Erythropoietin and its receptors in the brainstem of adults with fatal falciparum malaria

Isabelle M Medana,Gareth Dh Turner,Nicholas Pj Day,Tran Tinh Hien,Nicholas J White

doi:10.1186/1475-2875-8-261

Abstract

BackgroundFacilitation of endogenous neuroprotective pathways, such as the erythropoietin (Epo) pathway, has been proposed as adjuvant treatment strategies in cerebral malaria. Whether different endogenous protein expression levels of Epo or differences in the abundance of its receptor components could account for the extent of structural neuropathological changes or neurological complications in adults with severe malaria was investigated.MethodsHigh sensitivity immunohistochemistry was used to assess the frequency, distribution and concordance of Epo and components of its homodimeric and heteromeric receptors, Epo receptor and CD131, within the brainstem of adults who died of severe malaria. The following relationships with Epo and its receptor components were also defined: (i) sequestration and indicators of hypoxia; (ii) vascular damage in the form of plasma protein leakage and haemorrhage; (iii) clinical complications and neuropathological features of severe malaria disease. Brainstems of patients dying in the UK from unrelated non-infectious causes were examined for comparison.ResultsThe incidence of endogenous Epo in parenchymal brain cells did not greatly differ between severe malaria and non-neurological UK controls at the time of death. However, EpoR and CD131 labelling of neurons was greater in severe malaria compared with non-neurological controls (P = .009). EpoR labelling of vessels was positively correlated with admission peripheral parasite count (P = .01) and cerebral sequestration (P < .0001). There was a strong negative correlation between arterial oxygen saturation and EpoR labelling of glia (P = .001). There were no significant correlations with indicators of vascular damage, neuronal chromatolysis, axonal swelling or vital organ failure.ConclusionCells within the brainstem of severe malaria patients showed protein expression of Epo and its receptor components. However, the incidence of endogeneous expression did not reflect protection from vascular or neuronal injury, and/or clinical manifestations, such as coma. These findings do not provide support for Epo as an adjuvant neuroprotective agent in adults with severe malaria.

Highlights

Facilitation of endogenous neuroprotective pathways, such as the erythropoietin (Epo) pathway, has been proposed as adjuvant treatment strategies in cerebral malaria
It is unlikely that the low CD131 signal reflects degradation of the antigen in the malaria sections since the CSA kit was required for optimal staining of the lymphoma positive control sections
No differences were observed between the frequency of Epo or erythropoietin receptor (EpoR) labelled cells visualized with the Novolink or CSA kit but high diffuse background noise was less frequently observed with Novolink for these antibodies

Summary

Introduction

Facilitation of endogenous neuroprotective pathways, such as the erythropoietin (Epo) pathway, has been proposed as adjuvant treatment strategies in cerebral malaria. Whether different endogenous protein expression levels of Epo or differences in the abundance of its receptor components could account for the extent of structural neuropathological changes or neurological complications in adults with severe malaria was investigated. The ability of the brain to adapt to a range of insults may be critical in determining whether patients are protected from neurological complications and death during severe malaria infection. Boosting endogenous protective mechanisms is a potential treatment strategy of current interest in neurological diseases [1]. Epo and its receptors are expressed in tissue outside the haematopoietic system and Epo has been identified as a cytoprotective agent in both neuronal and vascular systems. Whether Epo is indifferent, protects or damages the brain appears to be related to the amount of Epo reaching the brain (reviewed in [3])

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