Mood-stabilizing drug could treat inherited liver disease

February 3, 2014, University of Pittsburgh Schools of the Health Sciences

Opening up a can of worms is a good way to start hunting for new drugs, recommend researchers from Children's Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine. In a study published today in the Public Library of Science One, they used a primitive worm model to show that a drug typically used to treat agitation in schizophrenia and dementia has potential as a treatment for α-1 antitrypsin (AT) deficiency, an inherited disease that causes severe liver scarring.

In the classic form of AT deficiency, which affects 1 in 3,000 live births, a gene mutation leads to production of an abnormal protein, dubbed ATZ, that unlike its normal counterpart is prone to clumping, explained David H. Perlmutter, M.D., physician-in-chief and scientific director, Children's Hospital, and Distinguished Professor and Vira I. Heinz Endowed Chair, Department of Pediatrics, Pitt School of Medicine.

"These protein aggregates accumulate in liver cells and eventually lead to scarring of the organ or to tumor formation," Dr. Perlmutter said. "If we could find a drug that slows or stops this process, we might be able to prevent the need for liver transplantation in these patients."

To find that drug, Dr. Perlmutter's team worked with Pitt's Stephen Pak, Ph.D., assistant professor of pediatrics, and Gary Silverman, M.D., Ph.D., Twenty-five Club Professor of Pediatrics, Cell Biology and Physiology, who developed a model of AT deficiency in Caenorhabditis elegans, or C. elegans, a harmless microscopic worm or nematode typically found in soil. Previous experiments conducted by Drs. Pak and Silverman, in which more than 2,000 compounds were screened, showed that fluphenazine, a drug approved for human use as a mood stabilizer, could reduce ATZ accumulation in the worm, so the team studied it further.

Worms that produce ATZ die sooner than normal ones, which typically have a life span of fewer than 20 days. Those that were exposed to fluphenazine, however, had lower burdens of ATZ and lived more than a day longer that untreated animals. The lifespan of normal worms was unchanged by fluphenazine exposure. The researchers also labeled with fluorescent markers intracellular structures called autophagosomes, which help clear abnormal proteins out of the cell in a process called autophagy. Fluphenazine exposure was associated with a greater presence of autophagosomes, suggesting that increased autophagy led to reduced ATZ accumulation.

Follow-up experiments showed that fluphenazine reduced ATZ accumulation in several mammalian-cell line models of AT deficiency, D. Silverman said.

"We found when we gave this drug for three weeks to mice with the disease, autophagy is activated, the abnormal protein load is diminished, and liver scarring is reversed. It's truly amazing," he said. "And because fluphenazine is already being safely prescribed for other conditions, it should be easier to bring it to clinical trials for AT deficiency."

The project also reveals the power of the worm model to rapidly screen drug candidates, Dr. Perlmutter noted.

"This is the first extensive investigation of a drug that was discovered through the C. elegans screening method," he said. "It's remarkable that you can take a completely unbiased, high-content screen using a primitive organism and end up identifying a drug that reduces the accumulation of an in mammalian cell lines and a living mouse. It's proof-of-principle of this research pipeline. Furthermore, this is very similar pharmacologically to carbamazepine, another mood stabilizer that we found to enhance autophagy and reverse liver fibrosis in the mouse model of α1-antitrypsin deficiency."

Explore further: Worming our way to new treatments for Alzheimer's disease

Related Stories

Worming our way to new treatments for Alzheimer's disease

March 7, 2013
According to a 2012 World Health Organization report, over 35 million people worldwide currently have dementia, a number that is expected to double by 2030 (66 million) and triple by 2050 (115 million). Alzheimer's disease, ...

Obesity-induced fatty liver disease reversed in mice

January 29, 2014
Johns Hopkins researchers have discovered that valproic acid, a widely prescribed drug for treating epilepsy, has the additional benefits of reducing fat accumulation in the liver and lowering blood sugar levels in the blood ...

Autophagy predicts which cancer cells live and die when faced with anti-cancer drugs

January 10, 2014
(Medical Xpress)—When a tumor is treated with an anti-cancer drug, some cells die and, unfortunately, some cells tend to live. A University of Colorado Cancer Center study published in the journal Nature Cell Biology details ...

RCSI research breakthrough in understanding hereditary emphysema

January 13, 2014
Researchers from the Royal College of Surgeons in Ireland (RCSI) and Beaumont Hospital have made an important breakthrough in the understanding and treatment of hereditary emphysema.  Their research findings were published ...

The benefits of a spotless mind

November 15, 2013
Alzheimer's disease is an age-related memory disorder characterized by the accumulation of clumps of the toxic amyloid-β (Aβ) protein fragment in the extracellular space around neurons in the brain. Drugs that help to 'clean ...

Recommended for you

Researchers illustrate how muscle growth inhibitor is activated, could aid in treating ALS

January 19, 2018
Researchers at the University of Cincinnati (UC) College of Medicine are part of an international team that has identified how the inactive or latent form of GDF8, a signaling protein also known as myostatin responsible for ...

Bioengineered soft microfibers improve T-cell production

January 18, 2018
T cells play a key role in the body's immune response against pathogens. As a new class of therapeutic approaches, T cells are being harnessed to fight cancer, promising more precise, longer-lasting mitigation than traditional, ...

Weight flux alters molecular profile, study finds

January 17, 2018
The human body undergoes dramatic changes during even short periods of weight gain and loss, according to a study led by researchers at the Stanford University School of Medicine.

Secrets of longevity protein revealed in new study

January 17, 2018
Named after the Greek goddess who spun the thread of life, Klotho proteins play an important role in the regulation of longevity and metabolism. In a recent Yale-led study, researchers revealed the three-dimensional structure ...

The HLF gene protects blood stem cells by maintaining them in a resting state

January 17, 2018
The HLF gene is necessary for maintaining blood stem cells in a resting state, which is crucial for ensuring normal blood production. This has been shown by a new research study from Lund University in Sweden published in ...

Magnetically applied MicroRNAs could one day help relieve constipation

January 17, 2018
Constipation is an underestimated and debilitating medical issue related to the opioid epidemic. As a growing concern, researchers look to new tools to help patients with this side effect of opioid use and aging.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.