Through experiments on mice, scientists in Japan believe they have happened upon a new drug to tackle schizophrenia, and one that is already approved for use as a dietary supplement. The repurposed drug appears to work by safeguarding the construction of the cellular skeleton of neurons, with mice with a genetic mutation that causes schizophrenia found to exhibit normal behaviors after being treated with the compound.
The drug at the center of the research is called betaine and it's used as a supplement to treat an inherited metabolic disease called homocystinuria. The authors of the new study, from the University of Tokyo, became interested in the compound on the back of studies that uncovered potential links between the gene behind the body's natural synthesis of betaine and schizophrenia, along with another gene by the name of kif3b.
The kif3b gene belongs to what's known as a kinesin superfamily of genes. These genes play an important role in mammals by encoding for motor proteins that work together to transport materials throughout neurons by moving up and down the cell's skeleton structure.
Mice with genetic mutations that leave them with just one functional copy of the kif3b gene often serve as animal models of schizophrenia, as they tend to avoid social interactions and respond similarly to human schizophrenia patients to what's known as a prepulse inhibition test, which subjects them to sudden, loud sounds after quieter sounds and measures how startled they are.
As the mice grew, the University of Tokyo scientists supplemented their diets with three times the amount of betaine they would normally consume, and found that they exhibited normal behavior. To dig into the reasons behind this, the team turned to nerve cells featuring the kif3b mutation that were grown in the lab and were fixed with fluorescent labels so the scientists could observe the activity around the cellular skeleton.
These mutant cells could be seen to grow differently to the way normal, healthy neurons develop, forming an unusually high amount of branch-like structures called dendrites. These types of neurons have also been observed in brain samples donated by people with schizophrenia, as has a type of chemical damage called carbonyl stress.
This stress impacts a protein called CRMP2 and inhibits its ability to assemble key components of the neuron's cellular skeleton, and a similar process was found to be at play in the kif3b mutant mice where the proteins were instead found to clump together. Because betaine is know to prevent carbonyl stress that leads to CRMP2 malfunction, the scientists believe that the supplement therefore clears the way for a healthy cellular skeleton to form, and for the kif3b proteins to perform their normal role of transporting materials throughout the neuron.
“We know that the amount of betaine decreases in schizophrenia patients’ brains, so this study strongly suggests betaine could be therapeutic for at least some kinds of schizophrenia,” says Nobutaka Hirokawa, who led the research.
The team now hopes to carry out further investigations involving clinical studies that explore the potential of betaine supplements as a schizophrenia treatment. Working in its favor is the fact that the drug is already considered safe for human consumption.
“I don’t encourage anyone to take betaine for no reason, if a doctor has not recommended it," says Hirokawa. "But, we know this drug is already used clinically, so repurposing it to treat schizophrenia should be safe."
The research was published in the journal Cell Reports.
Source: University of Tokyo
