KITCHAWAN, New YorkBeyond its "classical" hormonal role
signaling bone marrow to increase circulating red blood cells,
erythropoietin (EPO) and its receptor (EPO-R) may have critical roles in the
development, maintenance, protection, and repair of the brain. These roles
rely on the status of the EPO and EPO-R molecules as cytokines and have been
demonstrated by animal studies. Michael L. Brines, MD, PhD, senior member at
the Kenneth S. Warren Institute in Kitchawan, New York, reported on these
studies as well as "highly positive" results of the first human
trial using recombinant human EPO to treat stroke.
"When the erythropoietin gene was cloned in the mid 1980s and its
receptor in the 1990s, it became clear immediately that these molecules were
actually related to cytokines and were members of a very large family, a
super family, of cytokines that had many effects in many different parts of
the body," Dr. Brines said.
Dr. Brines cited an experiment with mice stripped of their EPO and EPO-R.
As expected, the effect in these knock-out mice "is lethal before birth
because no red blood cells were formed," Dr. Brines said. "But, in
addition, if you look carefully at those embryos, one finds that the brain
doesn’t develop properly." The brain and the hearts were hypoplastic
and if other tissues are examined closely, they may display abnormalities as
Crosses Blood-Brain Barrier
While developing an animal model to evaluate the effects of
erythropoietin on the feeling of well-being, researchers in Dr. Brines’s
laboratory found that peripherally administered erythropoietin "was
having remarkable effects on behavior. This implied that the administered
erythropoietin made it through the blood-brain barrier somehow, even though
it is a large molecule that’s highly glycosylated." This discovery
led to a series of experiments using animal models to evaluate EPO’s
potential to treat human disease.
"Some of the aspects of erythropoietin activity in the brain are
similar to what occurs in the periphery," Dr. Brines explained. In its
hormonal roles, EPO is produced by the kidney under hypoxic stress. In vitro
studies conducted nearly a decade ago revealed that astrocytes removed from
the brain make erythropoietin under stress. "Subsequent studies show
that one principal target is neurons and the effect is to increase tolerance
to the stressor, in this case, hypoxia," he added (see Figure 1). The
erythropoietin gene and its receptor make up a signaling system that
influences the gene expression program in specific neurons and responds to
local ischemic stress.
To determine if peripherally administered erythropoietin actually crosses
the blood brain barrier, researchers injected erythropoietin systemically
into rats and then tested the cerebral spinal fluid (CSF) since most
substances that make it into the brain are cleared by the CSF. After a delay
of 1.5 hours, the rats had levels of erythropoietin substantially above the
basal level and high enough to confer neuroprotection, Dr. Brines reported.
These data have been replicated
by two independent laboratories,
one using sheep and the other using primates.