An experimental anticancer drug appears to reverse schizophrenia-related behavior and restore some lost brain cell function in young mice with a rodent version of the illness, researchers say.
The compound, called FRAX486, appears to halt an out-of-control biological “pruning” process in the schizophrenic brain that unnecessarily destroys important connections among brain cells, according to a new study published online in the Proceedings of the National Academy of Sciences.
“By using this compound to block excess pruning in adolescent mice, we also normalized the behavior deficit,” says study leader Akira Sawa, professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine. “That we could intervene in adolescence and still make a difference in restoring brain function in these mice is intriguing.”
FRAX486 is a PAK inhibitor, one of a class of drugs shown in animal experiments to confer some protection from brain damage due to Fragile X syndrome, an inherited disease in humans marked by mental retardation. There also is some evidence, experts say, that PAK inhibitors can be used to treat Alzheimer’s disease. And because the PAK protein itself can initiate cancer and cell growth, PAK inhibitors have also been tested for cancer.
Working with mice that mimic schizophrenia and related disorders, the researchers were able to partially restore disabled neurons so they could connect to other nerve cells. The findings in adolescent mice are an especially promising step in efforts to develop better therapies for schizophrenia in humans, researchers say, because schizophrenia symptoms typically appear in late adolescence and early adulthood.
Schizophrenia is a chronic, severe mental disorder that affects about one in 100 people, the National Institute of Mental Health says. Patients may experience hallucinations—often hearing non-existent voices—and delusions, and they may not make sense when they speak. Among other problems, they may also appear agitated or have cognitive problems such as difficulty focusing or issues with working memory.
The researchers began their study by chemically turning down expression in their mice of a gene known as Disrupted-in-Schizophrenia 1. DISC1, as it is called, makes a protein that appears to regulate neurons in the cerebral cortex responsible for “higher-order” functions, like information processing.
In studies of rodent brain cells, the researchers found that a DISC1 deficit caused deterioration of vital parts of the neuron called spines, which help neurons communicate with one another.
Reduced amounts of DISC1 protein also impact the development of a protein called Kalirin-7 (KAL7), which is needed to regulate another protein called Rac1. Without enough DISC1, KAL7 can’t adequately control Rac1 production and the development of neuronal spines. Excess Rac1 apparently erases spines and leads to excess PAK in the mice.
By using FRAX486 to reduce the activity of PAK, the researchers were able to protect against the deterioration of the spines caused by too little DISC1, halting the process. This normalized the excess pruning and resulted in the restoration of missing spines.
The scientists were able to see this by peering into the brains of the mice with DISC1 mutations on the 35th and 60th day of their lives, the equivalent of adolescence and young adulthood.
Sawa cautions that it has not yet been shown that PAK is elevated in the brains of people with schizophrenia. It will be important, he says, to follow up on the mouse study to determine if a haywire PAK cascade also occurs in humans.
The researchers also found that mice behavior improved when PAK inhibitors were used. The mice were tested for their reaction to noises. There is a neuropsychiatric phenomenon in which any organism will react less to a strong, startling sound when they have first been primed by hearing a weaker one. In schizophrenia, the first noise makes no impact on the reaction to the second one.
Twice the benefit
The mice in the study showed improvements in their reactions after being treated with the PAK inhibitor. The drug was given in small doses and appeared to be safe for the animals.
“Drugs aimed at treating a disease should be able to reverse an already existing defect as well as block future damage,” Sawa says. “This compound has the potential to do both.”
Other researchers working on the study came from Johns Hopkins, the University at Buffalo, the University of Tokyo, PRESTO, the Japanese Science and Technology Agency, and Afraxis Inc., which makes FRAX486.
Grants from the National Institutes of Health, the Stanley Foundation, the RUSK Foundation, the S-R Foundation, the National Alliance for Research on Schizophrenia and Depression, Johns Hopkins Medicine’s Brain Science Institute, the Maryland Stem Cell Research Fund, the Japan Society for the Promotion of Science, PREST, and the Howard Hughes Medical Institute supported the work.
Source: Johns Hopkins University