Neuroprotective effects of erythropoietin pretreatment in a rodent model of transient middle cerebral artery occlusion

Ratilal, Bernardo O; Arroja, Mariana Moreira Coutinho; Rocha, José Antonio; Fernandes, Adelaide; Barateiro, Andreia; Brites, Dora; Pinto, Rui; Sepodes, Bruno; Mota-Filipe, Hélder

doi:10.3171/2014.2.jns132197

Cited by 25 publications

(20 citation statements)

References 43 publications

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“…For gelatin zymography and Western blot analysis, the same animals were perfused via the ascending aorta with phosphate buffer saline solution, pH 7.4 (PBS). Brains were quickly removed, snap-frozen, and cryopreserved at −80°C for at least 24 h. Protein extracts were obtained by lysing the brain tissue with radioimmunoprecipitation assay (RIPA) buffer (Tris Buffer 1 M pH 8.0, EDTA 0.5 M pH 8.0, NaCl 5 M, 10% NP-40, 50% glycerol, 10% SDS) [ 53 ]. For cryo-histological analysis, B6 CX3CR1 gfp/+ animals were perfused with 4% PFA in PBS.…”

Section: Methodsmentioning

confidence: 99%

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Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects

Cardoso

Herz

Fernandes

et al. 2015

J Neuroinflammation

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BackgroundThe inflammatory mediator lipopolysaccharide (LPS) has been shown to induce acute gliosis in neonatal mice. However, the progressive effects on the murine neurodevelopmental program over the week that follows systemic inflammation are not known. Thus, we investigated the effects of repeated LPS administration in the first postnatal week in mice, a condition mimicking sepsis in late preterm infants, on the developing central nervous system (CNS).MethodsSystemic inflammation was induced by daily intraperitoneal administration (i.p.) of LPS (6 mg/kg) in newborn mice from postnatal day (PND) 4 to PND6. The effects on neurodevelopment were examined by staining the white matter and neurons with Luxol Fast Blue and Cresyl Violet, respectively. The inflammatory response was assessed by quantifying the expression/activity of matrix metalloproteinases (MMP), toll-like receptor (TLR)-4, high mobility group box (HMGB)-1, and autotaxin (ATX). In addition, B6 CX3CR1gfp/+ mice combined with cryo-immunofluorescence were used to determine the acute, delayed, and lasting effects on myelination, microglia, and astrocytes.ResultsLPS administration led to acute body and brain weight loss as well as overt structural changes in the brain such as cerebellar hypoplasia, neuronal loss/shrinkage, and delayed myelination. The impaired myelination was associated with alterations in the proliferation and differentiation of NG2 progenitor cells early after LPS administration, rather than with excessive phagocytosis by CNS myeloid cells. In addition to disruptions in brain architecture, a robust inflammatory response to LPS was observed. Quantification of inflammatory biomarkers revealed decreased expression of ATX with concurrent increases in HMGB1, TLR-4, and MMP-9 expression levels. Acute astrogliosis (GFAP+ cells) in the brain parenchyma and at the microvasculature interface together with parenchymal microgliosis (CX3CR1+ cells) were also observed. These changes preceded the migration/proliferation of CX3CR1+ cells around the vessels at later time points and the subsequent loss of GFAP+ astrocytes.ConclusionCollectively, our study has uncovered a complex innate inflammatory reaction and associated structural changes in the brains of neonatal mice challenged peripherally with LPS. These findings may explain some of the neurobehavioral abnormalities that develop following neonatal sepsis.

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Section: Methodsmentioning

confidence: 99%

“…Western blot analysis was performed as previously described [ 53 ] with minor alterations. Briefly, 100 μg of protein from tissue extracts were separated on a 12% SDS-PAGE gel.…”

