Intravenous recombinant erythropoietin does not lead to an increase in cerebrospinal fluid erythropoietin concentration

Michele Buemi1, Alessandro Allegra1, Francesco Corica1, Fulvio Floccari1, Domenico D'Avella2, Carmela Aloisi1, Gioacchino Calapai3, Gerardo Iacopino2 and Nicola Frisina1

1 Department of Internal Medicine, 2 Institute of Neurosurgery and 3 Institute of Pharmacology, University of Messina, Italy

Correspondence and offprint requests to: Prof. Michele Buemi, Via Salita Villa Contino 30, I-98100 Messina, Italy.

Keywords: brain; cerebrospinal fluid; erythropoietin



   Introduction
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 Introduction
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Many studies have shown a close link between erythropoietin (Epo) and the brain. Epo mRNA has been found in biopsies from the human hippocampus, amygdala and temporal cortex. Low levels of oxygen can lead to increased Epo mRNA levels in the monkey brain, similar to that found in the mouse brain during the state of anaemia [1]. Moreover, brain capillary endothelial cells express two forms of Epo mRNA receptor [2] and Epo receptors are found in the central nervous system of mid-trimester human fetuses [3]. Moreover, in vitro studies have shown that Epo has a neuroprotective effect and this can prevent neuronal death induced by glutamate in a dose-dependent manner [4].

Recent findings by Marti et al. [5] demonstrate that Epo can originate directly from the brain. In the absence of important lesions, Epo produced by the kidney does not cross the blood brain barrier (BBB) [5]. To our knowledge, it is not known whether i.v. recombinant human erythropoietin (rHuEpo) can modify cerebral flow parameters and the characteristics of cerebrospinal fluid (CSF).



   Case
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 Case
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A 44-year-old white female underwent surgery for a primary tumour of the cranial fossa and right frontal ventriculostomy 7 days before the study. The patient had no other diseases and was not taking any medication. A radial artery was cannulated to obtain blood samples for gas analyses and for continuous monitoring of blood pressure. Permanent indwelling ventricular catheters (IVC) were inserted for the evaluation of cerebrospinal pressure and, if necessary, withdrawal of CSF. During the study the patient breathed normally, had no fever, was awake and not on sedation. The patient's head elevation was about 30°. An haemochromocytometric examination made in the morning showed Hb values of 12.3 g%. After obtaining the patient's informed consent, i.v. rHuEpo (6000 U) was administered at 8.00 a.m., following 12 h of fasting. Five minutes before and at 1 and 60 min after drug administration the following investigations were undertaken: CSF and serum Epo (Predicta Epo; Elisa Kit Genzyme Diagnostics), arterial blood gas analysis, CSF gas analysis, measurement of Na+, K+ and Ca2+ concentrations in plasma and CSF, CSF osmolarity and pressure (Nova biomedical), systemic arterial pressure and cardiac frequency.

The CSF/serum albumin ratio was calculated as a parameter of BBB function as described elsewhere [5]. A value of 0.008 was obtained. Evaluations of the cerebral flow at 0, 1, 5, 10 and 30 min were made using transcranial Doppler sonography (Emand Medasonics) with a 2 MHz probe with a time window.

We found no modifications in the cerebrospinal fluid concentrations of Epo after intravenous rHuEpo administration (Table 1Go).


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Table 1. Serum and CSF parameters at baseline and 1 min and 60 min after intravenous rHuEpo administration
 
TDS study showed an increase in the pulse index a minute after the administration of rHuEpo (0.62 vs 0.51) which peaked after 5 min (0.76), returning to basal values at the tenth minute (0.45). A reduction in Na+ concentration, an increase in O2 tension, a simultaneous reduction in CO2 concentration and an elevation of pH (Table 1Go) were found in the CSF 60 min after rHuEpo administration.



   Discussion
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 Introduction
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 Discussion
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Our data suggest that rHuEpo does not cross the haematoencephalic barrier. However, studies both on animals and humans have demonstrated that this hormone provides protection against cerebrovascular damage [6,7].

In our study, i.v. rHuEpo appeared to modify several parameters in the nervous system. However, conclusions concerning the effects of rHuEpo administration cannot be drawn based on the findings in only one patient.

The variation in Na+ content after rHuEpo administration suggests that the drug can directly, or more probably indirectly, affect the mechanism underlying CSF production which is Na+ dependent. Changes in ionic CSF concentrations can explain, at least in part, the modifications found by us in the acid-base balance [8]. The vasoconstrictive effect of the hormone may also influence the underlying liquor composition [9,10].

Further studies on larger patient series will help clarify some important aspects of the physiopathology of Epo in the brain and CSF in humans. They should, moreover, clarify whether alterations in the haematoencephalic barrier other than those considered by us may have a different influence on the behaviour of rHuEpo toward the haematoencephalic barrier itself.



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Received for publication: 10. 8.99
Accepted in revised form: 2.11.99