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Galanin is interesting to Bartfai because this unassuming
peptide appears to be one way in which ACh levels are regulated
in the body. Galanin seems to have a local feedback in ACh
release, regulating the neuronal excitability in that part
of the brain, the hippocampus, and, in turn, influencing cognition.
"It is clear that [galanin has] quite a large effect on cognition,"
he says.
Galanin also controls the pain threshold at the spinal cord
level through the same neuronal action in the spinal cord
that morphine uses—hyperpolarizing primary sensory neurons.
Transgenic models with no galanin receptors, for instance,
have different pain thresholds. One possible application for
this is to develop a class of galanin receptor agonists—non-opiate
pain relievers that could be taken with morphine, for instance,
to lower the required dose of morphine eight-fold or more
as suggested by animal experiments.
Galanin is also a growth-promoting, or trophic, molecule,
and its local expression is required for the growth of certain
neurons. In Alzheimer's disease, galanin is overexpressed
in the basal forebrain. Moreover, as Alzheimer's disease wipes
out many of the cholinergic neurons of the hippocampus, those
that survive in the nucleus show elevated expression of galanin.
"We don't know how to use this observation, but it is clear
that galanin, as a modulator of cholinergic activity, is important
for the survival and function of the cholinergic nucleus,"
says Bartfai. "And the function of the cholinergic nucleus
is what we want to restore in [Alzheimer's] patients, because
that is the best replicated way of ensuring cognitive improvement."
For instance, the only approved Alzheimer drugs, Arisept and
Excellon, enhance cholinergic activity."
Despite everything that is known, however, Bartfai admits
he doesn't fully understand the mechanism of galanin's action
or how to use it. This is one of the things he aims to accomplish
at TSRI.
Bartfai's work has led to three galanin receptors becoming
the target of more than 20 projects in the pharmaceutical
industry. At the moment, Bartfai and his colleagues in the
Harold L. Dorris Neurological Research Center are looking
to establish combinatorial libraries that he hopes will eventually
lead to the creation of more effective galanin receptor antagonists
for antidepressant and cognition-enhancing therapies.
Coming Home to TSRI
Bartfai joined TSRI as a professor of neuropharmacology
in 1999, and was appointed director of the Harold L. Dorris
Neurological Research Center a few months later. The center
was founded with a remarkable $10 million endowment from Helen
L. Dorris of San Diego—the largest TSRI had ever received
for research in the neurosciences.
Bartfai came to TSRI after serving as senior vice president
in charge of central nervous system (CNS) research at Hoffman-LaRoche,
a department most famous for the drug Valium, and for its
Parkinson's disease drugs. He was brought there to develop
a major human genetics effort to aid discovery of new treatments
for schizophrenia and Alzheimer's disease. Prior to working
at Hoffman-LaRoche he was involved in the development of Zimelidine,
the first selective serotonin reuptake inhibitor (SSRI) and
two anti-psychotic agents used in the treatment of schizophrenia
as a consultant for ASTRA (now ASTRA–Zeneca).
"I reorganized and refocused [the research group at Hoffman-LaRoche],"
says Bartfai. "Once that was done, the job became very administrative,
and I came here."
After his appointment as director, he decided to focus on
the center to maximize the synergy between the researchers.
To do this, he recruited two associate and two assistant professors,
who, in addition to their own research agendas, had research
interests in common with Bartfai. These shared areas of interest
include developing new models for schizophrenia, finding faster-acting
anti depressants, addressing basic questions involving fever
and sleep as they tie into depression, and examining the role
of cytokines in inflammation and pain.
Bartfai sees the Harold L. Dorris Neurological Research
Center as the link between the chemistry at TSRI and the whole-organism
behavioral studies of the Neuropharmacology Department—with
the aim and the tools for doing nothing short of understanding
the brain's function in biochemical terms. He points to the
department's work on antidepressants as an example.
Depression is a widespread and often debilitating psychiatric
condition marked by persistent feelings of sadness or hopelessness,
inactivity, changes to sleep and eating patterns, and suicidal
tendencies. The National Institute of Mental Health estimates
that in any given year, about one out of every ten American
adults suffer through some major form of depression. And about
two percent of all Americans will use antidepressants at some
point in their lives.
Normal antidepressants take two or three weeks to take effect,
and as many as a third of patients do not respond to the drugs.
This is problematic because the core symptom of serious depression
is suicidal tendencies. In 1997, for instance, 30,535 Americans
committed suicide, making it the eighth leading cause of death
in the United States that year. One of Bartfai's longstanding
goals is to develop a quick-acting compound for the treatment
of depression. "We just don't know how to make such a tablet
yet," he says.
Electroconvulsive therapy and sleep deprivation are the
two known methods of bringing on a rapid antidepressive response,
but, while effective, neither method produces longlasting
effects. The antidepressant effect of sleep deprivation, for
example, only lasts about 48 hours. (Clinical sleep deprivation,
says Bartfai, must be monitored by professionals and is not
the same thing as staying up late. "That just makes people
irritated," he says).
Bartfai predicts that in the next three to four years, his
department should have identified some drug targets that,
when manipulated, will lead to a fast-acting antidepressant.
"That would be great," he says, because [in my lifetime]
there have been more young people [who have died] from suicide
than who died in World War II."
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