Section: Methodsmentioning

confidence: 99%

Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects

Cardoso

Herz

Fernandes

et al. 2015

J Neuroinflammation

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“…Erythropoietin reduces inflammation by decreasing inflammatory cytokines, by attenuating reactivation astrocytosis and microglia activation and by inhibiting immune cells recruitment into the injured area ( 5 , 13 ). Although several in-vivo studies have shown an anti-inflammatory effect of erythropoietin, the affirmation of its in-vitro effect is controversial ( 4 , 15 ).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effect of Erythropoietin in Postoperation Cervical Spinal Cord Injury: Case Report and Review

et al. 2015

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Introduction:New research shows shown that erythropoietin has neuro-protective effects. In preclinical trial and human clinical trials, it was demonstrated that erythropoietin is effective treatment for spinal cord injury. Early administration of medications after injury increases the hope of attenuating secondary damage and maximizing an improved outcome.Case presentation:A 42-year-old female patient presented with gait instability and progressive weakness in her right leg over a 6-year period. She was diagnosed as myelomalacia and was candidate for cervical discectomy. After surgery, she suffered from right hemiplegia due to spinal cord injury that did not respond well to routine treatment. Darbepoetin alpha (Aranesp) 100 mcg, subcutaneous daily for three days, was added to the patient’s treatment seven days after trauma and resulted in rapid improvement. The patient recovered progressively and was discharged from the hospital ten days after erythropoietin therapy.Conclusions:This case report supports the beneficial role of erythropoietin in function, maintenance, and recovery of neurons. Erythropoietin is a double-edge sword, as long-term erythropoietin therapy has some complications, like thromboembolism and stroke. Recent studies suggested that erythropoietin should be given as single high dose to exert a rapid neuro-protective effect with minimal hematopoietic side effects. We believe that the effects and other adverse consequences of erythropoietin and its non-erythropoietic derivatives should be evaluated in clinical trials.

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“…A small burr hole was drilled 1 mm posterior to bregma and 0.5 mm lateral to midline, and the micro-Doppler probe was positioned above the dura mater in a holder glued to the bone. LDF was monitored continuously and recorded at 15 min before ICH induction and at 15-min intervals thereafter until 3 h after injury [60,61]. …”

Section: Methodsmentioning

confidence: 99%

Sex-Specific Effects of Progesterone on Early Outcome of Intracerebral Hemorrhage

Hsieh¹,

Lei²,

Sheng³

et al. 2015

Neuroendocrinology

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Background: Preclinical evidence suggests that progesterone improves recovery after intracerebral hemorrhage (ICH); however, gonadal hormones have sex-specific effects. Therefore, an experimental model of ICH was used to assess recovery after progesterone administration in male and female rats. Methods: ICH was induced in male and female Wistar rats via stereotactic intrastriatal injection of clostridial collagenase (0.5 U). Animals were randomized to receive vehicle or 8 mg/kg progesterone intraperitoneally at 2 h, then subcutaneously at 5, 24, 48, and 72 h after injury. Outcomes included relevant physiology during the first 3 h, hemorrhage and edema evolution over the first 24 h, proinflammatory transcription factor and cytokine regulation at 24 h, rotarod latency and neuroseverity score over the first 7 days, and microglial activation/macrophage recruitment at 7 days after injury. Results: Rotarod latency (p = 0.001) and neuroseverity score (p = 0.01) were improved in progesterone-treated males, but worsened in progesterone-treated females (p = 0.028 and p = 0.008, respectively). Progesterone decreased cerebral edema (p = 0.04), microglial activation/macrophage recruitment (p < 0.001), and proinflammatory transcription factor phosphorylated nuclear factor-κB p65 expression (p = 0.0038) in males but not females, independent of tumor necrosis factor-α, interleukin-6, and toll-like receptor-4 expression. Cerebral perfusion was increased in progesterone-treated males at 4 h (p = 0.043) but not 24 h after injury. Hemorrhage volume, arterial blood gases, glucose, and systolic blood pressure were not affected. Conclusions: Progesterone administration improved early neurobehavioral recovery and decreased secondary neuroinflammation after ICH in male rats. Paradoxically, progesterone worsened neurobehavioral recovery and did not modify neuroinflammation in female rats. Future work should isolate mechanisms of sex-specific progesterone effects after ICH.

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Neuroprotective effects of erythropoietin pretreatment in a rodent model of transient middle cerebral artery occlusion

Cited by 25 publications

References 43 publications

Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects

Systemic inflammation in early neonatal mice induces transient and lasting neurodegenerative effects

Neuroprotective Effect of Erythropoietin in Postoperation Cervical Spinal Cord Injury: Case Report and Review

Sex-Specific Effects of Progesterone on Early Outcome of Intracerebral Hemorrhage

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