Larry H Bernstein, MD, FCAP, Reporter
![A Pot[age] to Die For](https://i0.wp.com/farm5.static.flickr.com/4102/4874343314_6aa1f56fd4_m.jpg?resize=240%2C180 "A Pot[age] to Die For")
A Pot[age] to Die For (Photo credit: jazzijava)
Curry chemical shows promise for treating the memory-robbing disease
By Lauren K. Wolf
Department: Science & Technology
News Channels: Biological SCENE
Keywords: alternative medicine, dietary supplements, curcumin, tumeric,
Alzheimer’s disease
CURRY WONDER
Curcumin, derived from the rootstalk of the turmeric plant, not only gives Indian dishes their color but might treat Alzheimer’s.
Credit: Shutterstock
More than 5 million people in the U.S. currently live with Alzheimer’s disease. And according to the Alzheimer’s Association, the situation is only going to get worse.
By 2050, the nonprofit estimates, up to 16 million Americans will have the memory-robbing disease. It will cost the U.S. $1.1 trillion annually to care for them unless a successful therapy is found.
Pharmaceutical companies have invested heavily in developing Alzheimer’s drugs, many of which target amyloid-β, a peptide that misfolds and clumps in the brains of patients. But so far, no amyloid-β-targeted medications have been successful. Expectation for the most advanced drugs—bapineuzumab from Pfizer and Johnson & Johnson and solanezumab from Eli Lilly & Co.—are low on the basis of lackluster data from midstage clinical trials. That sentiment was reinforced last week when bapineuzumab was reported to have failed the first of four Phase III studies.
Even if these late-stage hopefuls do somehow work, they won’t come cheap, says Gregory M. Cole, a neuroscientist at the University of California, Los Angeles. These drugs “would cost patients tens of thousands of dollars per year,” he estimates. That hefty price tag stems from bapineuzumab and solanezumab being costly-to-manufacture monoclonal antibodies against amyloid-β.
“There’s a great need for inexpensive Alzheimer’s treatments,” as well as a backup plan if pharma fails, says Larry W. Baum, a professor in the School of Pharmacy at the Chinese University of Hong Kong. As a result, he says, a great many researchers have turned their attention to less pricy alternatives, such as compounds from plants and other natural sources.
Curcumin, a spice compound derived from the rootstalk of the turmeric plant (Curcuma longa), has stood out among some of the more promising naturally derived candidates.
When administered to mice that develop Alzheimer’s symptoms, curcumin decreases inflammation and reactive oxygen species in the rodents’ brains, researchers have found. The compound also inhibits the aggregation of troublesome amyloid-β strands among the animals’ nerve cells. But the development of curcumin as an Alzheimer’s drug has been stymied, scientists say, both by its low uptake in the body and a lack of funds for effective clinical trials—obstacles researchers are now trying to overcome.
In addition to contributing to curry dishes’ yellow color and pungent flavor, curcumin has been a medicine in India for thousands of years. Doctors practicing traditional Hindu medicine admire turmeric’s active ingredient for its anti-inflammatory properties and have used it to treat patients for ailments including digestive disorders and joint pain.
Only in the 1970s did Western researchers catch up with Eastern practices and confirm curcumin’s anti-inflammatory properties in the laboratory. Scientists also eventually determined that the polyphenolic compound is an antioxidant and has chemotherapeutic activity.
Bharat B. Aggarwal, a professor at the University of Texas M. D. Anderson Cancer Center, says curcumin is an example of a pleiotropic agent: It has a number of different effects and interacts with many targets and biochemical pathways in the body. He and his group have discovered that one important molecule targeted and subsequently suppressed by curcumin is NF-κB, a transcription factor that switches on the body’s inflammatory response when activated (J. Biol. Chem., DOI: 10.1074/jbc.270.42.24995).
Aside from NF-κB, curcumin seems to interact with several other molecules in the inflammatory pathway, a biological activity that Aggarwal thinks is advantageous. “All chronic diseases are caused by dysregulation of multiple targets,” he says. “Chemists don’t yet know how to design a drug that hits multiple targets.” With curcumin, “Mother Nature has already provided a compound that does so.”
