Recombinant Human Erythropoietin Protects against Experimental Spinal Cord Trauma Injury by Regulating Expression of the Proteins MKP-1 and p-ERK

Abstract

The present study explored the tissue-protective effect of erythropoietin in rats after experimental spinal cord injury (SCI) produced by dropping a weight onto surgically exposed spinal cord. Sixty rats were randomized to sham operation (spinal cord exposure; control), SCI plus intraperitoneal saline injection, or SCI plus intraperitoneal erythropoietin injection. Locomotor function was evaluated with Basso, Beattie and Bresnahan scores 1 day (24 h) and 7 days later, and rats were then killed for analysis of lesion site tissue. Compared with saline-treated SCI rats, erythropoietin-treated SCI rats showed significantly less locomotor dysfunction and faster locomotor recovery. Immunohistochemistry showed that erythropoietin-treated SCI rats had a significantly lower phospho-extracellular signal-regulated kinase (p-ERK) protein expression and a significantly higher mitogen-activated protein kinase phosphatase-1 (MKP-1) protein expression than saline-treated SCI rats. Haematoxylin–eosin staining showed progressive disruption of dorsal white matter and neuron loss after SCI; lesions were less severe and there was more neuron regeneration in the erythropoietin group than in the saline group. It is concluded that erythropoietin reduces pathological changes and SCI severity via down-regulation of p-ERK and up-regulation of MKP-1.

Keywords

Erythropoietin Spinal cord injury Immunohistochemistry Mitogen-activated protein kinase phosphatase-1 Phosphorylated extracellular signal-regulated kinase Rats

References

Zai

Yoo

Wrathall

: Increased growth factor expression and cell proliferation after contusive spinal cord injury. Brain Res 2005; 1052: 147–155.

Ashwell

Waite

: Advances in secondary spinal cord injury: Role of apoptosis. Spine 2000; 25: 1859–1866.

Park

Velumian

Fehlings

: The role of excitotoxicity in secondary mechanisms of spinal cord injury: A review with an emphasis on the implications for white matter degeneration. J Neurotrauma 2004; 21: 754–774.

Tei

Kaido

Nakase

: Secondary spinal cord hypoperfusion of circumscribed areas after injury in rats. Neurol Res 2005; 27: 403–408.

Segal

Pathak

: Optimal drug therapy and therapeutic drug monitoring after spinal cord injury: A population-specific approach. Am J Ther 2001; 8: 451–463.

Chen

Asavaritikrai

Prchal

: Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation. J Biol Chem 2007; 282: 25875–25883.

Cerami

Brines

Ghezzi

: Effects of epoetin alfa on the central nervous system. Semin Oncol 2001; 28: 66–70.

Gorostizaga

Brion

Maloberti

: Heat shock triggers MAPK activation and MKP-1 induction in Leydig testicular cells. Biochem Biophys Res Commun 2005; 327: 23–28.

Valere

Garnotel

Villena

: Activation of the cellular mitogen-activated protein kinase pathways ERK, P38 and JNK during Toxoplasma gondii invasion. Parasite 2003; 10: 59–64.

10.

Franceschini

Giusti

Skaper

: MEK inhibition exacerbates ischemic calcium imbalance and neuronal cell death in rat cortical cultures. Eur J Pharmacol 2006; 553: 18–27.

11.

Bernaudin

Tang

Reilly

: Brain genomic response following hypoxia and reoxygenation in the neonatal rat. Identification of genes that might contribute to hypoxia-induced ischemic tolerance. J Biol Chem 2002; 277: 39728–39738.

12.

Basso

Beattie

Bresnahan

: A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 1995; 12: 1–21.

13.

Kang

Yeo

Kang

: Cytoplasmic extracts from adipose tissue stromal cells alleviates secondary damage by modulating apoptosis and promotes functional recovery following spinal cord injury. Brain Pathol 2007; 17: 263–275.

14.

Wingrave

Schaecher

Sribnick

: Early induction of secondary injury factors causing activation of calpain and mitochondria-mediated neuronal apoptosis following spinal cord injury in rats. J Neurosci Res 2003; 73: 95–104.

15.

Louro

Pearse

: Stem and progenitor cell therapies: Recent progress for spinal cord injury repair. Neurol Res 2008; 30: 5–16.

16.

Yatsiv

Grigoriadis

Simeonidou

: Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury. FASEB J 2005; 19: 1701–1703.

17.

Chi

Flavell

: Acetylation of MKP-1 and the control of inflammation. Sci Signal 2008; 1: pe44.

18.

Choi

Hur

Lee

: Protein kinase Cδ-mediated proteasomal degradation of MAP kinase phosphatase-1 contributes to glutamate-induced neuronal cell death. J Cell Sci 2006; 119: 1329–1340.

19.

Jin

Mao

Zhu

: MEK and ERK protect hypoxic cortical neurons via phosphorylation of Bad. J Neurochem 2002; 80: 119–125.