Neonatal Hypoxia/Ischemia Is Associated With Decreased Inflammatory Mediators After Erythropoietin Administration

Abstract

Background and Purpose-Erythropoietin (EPO), a hematopoietic growth factor, has been shown to be neuroprotective when administered as either a pretreatment or posttreatment. This study tested the hypothesis that one of the mechanisms of protection afforded by posttreatment with recombinant human EPO (rh-EPO) is an anti-inflammatory effect via inhibition of interleukin (IL)-1␤. Methods-Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 90 minutes of hypoxia (8% O 2 at 37°C). Pups were divided into the following groups: control, hypoxia/ischemia, and hypoxia/ischemia plus rh-EPO. In the rh-EPO-treated pups, rh-EPO (5 U/g body weight IP) was administered starting 24 hours after the insult and then for 2 additional days. Samples were collected at 3, 7, 14, and 21 days after the insult. IL-1␤ mRNA and protein levels were determined by quantitative real-time reverse transcription-polymerase chain reaction and ELISA. Tumor necrosis factor (TNF)-␣ mRNA levels were determined by colorimetric microplate assay. Results-rhEPO attenuated brain injury, as assessed by brain weight, and attenuated both the hypoxia/ischemia-induced increases in IL-1␤ mRNA and protein levels. TNF-␣ mRNA levels did not increase at 3 to 14 days after the hypoxic/ischemic insult. Conclusions-Administration of exogenous rh-EPO starting 24 hours after a hypoxic/ischemic insult is neuroprotective in the neonatal rat. This neuroprotective activity prevented the secondary, delayed rise in IL-1␤ and attenuated the infiltration of leukocytes into the ipsilateral hemisphere.

Edaravone Inhibits DNA Peroxidation and Neuronal Cell Death in Neonatal Hypoxic-Ischemic Encephalopathy Model Rat

“…The apoptotic cells after 48 h of HI insult can be involved in other factors, such as inflammatory cytokines, in relation to microglial activation. IL-1beta (IL-1␤) expression gradually increases during 1-14 d after HI insult, and erythropoietin inhibits microglial activation and reduces brain damage (33). On the contrary, under the condition of hypoglycemia and hypoxemia by HI insult, IL-1␤ directly or indirectly attacks neurons and leads to neuronal cell death (34).…”

Effects of recombinant human erythropoietin on neuropathic pain and cerebral expressions of cytokines and nuclear factor-kappa B

“…8 NF-jB ''decoy'' (a new anti-gene approach) alleviates the hyperalgesia induced by spinal nerve ligation injury. 9 Furthermore, inhibition of IjB kinase (which phosphorylates IjB to activate NF-jB) reduces hyperalgesia in inflammatory and neuropathic pain models of rats. 22 Anti-inflammatory cytokine, IL-10, may inhibit a positive feed-forward loop between pro-inflammatory cytokines and NF-jB in both inflammation and neuropathic pain states.…”

“…6 rhEPO has neuroprotective effects in experimental models of central nervous system injury. [9][10][11] The possible mechanisms include anti-inflammation effects, 9-11 alterations in NF-jB activity, 21 and activation of glial cells 9 and antiapoptotic genes. 10,12 Few reports have suggested that systemically administered rhEPO can facilitate the recovery from behavioural changes during neuropathic pain associated with CCI, L5 spinal nerve crush, or nerve root injury.…”

“…2 Activated NF-jB is thus involved in the initiation and development of neuropathic pain via a neuron-mediated way of central sensitization and glia-mediated expressions of pro-inflammatory cytokines and pain mediators. 2,7,8 Several animal studies [9][10][11] have demonstrated that erythropoietin (EPO) or recombinant human erythropoietin (rhEPO) play a potent neuroprotective effect via antiinflammation following cerebral ischemia or traumatic brain injury. EPO may also alleviate the behavioural changes associated with neuropathic pain [12][13][14] ; however, the underlying mechanisms remain unclear.…”

Erythropoietin ameliorates chemotherapy‐induced fibrosis of the lungs in a preclinical murine model

“…The role of these cytokines in inflammation, edema formation, fibrosis and tissue remodeling has been well-documented. 24,25 For many years, EPO was considered to be a renally-produced, monolineage-specific hormone which functioned to stimulate the survival, proliferation and differentiation of erythroid cells. 6 However, several recent studies from our laboratory and others have shown that EPO has pleiotropic properties.…”