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Ketamine Findings Suggest Path to New Schizophrenia Drugs

Compounds that inhibit NADPH oxidase without affecting its natural protective function of killing bacteria could open the door to new therapies for schizophrenia.

The street drug ketamine—already known to cause schizophrenia-like symptoms by blocking the NMDA receptor—appears also to disrupt brain circuitry by overexcitation of an inflammatory enzyme in the brain.

The drug has been found to increase the activity of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme complex, which is naturally found in white blood cells circulating outside the brain. The enzyme helps to kill bacterial and fungal infections by producing "superoxide," a toxic, free radical that causes substantial damage to cells.

But overexcitation of the enzyme by ketamine causes it to attack neurons critical to signaling in the brain, according to a report published in the December 7, 2007, Science.

The lead author of the report was M. Margarita Behrens, Ph.D., associate project scientist in the Department of Medicine at the University of California, San Diego School of Medicine (UCSD).

The result is impairment of the brain circuitry involved in memory, attention, and other key functions related to learning. Loss of such functions is believed to lead to symptoms that are indistinguishable from schizophrenia—deficits in information processing, hallucinations, delusions, social withdrawal, and cognitive problems.

Using ketamine, Behrens and colleagues elicited schizophrenia-like features in mice and then analyzed neurons in a region of the mouse brain that corresponds to the prefrontal cortex in humans. The researchers found a substantial increase in the activity of NADPH oxidase and that this activity caused a decrease in critical neurons, known as parvalbumin interneurons.

The latter are involved in the temporal encoding and storage or recall of information required for working memory, according to the report in Science.

When the researchers blocked the activity of NADPH oxidase with an inhibitor or with a compound that annihilates superoxide, these neurons were protected.

Behrens and colleagues suggested that if compounds could be developed that inhibit NADPH oxidase without affecting its natural protective function of killing bacteria, it could open the door to new therapies for schizophrenia.

"We hypothesize that NADPH oxidase may be a contributor to oxidative mechanisms involved not only in the psychotomimetic effects of NMDA-R antagonists, but also in schizophrenia and other processes involving increased oxidative stress in the brain," Behrens and colleagues wrote. "Further understanding of mechanisms underlying activation or induction of brain NADPH oxidase may provide a completely new avenue for drug discovery aimed at the treatment of psychosis and cognitive deficits."

The research was funded by a private endowment to UCSD and by NARSAD.

"Ketamine-Induced Loss of Phenotype of Fast-Spiking Interneurons Is Mediated by NADPH-Oxidase" is posted at <www.sciencemag.org/cgi/content/full/318/5856/1645>.

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