normally degrades amyloid beta, a peptide that can accumulate in the brain, where it contributes to Alzheimer's disease, as well as in the eye, where it is implicated in macular degeneration. The balance between the production and clearance of amyloid beta is crucial to the pathogenesis of Alzheimer's disease and is suspected to influence the development of macular degeneration. In animal models, blocking neprilysin disturbs that balance and exacerbates the development of Alzheimer's pathology.

New heart failure drug may increase patients' risk of Alzheimer's disease, macular degeneration

Potential drug for treatement of Alzheimer's disease investigated

Cannabinoid type 2 (CB₂) agonists are neuroprotective and appear to play modulatory roles in neurodegenerative processes in Alzheimer's disease. We have studied the effect of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl) carbonyl) piperidine (MDA7 see below structure), a novel selective CB₂ agonist that lacks psychoactivity—on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment induced by bilateral microinjection of amyloid-β (Aβ)_1–40 fibrils into the hippocampal CA1 area of rats. In rats injected with Aβ_1–40 fibrils, compared with the administration of intraperitoneal saline for 14 days, treatment with 15 mg/kg of intraperitoneal MDA7 daily for 14 days (1) ameliorated the expression of CD11b (microglia marker) and glial fibrillary acidic protein (astrocyte marker), (2) decreased the secretion of interleukin-1β, (3) decreased the upsurge of CB₂ receptors, (4) promoted Aβ clearance, and (5) restored synaptic plasticity, cognition, and memory. Our findings suggest that MDA7 is an innovative therapeutic approach for the treatment of Alzheimer's disease.

Potential drug for treatement of Alzheimer's disease investigated

Memantine, Drug Shown to Improve Memory in Those With Down Syndrome

In continuation of my update on  memantine

Costa, an associate professor of medicine, and his colleagues studied 38 adolescents and young adults with Down syndrome. Half took the drug memantine, used to treat Alzheimer's disease, and the others took a placebo.

Costa's research team hypothesized that memantine, which improved memory in mice with Down syndrome, could increase test scores of young adults with the disorder in the area of spatial and episodic memory, functions associated with the hippocampus region of the brain.

Participants underwent a 16-week course of either memantine or a placebo while scientists compared the adaptive and cognitive function of the two groups.

While they found no major difference between the groups in adaptive and most measures of cognitive ability, researchers discovered that those taking memantine showed significant improvement in verbal episodic memory. One of the lowest functioning individuals in the study saw a ten-fold increase in memory skills.

"People who took the medicine and memorized long lists of words did significantly better than those who took the placebo," said Costa, a neuroscientist specializing in Down syndrome research. "This is a first step in a longer quest to see how we can improve the quality of life for those with Down syndrome."

Translational Psychiatry - Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial

Trial will evaluate resveratrol in Alzheimer's dementia

In continuation of my update on Resveratrol

Researchers at Georgetown University and 25 other U.S. academic institutions affiliated with the Alzheimer's Disease Cooperative Study will be conducting a phase II double-blinded, placebo-controlled trial that will test the effects of resveratrol in Alzheimer's disease patients. "This is the gold-standard for conducting a clinical study because it allows us to objectively determine if resveratrol is offering any benefits," stated Brigid Reynolds, NP, who is the lead researcher for the study's center at Georgetown.

The twelve-month trial, funded by the National Institute on Aging, will enroll men and women age 50 and over with mild to moderate dementia diagnosed as probable Alzheimer's disease and will require one caregiver or friend for each patient. Participants will be initially assigned to 500 milligrams resveratrol or a placebo daily, with dosage to be increased at 13 week intervals to a maximum of 1,000 milligrams twice per day. Lumbar punctures, brain magnetic resonance imaging (MRI) scans, and blood and urine tests will monitor the subjects' progress over the course of ten visits. The researchers hope to determine whether supplementation with resveratrol is helpful in delaying or altering the deterioration of memory and daily function that occurs in Alzheimer's disease.

"Most resveratrol studies showing any health benefits have been conducted in animal models, such as mice, and with doses that far exceed intake from sipping wine or nibbling on chocolate," stated R. Scott Turner, MD, PhD, who is the director of Georgetown University Medical Center's Memory Disorders Program and the national study's lead investigator. "With this clinical trial, we'll find out if daily doses of pure resveratrol can delay or alter memory deterioration and daily functioning in people with mild to moderate dementia due to Alzheimer's."

