Johns Hopkins brain scientists have hit on how and why
some powerful drugs used for treating mental illnesses
cause patients to gain so much weight that they often
develop life-threatening complications such as diabetes and
heart disease.
"We've now connected a whole class of antipsychotics
to natural brain chemicals that trigger appetite," said
Solomon H. Snyder, professor of
neuroscience at the Johns Hopkins School of Medicine.
"Our identification of the molecular players that link such
drugs to increased food intake means there's now hope for
finding a newer generation of drugs without the weight-gain
side effects."
The discovery will be published online this week at
the Proceedings of the National Academy of
Sciences.
Previous research had fingered increased levels and
actions of one particular enzyme, AMPK, in brain cells as a
control lever for appetite in mice and presumably humans.
Suspecting that antipsychotic drugs might spike AMPK in the
brain to overact, the Johns Hopkins team injected mice with
clozapine (Clozaril), which, with olanzapine (Zyprexa) and
risperidone (Risperdal), is commonly prescribed for
schizophrenia and bipolar disorder in people who do poorly
on conventional drugs.
Mice given clozapine showed quadrupled AMPK activity
compared to activity measured pre-drug.
The researchers then gave the mice leptin, a hormone
that suppresses appetite and, as suspected, saw lowered
AMPK levels.
Drilling down further into what controls AMPK and its
boost of hunger, Sangwon Kim, a research associate and lead
author of the study, "rounded up the usual suspects-brain
proteins known to relay communication from cell to
cell."
Systematically manipulating these cell-signaling
proteins, Snyder's team found that blocking one in
particular, a receptor site for histamine, a well-known
player in triggering classic allergy symptoms, activates
AMPK to the same extent as clozapine. To confirm that the
histamine receptor connects the drug, AMPK activity and
appetite, the team gave clozapine to mice genetically
engineered without a histamine receptor.
Results? Peace. No heightened AMPK activity.
"Histamine also has a long history as a suspect in
weight control, but no one ever could put a finger on the
exact link," Snyder said. "The connection we've made
between its receptor and appetite control is incredibly
intriguing and opens new avenues for research on weight
control, possibly including drugs that suppress appetite
safely."
The research was funded by the U.S. Public Health
Service, Canadian Institute of Health Research, National
Institutes of Health and National Multiple Sclerosis
Society.
Authors on the paper are Kim, Alex Huang, Adele
Snowman and Snyder, all of Johns Hopkins; and Cory
Teuscher, of the University of Vermont College of
Medicine.
GO TO