Curcumin’s pleiotropy also brought it to the attention of UCLA’s Cole during the early 1990s while he was searching for possible Alzheimer’s therapeutics. “That was before we knew about amyloid-β” and its full role in Alzheimer’s, he says. “We were working on the disease from an oxidative damage and inflammation point of view—two processes implicated in aging.”
When Cole and his wife, Sally A. Frautschy, also at UCLA, searched the literature for compounds that could tackle both of these age-related processes, curcumin jumped out at them. It also didn’t hurt that the incidence of Alzheimer’s in India, where large amounts of curcumin are consumed regularly, is lower than in other parts of the developing world (Lancet Neurol., DOI:10.1016/s1474-4422(08)70169-8).
In 2001, Cole, Frautschy, and colleagues published the first papers that demonstrated curcumin’s potential to treat neurodegenerative disease (Neurobiol. Aging, DOI: 10.1016/s0197-4580(01)00300-1; J. Neurosci.2001, 8370). The researchers studied the effects of curcumin on rats that had amyloid-β injected into their brains, as well as mice engineered to develop amyloid brain plaques. In both cases, curcumin suppressed oxidative tissue damage and reduced amyloid-β deposits.
Those results, Cole says, “turned us into curcuminologists.”
Although the UCLA team observed that curcumin decreased amyloid plaques in animal models, at the time, the researchers weren’t sure of the molecular mechanism involved.
Soon after the team’s first results were published, Cole recalls, a colleague brought to his attention the structural similarity between curcumin and the dyes used to stain amyloid plaques in diseased brain tissue. When Cole and Frautschy tested the spice compound, they saw that it, too, could stick to aggregated amyloid-β. “We thought, ‘Wow, not only is curcumin an antioxidant and an anti-inflammatory, but it also might be an anti-amyloid drug,’ ” he says.
In 2004, a group in Japan demonstrated that submicromolar concentrations of curcumin in solution could inhibit aggregation of amyloid-β and break up preformed fibrils of the stuff (J. Neurosci. Res., DOI: 10.1002/jnr.20025). Shortly after that, the UCLA team demonstrated the same (J. Biol. Chem., DOI: 10.1074/jbc.m404751200).
As an Alzheimer’s drug, however, it’s unclear how important it is that the spice compound inhibits amyloid-β aggregation, Cole says. “When you have something that’s so pleiotropic,” he adds, “it’s hard to know” which of its modes of action is most effective.
Having multiple targets may be what helps curcumin have such beneficial, neuroprotective effects, says David R. Schubert, a neurobiologist at the Salk Institute for Biological Studies, in La Jolla, Calif. But its pleiotropy can also be a detriment, he contends.
The pharmaceutical world, Schubert says, focuses on designing drugs aimed at hitting single-target molecules with high affinity. “But we don’t really know what ‘the’ target for curcumin is,” he says, “and we get knocked for it on grant requests.”
Another problem with curcumin is poor bioavailability. When ingested, UCLA’s Cole says, the compound gets converted into other molecular forms, such as curcumin glucuronide or curcumin sulfate. It also gets hydrolyzed at the alkaline and neutral pHs present in many areas of the body. Not much of the curcumin gets into the bloodstream, let alone past the blood-brain barrier, in its pure, active form, he adds.
Unfortunately, neither Cole nor Baum at the Chinese University of Hong Kong realized the poor bioavailability until they had each launched a clinical trial of curcumin. So the studies showed no significant difference between Alzheimer’s patients taking the spice compound and those taking a placebo (J. Clin. Psychopharmacol., DOI: 10.1097/jcp.0b013e318160862c).
“But we did show curcumin was safe for patients,” Baum says, finding a silver lining to the blunder. “We didn’t see any adverse effects even at high doses.”