"During this study, we will also test whether resveratrol improves glucose and insulin metabolism in older individuals -- although those who already have diabetes will not be included in this study," he added....

Ref : http://explore.georgetown.edu/news/?ID=64145

Paclitaxel drug slows damage and symptoms in (Alzheimer's disease) animal model

A compound,  epothilone D (EpoD) that previously progressed to Phase II clinical trials for cancer treatment slows neurological damage and improves brain function in an animal model of Alzheimer's disease, according to a new study.  Compound is effective in preventing further neurological damage and improving cognitive performance in a mouse model of Alzheimer's disease (AD). The results establish how the drug might be used in early-stage AD patients......

Potential Alzheimer's disease drug slows damage and symptoms in animal model

New RAGE inhibitor shows promise against Alzheimer's

In continuation on drug discovery for Alzheimer's disease....
New RAGE inhibitor shows promise against Alzheimer's: Researchers have taken another crack at a promising approach to stopping Alzheimer's disease that encountered a major hurdle last year. In research published this week in the Journal of Clinical Investigation, scientists have developed a compound that targets a molecular actor known as RAGE (Receptor for Advanced Glycation End Products), which plays a central role in mucking up the brain tissue of people with the disease.

Case Western Reserve University - One of the nation's top universities and the best college in Ohio

Neuroscientists at Case Western Reserve University School of Medicine have made a dramatic breakthrough in their efforts to find a cure for Alzheimer's disease. The researchers' findings, published in the journalScience, show that use of a drug in mice appears to quickly reverse the pathological, cognitive and memory deficits caused by the onset of Alzheimer's. The results point to the significant potential that the medication, bexarotene, has to help the roughly 5.4 million Americans suffering from the progressive brain disease. 

Bexarotene has been approved for the treatment of cancer by the U.S. Food and Drug Administration for more than a decade. These experiments explored whether the medication might also be used to help patients with Alzheimer's disease, and the results were more than promising. Landreth and his colleagues chose to explore the effectiveness of bexarotene for increasing ApoE expression. The elevation of brain ApoE levels, in turn, speeds the clearance of amyloid beta from the brain. Bexarotene acts by stimulating retinoid X receptors (RXR), which control how much ApoE is produced.

In particular, the researchers were struck by the speed with which bexarotene improved memory deficits and behavior even as it also acted to reverse the pathology of Alzheimer's disease. The present view of the scientific community is that small soluble forms of amyloid beta cause the memory impairments seen in animal models and humans with the disease. Within six hours of administering bexarotene, however, soluble amyloid levels fell by 25 percent; even more impressive, the effect lasted as long as three days. Finally, this shift was correlated with rapid improvement in a broad range of behaviors in three different mouse models of Alzheimer's.

More...

Case Western Reserve University - One of the nation's top universities and the best college in Ohio

Grape seed polyphenols may help prevent Alzheimer's disease

 In continuation of my update on the usefulness of polyphenols....

 Grape seed polyphenols may help prevent Alzheimer's disease

Grape polyphenols are also called Vineatrols (see structure : vineatrol / trans-resveratrol)

Protective properties of green tea uncovered

In continuation of my up date on the benefits of green tea...

Protective properties of green tea uncovered

Ref : doi:10.1016/j.phymed.2010.11.004

FDA Panel Backs Amyvid (Florbetapir) Approval

FDA approve a new chemical, Florbetapir, E)-4-(2-(6-(2-(2-(2-([¹⁸F]-fluoroethoxy)ethoxy)ethoxy)- pyridin-3-yl)vinyl)-N-methyl benzenamine (see structure) that can highlight the telltale signs of Alzheimer's in brain scans may one day help doctors diagnose the neurodegenerative disease, experts said. Amyvid (trade name), with one critical caveat, however manufacturer Eli Lilly and Co. must demonstrate that standards for interpreting brain scans that show amyloid plaques illuminated by Amyvid can be made consistent enough to routinely guarantee an accurate diagnosis.

Amyvid (florbetapir) is injected into patients who then undergo a PET scan; a negative result can help rule out Alzheimer's, according to Lilly. Experts agreed that the test could become a critical part of spotting Alzheimer's before symptoms have taken hold, but they noted that the clinical reality of that is far from imminent.

