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Before CNS Benefits of Erythropoietic Agents Can Be Realized, Transport Mechanisms Must Be Understood

Before CNS Benefits of Erythropoietic Agents Can Be Realized, Transport Mechanisms Must Be Understood

THOUSAND OAKS, California—How do endogenous and exogenous
erythropoietin (EPO) directly and indirectly affect the central nervous
system (CNS)? How can erythropoietic agents penetrate the
blood-brain/blood-cerebrospinal fluid (CSF) barrier so that their potential
neuroprotective benefits can be realized?

While these questions are still being investigated, some interim findings
were presented by Nelson L’ntshotsholé Jumbe, PhD, research scientist,
pharmacokinetics and drug metabolism, at Amgen in Thousand Oaks, California.

"Astrocytes and neurons have been shown to produce erythropoietin
and to express erythropoetic receptors," Dr. Jumbe said. "There’s
also evidence that CNS EPO mRNA, like systemic mRNA, is
hypoxia-inducible."

A learning test study with gerbils showed that brain activity requires
free-floating erythropoietin in the interstitial space, Dr. Jumbe reported.
In animals with 3-minute forebrain ischemia, exogenous erythropoietin had a
neuroprotective effect at doses ranging from 0.5 to 25 units/day over 7
days, administered as continuous infusion and started 8 to 24 hours before
the ischemic event. The effect was not concentration-dependent. "It was either an on or off mechanism; either it occurred or it didn’t,"
Dr. Jumbe said. He noted that no activity occurred at higher EPO
concentrations.

Soluble erythropoietic receptors reversed the effects of erythropoietic
therapy by binding with free-floating EPO. "This shows that you need
free-floating EPO in the interstitial space to get the neurons that are
destined for degeneration to survive...The same result was not seen when you
used denatured soluble erythropoietin receptor," Dr. Jumbe said.
"What the authors hypothesize from these data is that brain EPO is
pivotal in maintenance and recovery of neuronal viability."

Central and Peripheral EPO

Dr. Jumbe cited work by Chikuma et al (1998) that found no direct link
between central and peripheral EPO. During continuous hypoxia over 24 hours,
EPO mRNA was induced in the kidney and cerebrum of mice. In the kidney,
"after 4 hours, the message was downregulated and the serum levels also
followed suit," Dr. Jumbe reported. "However, in the CNS, the
total message was upregulated throughout the 24-hour period. This shows that
the CNS and systemic messages are actually not linked at all and that these
systems behave quite differently. This might be due to the different roles
that EPO plays in different regions," he explained.

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