A chemical called kynurenic acid may play a role in diseases characterised by cognitive impairments or psychosis, including schizophrenia, Alzheimer’s disease and bipolar disorder. Newly developed drugs that reduce this acid in the brain show promise in reducing symptoms of these conditions.
Kynurenic acid is in nearly every cell in every organism, though in humans it is most abundant in the brain where it regulates the release of neurotransmitters like glutamate and dopamine, says at the Karolinska Institute in Sweden.
Kynurenic acid increases during strokes, seizures and other conditions to protect against a process called , which is when excessive glutamate damages and kills neurons – but too much kynurenic acid can also be detrimental.
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In 2001, at the University of Maryland and his colleagues showed . They analysed tissue samples from the prefrontal cortex of 61 people who had died, 30 of whom had been diagnosed with schizophrenia. They found that, on average, kynurenic acid levels were more than 50 per cent higher in people with schizophrenia compared to those without.
Since then, researchers have found elevated levels of kynurenic acid in the brains and spinal fluid of people with Alzheimer’s disease, bipolar disorder and HIV, all of which can also cause psychosis. “We see that the highest levels of kynurenic acid is among [people] that have psychotic features,” says Erhardt, who presented these findings on 28 October at a symposium held by the Brain & Behaviour Research Foundation in New York City.
While these findings are only associations, other studies have found that increasing kynurenic acid in the brains of rodents and monkeys impairs cognition, particularly memory, learning, and visual and auditory abilities. Such deficits , says Erhardt.
Reducing kynurenic acid in rats also improves cognition, according to research from Schwarcz. More than 70 per cent of kynurenic acid in the brain is produced by an enzyme called KAT II.
In a 2014 study, Schwarcz and his colleagues gave 10 rats a 30 milligram per kilogram oral dose of a drug that inhibits KAT II once a day for five days, which between 25 and 35 per cent for about 1 hour.
The first day the rats had to find a platform in a water maze surrounded by signs, such as different coloured shapes, that they could use as landmarks. The rats repeated the experiment the following 4 days, but this time the platform was removed. Mice that were given the drug crossed into the area formerly occupied by the platform about twice as often, on average, as those who weren’t, indicating better spatial memory skills.
He and his colleagues have since developed and patented a similar KAT II inhibitor designed for use in humans that had no serious side effects when tested in primates for one month. Data from this trial is confidential.
“We have a drug that seems safe, so now it comes down to the big question: is it going to work?” says Schwarcz, who also presented his research at the Brain & Behaviour Research Foundation symposium. “It’s all based on animal experiments, and we need to see what happens when you reduce kynurenic acid production in humans.”
A phase I clinical trial of the drug is planned to begin next year in people with schizophrenia, he says.
“There’s a huge need for developing new drugs for patients with schizophrenia,” says Erhardt, who has developed a similar drug, though it hasn’t been tested in animals yet. “I think that if [these] drugs are successful, that will help many patients get back to a normal life.”
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