"It may well be that amyloid imaging will join colonoscopy, mammography, etc. as mid-life surveillance tests, and that anti-amyloid interventions are most effective in the pre-symptomatic stages of Alzheimer's disease," said Dr. Sam Gandy, the Mount Sinai Chair in Alzheimer's Disease Research in New York City. However, this possibility is years away, he added..............

Ref : http://newsroom.lilly.com/releasedetail.cfm?ReleaseID=544894

Journal of Alzheimer's Disease highlights latest scientific studies of AD

Journal of Alzheimer's Disease highlights latest scientific studies of AD

Trends in drug discovery for Alzheimer's disease.....

In continuation of my update on Alzheimer' disease and drug discovery...

We  know that Alzheimer’s disease(named after Dr. Alois Alzheimer. In 1906) is an irreversible, progressive brain disease that slowly destroys memory and thinking skills, and eventually even the ability to carry out the simplest tasks. In most people with Alzheimer’s, symptoms first appear after age 60. 

Alzheimer’s disease is the most common cause of dementia(loss of cognitive functioning—thinking, remembering, and reasoning to such an extent that it interferes with a person’s daily life and activities) among older people. Dementia is the  Estimates vary, but experts suggest that as many as 5.1 million Americans may have Alzheimer’s and Alzheimer's is predicted to affect 1 in 85 people globally by 2050. 

Future drugs for Alzheimer’s disease : 

Thirty years ago, we knew very little about Alzheimer’s disease (with four medications approved so for...). Since then, scientists have made many important advances. Research supported by NIA and other organizations has expanded knowledge of brain function in healthy older people, identified ways we might lessen normal age-related declines in mental function, and deepened our understanding of the disease. Many scientists and physicians are now working together to untangle the genetic, biological, and environmental factors that, over many years, ultimately result in Alzheimer’s. This effort is bringing us closer to the day when we will be able to manage successfully or even prevent this devastating disease.

A recent research survey claim that, symptomatic market will remain active in this disease. New symptomatic entrants to the market will include Aricept patch and the first-in-class 5-HT6 receptor antagonist SB-742457.  Datamonitor forecasts that the current late-stage pipeline will yield three blockbusters, but this is by no means guaranteed considering the high risk of failure in Phase III Alzheimer’s disease trials. Of the pipeline drugs, Datamonitor believes that bapineuzumab(an antibody to the beta-amyloid (Aβ) plaques) and solanezumab (a humanized antibody that binds to soluble ß-amyloid and thereby may draw the peptide away from the brain through the blood and this could reduce the formation of amyloid plaque)have the most commercial and clinical potential. Research survey conclude that value of the Alzheimer’s disease market across the seven major markets was $4.7bn in 2009 and is forecast to reach $11.9bn by 2019. More....

 

Antihypertensive Drugs May Protect Against Alzheimer's Disease....

Researchers at Mount Sinai School of Medicine have found that the drug carvedilol (see structure), currently prescribed for the treatment of hypertension, may lessen the degenerative impact of Alzheimer's Disease and promote healthy memory functions.  

"These studies are certainly very exciting, and suggest for the first time that certain antihypertensive drugs already available to the public may independently influence memory functions while reducing degenerative pathological features of the Alzheimer’s disease brain," said study author Giulio Maria Pasinetti, MD, PhD, Saunders Family Professor of Neurology and Director of the Center of Excellence for Novel Approaches to Neurotherapeutics at Mount Sinai School of Medicine....

Dr. Pasinetti’s team found for the first time that carvedilol, a blood pressure lowering agent, is capable of exerting activities that significantly reduce Alzheimer’s disease-type brain and memory degeneration. This benefit was achieved without blood pressure lowering activity in mice genetically modified to develop Alzheimer’s disease brain degeneration and memory impairment.

They also found that carvedilol treatment was capable of promoting memory function, based on assessments of learning new tasks and information and recall of past information, which is already chemically stored in the brain. In the study, one group of mice received carvedilol treatment and the other group did not. The scientists conducted behavioral and learning tests with each group of mice, and determined that it took the mice in the carvedilol significantly less time to remember tasks than the other group.

Ongoing clinical research is in progress to test the benefits of carvedilol, which may prove to be an effective agent in the treatment of symptoms of Alzheimer’s disease,   hope they will come out with positive results...