Some researchers, such as Salk’s Schubert, are tackling curcumin’s low bioavailability by modifying the compound to improve its properties. Schubert and his group have come up with a molecule, called J147, that’s a hybrid of curcumin and cyclohexyl-bisphenol A. Like Cole and coworkers, they also came upon the compound not by initially screening for the ability to interact with amyloid-β, but by screening for the ability to alleviate age-related symptoms.
The researchers hit upon J147 by exposing cultured Alzheimer’s nerve cells to a library of compounds and then measuring changes to levels of biomarkers for oxidative stress, inflammation, and nerve growth. J147 performed well in all categories. And when given to mice engineered to accumulate amyloid-β clumps in their brains, the hybrid molecule prevented memory loss and reduced formation of amyloid plaques over time (PLoS One, DOI: 10.1371/journal.pone.0027865).
Other researchers have tackled curcumin’s poor bioavailability by reformulating it. Both Baum and Cole have encapsulated curcumin in nanospheres coated with either polymers or lipids to protect the compound from modification after ingestion. Cole tells C&EN that by packaging the curcumin in this way, he and his group have gotten micromolar quantities of it into the bloodstream of humans. The researchers are now preparing for a small clinical trial to test the formulation on patients with mild cognitive impairment, who are at an increased risk of developing Alzheimer’s.
An early-intervention human study such as this one comes with its own set of challenges, Cole says. People with mild cognitive impairment “have good days and bad days,” he says. A large trial over a long period would be the best way to get any meaningful data, he adds. Such a trial can cost up to $100 million, a budget big pharma might be able to scrape together but that is far out of reach for academics funded by grants, Cole says. “If you’re down at the level of what an individual investigator can do, you’re running a small trial,” he says, “and even if the result is positive, it might be inconclusive” because of its small size or short duration. That’s one of the reasons the curcumin work is slow-going, Cole contends.
NIH-Funded Research Provides New Clues on How ApoE4 Affects Alzheimer’s Risk
Published: Tuesday, October 30, 2012
Last Updated: Tuesday, October 30, 2012
Researchers found that ApoE4 triggers an inflammatory reaction that weakens the blood-brain barrier.
Common variants of the ApoE gene are strongly associated with the risk of developing late-onset Alzheimer’s disease, but the gene’s role in the disease has been unclear.
Now, researchers funded by the National Institutes of Health have found that in mice, having the most risky variant of ApoE damages the blood vessels that feed the brain.
The researchers found that the high-risk variant, ApoE4, triggers an inflammatory reaction that weakens the blood-brain barrier, a network of cells and other components that lines brain’s brain vessels.
Normally, this barrier allows nutrients into the brain and keeps harmful substances out.
The study appears in Nature, and was led by Berislav Zlokovic, M.D., Ph.D., director of the Center for Neurodegeneration and Regeneration at the Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles.
“Understanding the role of ApoE4 in Alzheimer’s disease may be one of the most important avenues to a new therapy,” Dr. Zlokovic said. “Our study shows that ApoE4 triggers a cascade of events that damages the brain’s vascular system,” he said, referring to the system of blood vessels that supply the brain.
The ApoE gene encodes a protein that helps regulate the levels and distribution of cholesterol and other lipids in the body. The gene exists in three varieties.
ApoE2 is thought to play a protective role against both Alzheimer’s and heart disease, ApoE3 is believed to be neutral, and ApoE4 confers a higher risk for both conditions.
Outside the brain, the ApoE4 protein appears to be less effective than other versions at clearing away cholesterol; however, inside the brain, exactly how ApoE4 contributes to Alzheimer’s disease has been a mystery.
Dr. Zlokovic and his team studied several lines of genetically engineered mice, including one that lacks the ApoE gene and three other lines that produce only human ApoE2, ApoE3 or ApoE4. Mice normally have only a single version of ApoE.
The researchers found that mice whose bodies made only ApoE4, or made no ApoE at all, had a leaky blood-brain barrier. With the barrier compromised, harmful proteins in the blood made their way into the mice’s brains, and after several weeks, the researchers were able to detect loss of small blood vessels, changes in brain function, and a loss of connections between brain cells.
