Ketamine Impairs Brain by Releasing Superoxide

THURSDAY Dec. 6, 2007 -- Researchers say they have figured out how the drug ketamine impairs the brain, a finding they claim could lead to new treatments for schizophrenia.

The anesthetic/antidepressant triggers increased production of a toxic free radical called superoxide and induces schizophrenia-like behavior in drug users, but that action can be blocked, say researchers at the University of California, San Diego, School of Medicine (UCSD).

The findings are published in the Dec. 7 issue of Science.

In this study with mice, the researchers discovered a link between an inflammatory enzyme complex (NADPH oxidase) and the dysfunction of certain brain neurons exposed to ketamine. Normally, NADPH is found in white blood cells circulating outside the brain, where it helps kill infections by producing superoxide.

"Because of NADPH oxidase's protective role in fighting infection, it was very surprising to find that the complex wears a second hat -- it is also critical for modulating signaling in the brain," study first author M. Margarita Behrens, of the geriatric medicine division at the UCSD School of Medicine, said in a prepared statement.

It was known that ketamine can impair inhibitory circuitry in the brain by blocking a receptor that controls neuron activity. But the UCSD team found that ketamine also greatly boosts the activity of NADPH, which results in further disruption of neuron signaling and impairment of brain circuitry involved in memory, attention and other important learning functions.

The researchers used ketamine to induce schizophrenia-like symptoms in mice and found that changes in the rodents' brains occurred in an area similar to where brain changes occur in people with schizophrenia.

When the researchers used an inhibitor to block the activity of NADPH, or a compound that wipes out superoxide, neurons in this brain area were protected.

"Our findings suggest that compounds that inhibit NADPH oxidase in the brain, without totally blocking its protective function of killing bacteria, could provide future therapies for schizophrenia or other diseases in humans that exhibit similar changes in neural circuitry," Behrens said.

More information

Mental Health America has more about schizophrenia.

Posted: December 2007


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