Ref : http://www.j-alz.com/issues/21/vol21-2.html

Resveratrol in Red Wine Neutralizes Toxicity of Proteins Related to Alzheimer's

We know that, Resveratrol (found in the skin of red grapes and is a constituent of red wine, see structure)  (trans-resveratrol) is a phytoalexin produced naturally by several plants when under attack by pathogens such as bacteria or fungi.  And also it has been reported to possess diverse activities such as, anti-cancer, anti-inflammatory, blood-sugar-lowering and other beneficial cardiovascular effects in mouse and rat models of testings. In the only positive human trial, extremely high doses (3–5 g) of resveratrol in a proprietary formulation have been necessary to significantly lower blood sugar.Claims of anti-aging effects of the same compounds is to be still established.

Now researchers led by Rensselaer Professor Peter M. Tessier, have come up with an interesting finding i.e., resveratrol - has the ability to neutralize the toxic effects of proteins linked to Alzheimer's disease. 

As per the claims by the researchers, resveratrol picks out the clumps of peptides that are bad and leaves alone the ones that are benign, it helps us to think about the structural differences between the peptide isoforms (different packing arrangements of a particular peptide) Deformations of a particular peptide  the Aβ1-42 peptide,   have been linked to Alzheimer's disease. 

Improperly folded peptides have been shown to collect in accumulations called "plaques (often found near areas of cell death in diseased brain)" within the brain.

Researchers conclude that, though it is not clear that resveratrol is able to cross the blood-brain barrier. However, the molecule has garnered interest in recent years for its potential impact on cancer and aging...

Ref : http://www.jbc.org/content/early/2010/05/28/jbc.M110.133108....

BQCA improves symptoms of Alzheimer’s disease in rodents.....

The compound  benzylquinolone carboxylic acid (BQCA)  has been shown in earlier studies (rodent)  to lessen the occurrence and severity of the behavioral disturbances often symptomatic of Alzheimer's, such as hallucinations, delusions, paranoia and outbursts. But the important feature of this research lies in the fact that the compound, was able to change the way the brain works and whether or not it improved memory in our 'Alzheimer's mice,' which are experiencing progressive cognitive decline much like a person with Alzheimer's does.

Other attempts to identify such a specific treatment for Alzheimer's have failed, according to Dr.Michelle  Nicolle, the lead researcher. As per her claim "current treatments only treat the symptoms while the underlying disease is still progressing and  so recent research efforts are focusing on stopping disease progression instead of symptomatic treatment".

The researchers' findings suggest that  the compound BQCA,  could alter the progression of disease in mice and  ultimately  hold importance for humans as well.

BQCA activates a specific neurotransmitter receptor in the brain called the M1 muscarinic acetylcholine receptor. M1 receptors have been the focus of research into treatment of Alzheimer's disease because they affect the part of the brain that stimulates the memory and learning functions the disease inhibits. Until now, scientists have not found a treatment selective enough to activate the receptors without producing side effects such as nausea, vomiting and increased frequency of urination. As per the claim, BCQA is specific and BQCA also seemed to inhibit production of amyloid beta, one of the markers of Alzheimer's disease in the brain - perhaps key to the compound's potential for slowing the progression of the disease. Though detailed studies are still to be established its an interesting research. I found an interesting article in the same lines, those interested can read.

Ref : http://www.wfubmc.edu/News-Media-Resources/

DBZ an Alzheimer drug in clinical trails - a new hope for oesophageal cancer ?

Though there are some drugs for other cancers, but there is no good treatment, and sufferers for the cancer of  oesophagus  or gullet  and the patients  frequently face a short, painful battle which ends all too quickly in death. Many of the cancers diagnosed are in people with a long history of heartburn.

About Oesophagus cancer :

Chronic heartburn leads to the lower parts of the gullet being bathed in a toxic acid solution, and the lining of the gullet defends itself against this by changing itself into something which looks a lot like the lining of the lower intestines. Although the damaged tissue, called Barrett's oesophagus, is not cancerous in itself, its presence warns doctors that the patient has taken the first step towards cancer, and triggers a rigorous programme of monitoring, coupled with therapy to prevent further damage.

Patients with Barrett's oesophagus can be stabilised, and most do not go on to develop cancer, but once it is there, the mutated tissue is almost impossible to eradicate, so the risk always remains. Researchers have long been searching for new drugs able to revert Barrett's oesophagus to the healthy, normal lining of the gullet, and now, a team led by Hans Clevers of the Hubrecht Institute, Utrecht, have come up with a drug DBZ (see structure : source : Paul J. Ciaccio)  a drug already in clinical trails for the Alzheimer's disease.