“The study demonstrates that damage to the brain’s vascular system may play a key role in Alzheimer’s disease, and highlights growing recognition of potential links between stroke and Alzheimer’s-type dementia,” said Roderick Corriveau, Ph.D., a program director at NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the research. “It also suggests that we might be able to decrease the risk of Alzheimer’s disease among ApoE4 carriers by improving their vascular health.”
The researchers also found that ApoE2 and ApoE3 help control the levels of an inflammatory molecule called cyclophilin A (CypA), but ApoE4 does not. Levels of CypA were raised about five-fold in blood vessels of mice that produce only ApoE4.
The excess CypA then activated an enzyme, called MMP-9, which destroys protein components of the blood-brain barrier. Treatment with the immunosuppressant drug cyclosporine A, which inhibits CypA, preserved the integrity of the blood-brain barrier and lessened damage to the brain.
An inhibitor of the MMP-9 enzyme had similar beneficial effects. In prior studies, inhibitors of this enzyme have been shown to reduce brain damage after stroke in animal models.
“These findings point to cyclophilin A as a potential new drug target for Alzheimer’s disease,” said Suzana Petanceska, Ph.D., a program director at NIH’s National Institute on Aging (NIA), which also funded Dr. Zlokovic’s study.
“Many population studies have shown an association between vascular risk factors in mid-life, such as high blood pressure and diabetes, and the risk for Alzheimer’s in late-life. We need more research aimed at deepening our understanding of the mechanisms involved and to test whether treatments that reduce vascular risk factors may be helpful against Alzheimer’s.”
Alzheimer’s disease is the most common cause of dementia in older adults, and affects more than 5 million Americans. A hallmark of the disease is a toxic protein fragment called beta-amyloid that accumulates in clumps, or plaques, within the brain.
Gene variations that cause higher levels of beta-amyloid are associated with a rare type of Alzheimer’s that appears early in life, between age 30 and 60.
However, it is the ApoE4 gene variant that is most strongly tied to the more common, late-onset type of Alzheimer’s disease. Inheriting a single copy of ApoE4 from a parent increases the risk of Alzheimer’s disease by about three-fold. Inheriting two copies, one from each parent, increases the risk by about 12-fold.
Dr. Zlokovic’s study and others point to a complex interplay between beta-amyloid and ApoE4. On the one hand, beta-amyloid is known to build up in and damage blood vessels and cause bleeding into the brain.
On the other hand, Dr. Zlokovic’s data suggest that ApoE4 can damage the vascular system independently of beta-amyloid. He theorizes that this damage makes it harder to clear beta-amyloid from the brain.
Some therapies under investigation for Alzheimer’s focus on destroying amyloid plaques, but therapies designed to compensate for ApoE4 might help prevent the plaques from forming, he said.
Compound Could Become Alzheimer’s Treatment
Thu, 10/11/2012 – 1:29pm
A new molecule designed to treat Alzheimer’s disease has significant promise and is potentially the safest to date, according to researchers.
Purdue University professor Arun Ghosh designed the molecule, which is a highly potent beta-secretase inhibitor with unique features that ensure it goes only to its target and does not affect healthy physiological processes, he said.
“This molecule maintains the disease-fighting properties of earlier beta-secretase inhibitors, but is much less likely to cause harmful side effects,” said Ghosh, the Ian P. Rothwell Distinguished Professor of Chemistry and Medicinal Chemistry and Molecular Pharmacology. “The selectivity we achieved is unprecedented, which gives it great promise for the long-term medication required to treat Alzheimer’s. Each time a treatment misses its disease target and instead interacts with a healthy cell or molecule, damage is done that we call toxicity. Even low levels of this toxicity could build up over years and years of treatment, and an Alzheimer’s patient would need to be treated for the rest of his or her life.”
The new molecule shows a 7,000-fold selectivity for its target enzyme, which far surpasses the benchmark of a 1,000-fold selectivity for a viable treatment molecule, and dwarfs the selectivity values in the hundreds for past beta-secretase inhibitors, he said. A paper detailing the work will be published in an upcoming Alzheimer’s research issue of the Journal of Medicinal Chemistry and is currently available online. The National Institutes of Health funded the research.
