Cerebral calpain in fatal falciparum malaria

Medana, IM; Day, Nicholas; Hien, T T; H., Nt T.; Bethell, Delia; Phu, Nh H.; Turner, Gd D. H.; Farrar, Jeremy; White, Nicholas J.; Mm, Esiri

doi:10.1111/j.1365-2990.2006.00777.x

Cited by 14 publications

(20 citation statements)

References 40 publications

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“…The proposed mechanism suggests that Epo could increase axonal calcium levels as it has been shown to activate neural voltage-gated calcium channels [46]. Axonal injury in severe malaria is likely to involve increased levels of intracellular calcium reflected by increased levels of the calcium-activated cysteine protease, calpain [47]. …”

Section: Discussionmentioning

confidence: 99%

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

Medana

Day

Hien

et al. 2009

Malar J

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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.

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Section: Discussionmentioning

confidence: 99%

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

Medana

Day

Hien

et al. 2009

Malar J

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“…Some of these genes also have been implicated in neuronal death in neurological diseases (11,17,60), including CM (33,56). A number of protease inhibitors were expressed on the arrays, including CTLA-2␣ (22), and may represent a host mechanism to limit the damage mediated by proteases, particularly since these proteolytic processes can lead to development of intracerebral hemorrhaging (63), which is an invariable finding in human and murine CM.…”

Section: Discussionmentioning

confidence: 99%

Predominance of Interferon-Related Responses in the Brain during Murine Malaria, as Identified by Microarray Analysis

2008

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Cerebral malaria (CM) can be a fatal manifestation of Plasmodium falciparum infection. We examined global gene expression patterns during fatal murine CM (FMCM) and noncerebral malaria (NCM) by microarray analysis. There was differential expression of a number of genes, including some not yet characterized in the pathogenesis of FMCM. Some gene induction was observed during Plasmodium berghei infection regardless of the development of CM, and there was a predominance of genes linked to interferon responses, even in NCM. However, upon real-time PCR validation and quantitation, these genes were much more highly expressed in FMCM than in NCM. The observed changes included genes belonging to pathways such as interferon signaling, major histocompatibility complex processing and presentation, apoptosis, and immunomodulatory and antimicrobial processes. We further characterized differentially expressed genes by examining the cellular source of their expression as well as their temporal expression patterns during the course of malaria infection. These data identify a number of novel genes that represent interesting candidates for further investigation in FMCM.Malaria is a devastating disease affecting developing countries in the tropical and subtropical regions of the world. Cerebral malaria (CM), a severe manifestation of Plasmodium falciparum infection, can lead to neurological complications and death (64). Murine models of malaria are important tools for studying the pathogenesis of malaria, with numerous clinical and histopathological similarities between human and murine malaria having been described (19). Comparisons between fatal murine CM (FMCM) and noncerebral malaria (NCM) provide valuable insights into the pathogenesis of CM.A number of significant changes in the murine brain that characterize CM have been described, including breakdown of the blood-brain barrier (62), redistribution and activation of glia (31,32,34), apoptosis of endothelial cells and astrocytes (46,47), metabolic changes (44, 48), and distinct patterns of chemokine gene expression (38).A recent approach to identifying novel changes within the brain during CM is to profile gene expression changes using microarray technology (9, 30). Microarray studies can generate a plethora of data that pinpoint involvement of unknown or poorly characterized genes, stimulating investigation of their biological functions. Some studies have used microarrays to examine global gene expression patterns during murine malaria, defining gene expression profiles that are associated with susceptibility or resistance to murine CM (26, 27), identifying genes in the brain that discriminate between different outcomes of Plasmodium infection (5), or describing trends in gene expression within the brain (55). Studies on the spleen have been performed to find genes that differentiate between cerebral and noncerebral (55) and between lethal and nonlethal (52) forms of murine malaria. Microarrays also have been used to examine Plasmodium infection in humans (14, 41) and monke...

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“…Increased calpain levels have previously been reported in human and murine CM (45, 46). We corroborate these findings as we also found this when blotting for two independent markers of calpain activity: p25 and a 150 kDa fragment of α-spectrin.…”

Section: Discussionmentioning

confidence: 69%

“…We corroborate these findings as we also found this when blotting for two independent markers of calpain activity: p25 and a 150 kDa fragment of α-spectrin. Thus, aberrant VEGF signaling may activate calpains causing endothelial pathology and neuropathology (38, 45). We found that EPO therapy reduces cerebral VEGF and markers associated with calpain activity to levels comparable with uninfected mice.…”

Section: Discussionmentioning

confidence: 99%

“…Increased cerebral VEGF may directly contribute to neuropathology by promoting monocyte extravasation (56), BBB disruption, and calpain activity. Calpain activity is also increased in human CM (45) and inhibition of this pathway should be studied further. EPO reduces both hypoxia (64) and inflammation in murine CM (14, 15, 37), which likely prevents the upregulation of VEGF signaling pathway in the brain.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Systemic and Cerebral Vascular Endothelial Growth Factor Levels Increase in Murine Cerebral Malaria along with Increased Calpain and Caspase Activity and Can be Reduced by Erythropoietin Treatment

et al. 2014

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The pathogenesis of cerebral malaria (CM) includes compromised microvascular perfusion, increased inflammation, cytoadhesion, and endothelial activation. These events cause blood–brain barrier disruption and neuropathology and associations with the vascular endothelial growth factor (VEGF) signaling pathway have been shown. We studied this pathway in mice infected with Plasmodium berghei ANKA causing murine CM with or without the use of erythropoietin (EPO) as adjunct therapy. ELISA and western blotting was used for quantification of VEGF and relevant proteins in brain and plasma. CM increased levels of VEGF in brain and plasma and decreased plasma levels of soluble VEGF receptor 2. EPO treatment normalized VEGF receptor 2 levels and reduced brain VEGF levels. Hypoxia-inducible factor (HIF)-1α was significantly upregulated whereas cerebral HIF-2α and EPO levels remained unchanged. Furthermore, we noticed increased caspase-3 and calpain activity in terminally ill mice, as measured by protease-specific cleavage of α-spectrin and p35. In conclusion, we detected increased cerebral and systemic VEGF as well as HIF-1α, which in the brain were reduced to normal in EPO-treated mice. Also caspase and calpain activity was reduced markedly in EPO-treated mice.

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Cerebral calpain in fatal falciparum malaria

Cited by 14 publications

References 40 publications

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

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

Predominance of Interferon-Related Responses in the Brain during Murine Malaria, as Identified by Microarray Analysis

Systemic and Cerebral Vascular Endothelial Growth Factor Levels Increase in Murine Cerebral Malaria along with Increased Calpain and Caspase Activity and Can be Reduced by Erythropoietin Treatment

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