Does the neuroprotective agent Erythropoietin amplify diffuse axonal injury in its early stages?

Tubbs, R. Shane; Shoja, Mohammadali Mohajel; Jamshidi, Masoud; Shokouhi, Ghaffar

doi:10.1016/j.mehy.2007.03.002

Cited by 5 publications

(4 citation statements)

References 5 publications

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“…More recently, the possibility that Epo may amplify axonal injury in its early stages following TBI has been highlighted. 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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“…rEpo inhibits apoptosis of cultured neurons deprived of growth factors or exposed to kainic acid, and of endothelial cells by activating MEK‐ERK1/2 and phosphatidylinositol‐3 kinase‐Akt pathways 51. Also, rEpo is able to induce the expression of neuroprotective genes via nuclear factor‐κB 52…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin protects the developing brain from hyperoxia‐induced cell death and proteome changes

Kaindl

Sifringer

Koppelstaetter

et al. 2008

Annals of Neurology

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“…However, EPO can increase the calcium influx [147]. This can promote TAI progression in the early phase, so its applicability remains limited [148]. A recent RCT showed no improvement of neurological outcome 6 months after TBI after administration of erythropoietin [149,150].…”

Section: Treatment Preventing Secondary Axotomymentioning

confidence: 99%

Traumatic axonal injury (TAI): definitions, pathophysiology and imaging—a narrative review

et al. 2020

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Introduction Traumatic axonal injury (TAI) is a condition defined as multiple, scattered, small hemorrhagic, and/or non-hemorrhagic lesions, alongside brain swelling, in a more confined white matter distribution on imaging studies, together with impaired axoplasmic transport, axonal swelling, and disconnection after traumatic brain injury (TBI). Ever since its description in the 1980s and the grading system by Adams et al., our understanding of the processes behind this entity has increased. Methods We performed a scoping systematic, narrative review by interrogating Ovid MEDLINE, Embase, and Google Scholar on the pathophysiology, biomarkers, and diagnostic tools of TAI patients until July 2020. Results We underline the misuse of the Adams classification on MRI without proper validation studies, and highlight the hiatus in the scientific literature and areas needing more research. In the past, the theory behind the pathophysiology relied on the inertial force exerted on the brain matter after severe TBI inducing a primary axotomy. This theory has now been partially abandoned in favor of a more refined theory involving biochemical processes such as protein cleavage and DNA breakdown, ultimately leading to an inflammation cascade and cell apoptosis, a process now described as secondary axotomy. Conclusion The difference in TAI definitions makes the comparison of studies that report outcomes, treatments, and prognostic factors a daunting task. An even more difficult task is isolating the outcomes of isolated TAI from the outcomes of severe TBI in general. Targeted bench-to-bedside studies are required in order to uncover further pathways involved in the pathophysiology of TAI and, ideally, new treatments.

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Does the neuroprotective agent Erythropoietin amplify diffuse axonal injury in its early stages?

Cited by 5 publications

References 5 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

Erythropoietin protects the developing brain from hyperoxia‐induced cell death and proteome changes

Traumatic axonal injury (TAI): definitions, pathophysiology and imaging—a narrative review

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