Beta-secretase inhibitors, which could allow for intervention in the early stages of Alzheimer’s disease, have promise as a potential treatment. Several drugs based on this molecular target have made it to clinical trials, including one based on a molecule Ghosh designed previously. These molecules prevent the first step in a chain of events that leads to the formation of amyloid plaque in the brain, fibrous clumps of toxic proteins that are believed to cause the disease’s devastating symptoms.
The National Institute on Aging estimates that 5.1 million Americans suffer from Alzheimer’s disease, which leads to dementia by affecting parts of the brain that control thought, memory and language.
“Alzheimer’s is a progressive disease that destroys the brain and also destroys the quality of life for those who suffer from it,” Ghosh said. “It eventually robs people of their ability to recognize their own spouse or child and to complete basic tasks necessary for independence, like getting dressed. It is a truly devastating disease for those who suffer from it and for their friends and loved ones.”
Earlier versions of the beta-secretase inhibitor were able to stop and even reverse the progression of amyloid plaques in tests on mice, but potency and selectivity are only two of the three pillars of a viable Alzheimer’s treatment, Ghosh said. It has yet to be shown whether this molecule possesses the third pillar, the ability to be turned into an easily administered drug that passes through the blood-brain barrier.
Ghosh collaborates with Jordan Tang, the J.G. Puterbaugh Chair in Medical Research at the Oklahoma Medical Research Foundation, who in 2000 identified beta-secretase and its role in the progression of Alzheimer’s. Later that year Ghosh designed his first molecule that bound to and inhibited the activity of the enzyme. He has strived to create the needed improvements ever since.
Ghosh bypasses the usual lengthy process of trial and error in finding useful inhibitor molecules by using a structure-based design strategy. He uses the structures of the inhibitor bound to the enzyme as a guide to what molecular features are important for desirable and undesirable characteristics. Then he removes, replaces and adds molecular groups to amplify the desirable and eliminate the undesirable.
“I believe structure-based design is vital to the development of new and improved medicine,” said Ghosh, who also is a member of the Purdue University Center for Cancer Research. “These strategies have the potential to eliminate enormous costs and time needed in traditional random screening protocols for drug development. Structure-based strategies allow us to design molecules that do precisely what we need them to do with fewer undesirable side effects.”
Tang performed the X-ray crystallography and captured the crystal structures to reveal important insights and serve as a guide for Ghosh’s designs.
“Developing inhibitors into clinically useful drugs is an evolutionary process,” Tang said. “We learn what works and what doesn’t along the way, and the knowledge permits us to do better in the next step. The miracles of modern medicine are built on top of excellent scientific findings. We try to do good science and know that the consequence will be a better chance for conquering diseases and improving lives.”
Beta-secretase belongs to a class of enzymes called aspartyl proteases. Research into beta-secretase inhibitors faced setbacks when other aspartyl proteases similar in structure, called memapsin 1 and cathepsin D, were discovered and found to be involved in many important physiological processes. Earlier designed beta-secretase inhibitors were found also to work against the biologically necessary enzymes.
Ghosh’s team focused on developing ways to make the inhibitor more selective so that it would avoid these other, physiologically important enzymes. They compared the structures of beta-secretase and memapsin 1 as they interacted with the inhibitor to find an active area unique only to beta-secretase. Then they added a functional molecular feature that targets and interacts with the unique area, making the inhibitor more attractive to beta-secretase and less attractive to the other enzymes.
“The added feature serves as a bait on the inhibitor molecule that entices beta-secretase and also grabs onto it tightly, greatly enhancing its selectivity,” he said. “This is a fundamental insight into the origins of selectivity and ways to increase it.”
Ghosh said this work highlights an important purpose of academic research.
“Academic research lays out and shares the fundamentals to advance drug discovery,” he said. “Advances in treatment are built upon the basic research happening at universities.”
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