The interesting part of this research is the basis for testing the drug. Clevers' team, whose research into colon cancer is world-renowned, reasoned that as Barrett's oesophagus cells are very similar to the cells which line the colon, they might share vital control pathways.

Clevers and his team then put this together with the fact that  the anti-Alzheimer's drug DBZ, currently in clinical trials, is known to have side effects on the lower gut lining. Researchers used a rat model of oesophageal cancer to observe the effects of DBZ on Barrett's oesophagus tissue, and found that DBZ could halt the growth of Barrett's oesophagus, and in some cases completely destroyed the mutant tissue. Whilst the treatment is still a long way from being trialled in humans, it is an exciting step forward in the fight for a cure for oesophageal cancer.

New hope for therapy in heartburn-related cancer is presented in the Research Article entitled 'Conversion of metaplastic Barrett's epithelium into post-mitotic goblet cells by gamma-secretase inhibition',

Hans Clevers et. al., Disease Models & Mechanisms (DMM), Vol3, Issue 1/2,

I found an interesting article in the similar lines, those interested can read at the link...

New key factor (ßCTF, a small protein found in APP) identified in the development of Alzheimer's disease...

Inheritance of an extra copy of the gene- β -amyloid precursor protein, APP, in individuals with Down syndrome leads to the inevitable development of early onset Alzheimer's disease, known to be linked to the deposition of Amyloid β peptide or Aβ in the brain. However, a new study published online by Proceedings of the National Academy of Sciences identifies βCTF, a small protein found in APP, as a novel factor for the development of Alzheimer's disease related endosome abnormalities, which have also been tied previously to the loss of brain cells in Alzheimer's disease.

In their study, using the cells from individuals with Down syndrome that are genetically predisposed to developing Alzheimer's disease, the researchers showed that elevated levels of ßCTF, independent of Aß, cause a specific pattern of endosome defects with similar pathology of brain cells in Alzheimer's disease. As per the claim by Dr. Ying Jiang, (Department of Psychiatry at NYU Langone Medical Center. they were successfully able to pinpoint that ßCTF causes Alzheimer's disease-related endosome defects and successfully reverse these endosome defects by lowering ßCTF levels in the cells. Hope this study demonstrating an alternative protein factor, ßCTF, derived from the gene APP, is also unequivocally involved in Alzheimer's disease and may be of additional importance for the development of future effective therapies in the days to come...

Combination of EGCG & DAPH-12 - a treatment for brain disorders ?

Amyloid plaques are tightly packed sheets of proteins that infiltrate the brain. These plaques, which are stable and seemingly impenetrable, fill nerve cells or wrap around brain tissues and eventually (as in the case of Alzheimer's) suffocate vital neurons or brain cells, causing loss of memory, language, motor function and eventually premature death.

To date, researchers have had no success in destroying plaques in the human brain and only minimal success in the laboratory. One reason for these difficulties in finding compounds that can dissolve amyloids is their immense stability and their complex composition.

Yet, Dr. Duennwald ( Boston Biomedical Research Institute , BBRI) and co workers from Pennsylvania School of Medicine, experienced success in previous studies when he exposed amyloids in living yeast cells to EGCG (see the above structure). Furthermore, he and his collaborators also found before that DAPH-12, (see below structure) too, inhibits amyloid production in yeast.

About EGCG :

Epigallocatechin gallate, also known as Epigallocatechin 3-gallate, is the ester of epigallocatechin and gallic acid and a type of catechin. EGCG is the most abundant catechin in most notably tea, among other plants, and is also a potent antioxidant and that may have therapeutic properties for many disorders including cancer. It is found in green tea, but not black tea, as EGCG is converted into thearubigins in black teas. EGCG can be found in many supplements.

These findings are significant because it is the first time a combination of specific chemicals (EGCG & DAPH-12) has successfully destroyed diverse forms of amyloids at the same time.

Though the detailed mechanism is still to be established, its a good achievement and hope this combinatorial therapy will help those sufferings from Alzheimer's and other degenerative diseases (Huntington's, and Parkinson's) in the days to come.....

Ref : http://www.nature.com/nchembio/journal/v5/n12/pdf/nchembio.246.pdf