THOUSAND OAKS, CaliforniaHow do endogenous and exogenous erythropoietin(Drug information on 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.