Research ReportContinuous intraventricular infusion of erythropoietin exerts neuroprotective/rescue effects upon Parkinson's disease model of rats with enhanced neurogenesis
Introduction
Parkinson's disease (PD) is a neurodegenerative disease with clinical symptoms such as bradykinesia, rigidity, tremor and abnormal postural reflexes (Sethi, 2002). The medication using l-DOPA is established as an effective therapy, although long term administration of l-DOPA causes side effects including on–off phenomena, wearing-off phenomena, or drug-induced dyskinesia. Surgeries such as deep brain stimulation and thalamotomy are also established with a certain achievement. However the therapeutic tools for PD above described are all symptomatic, but not essential and regenerative. As hopeful therapeutic tools for PD, transplantation of fetal nigral cell or infusion of glial cell line-derived neurotrophic factor (GDNF) was developed. However, nigral cell transplantation just achieved partial effectiveness and GDNF therapy did not show any significant behavioral amelioration in several randomized controlled trials (Lang et al., 2006, Freed et al., 2001). Therefore, it is important to develop new therapies.
Erythropoietin (EPO) is a well-known hematopoietic hormone produced in the kidney. EPO is used for renal anemia and proven safe. Recent studies revealed various potentials of EPO other than hematopoiesis. Neuroprotective effects of EPO have been demonstrated in a variety of animal models of hypoxic/ischemic CNS disorders (Maurer et al., 2008). Neuroprotective effects of EPO were proved using preclinical models of CNS diseases including focal and global ischemia, neurotrauma, autoimmune encephalitis, kainate-induced seizures, subarachnoid hemorrhage and spinal cord injury. Furthermore, EPO is used for patients with cerebral infarct and effectiveness was demonstrated recently (Ehrenreich et al., 2002). The mechanisms of EPO-induced neuroprotection include prevention of glutamate-induced toxicity, inhibition of apoptosis, anti-inflammatory effects, anti-oxidant effects, and stimulation of angiogenesis (Montero et al., 2007, Zhang et al., 2006, Liu et al., 2005). In our study, we would like to clarify if EPO exerts neuroprotective/rescue and neurogeneic effects on 6-hydroxydopamine (6-OHDA)-treated dopaminergic neurons in vivo.
Section snippets
Intraventricular EPO infusion did not demonstrate significant hematopoietic effects
The low dose (100 IU/day) of EPO-treated rats slightly increased without significant differences in hematocrit (47 ± 3.5%) and hemoglobin (15.7 ± 0.7 g/dl), compared with the control (43 ± 4.1% and 14.1 ± 0.6; p = 0.11 and 0.08, respectively). All rats in the both groups were healthy and had no differences in the spontaneous behavior.
EPO reduced the number of amphetamine-induced rotation
There were no significant changes in the spontaneous behavior between EPO-treated and the control rats (data not shown). In the control rats, the number of
Discussion
In this study, continuous infusion of low dose of EPO exerted neuroprotective/rescue effects on Parkinson's disease model of rats behaviorally and immunohistochemically. The neuroprotective/rescue effects were at least partially mediated through anti-apoptotic effects via the increase of phosphorylated Akt and neurogeneic effects in the subventricular zone.
Conclusions
Continuous infusion of low dose of EPO exerted neuroprotective/rescue effects in reversing behavioral deficits associated with PD and prevented apoptosis of the dopaminergic neurons through the PI3K pathway. Additionally, EPO might enhance intrinsic neurogenesis and migration towards damaged striatum. Recent pharmacological development enabled us to take advantages of EPO without hematopoietic side effects (Lapchak, 2008, Villa et al., 2007, Leist et al., 2004). Consequently, EPO might be a
Experimental protocol
Neurotoxin, 6-hydroxydopamine (6-OHDA) was injected into the right striatum of female Sprague–Dawley rats. Thirty minutes later, rats were divided into 2 groups, that is, EPO-treated rats and the control rats. Because our preliminary study using single administration of EPO did not show any neuroprotective effects on PD model of rats, continuous administration of EPO was designed. In EPO-treated rats, EPO (100 IU/day) dissolved in rat serum albumin was continuously infused into the right
Acknowledgments
This work was supported in part by Grants-in-Aid for Scientific Research and by the grant from the Project for realization of regenerative medicine from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
References (28)
- et al.
Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation
J. Biol. Chem.
(2007) - et al.
Erythropoietin protects the developing brain against N-methyl-d-aspartate receptor antagonist neurotoxicity
Neurobiol. Dis.
(2004) - et al.
Exogenous erythropoietin provides neuroprotection of grafted dopamine neurons in a rodent model of Parkinson's disease
Brain Res.
(2006) - et al.
Comparison of neuroprotective effects of erythropoietin (EPO) and carbamylerythropoietin (CEPO) against ischemia-like oxygen-glucose deprivation (OGD) and NMDA excitotoxicity in mouse hippocampal slice cultures
Exp. Neurol.
(2007) - et al.
Ablation of the subthalamic nucleus protects dopaminergic phenotype but not cell survival in a rat model of Parkinson's disease
Exp. Neurol.
(2004) - et al.
Intrastriatal administration of erythropoietin protects dopaminergic neurons and improves neurobehavioral outcome in a rat model of Parkinson's disease
Neuroscience
(2007) - et al.
A potential role for erythropoietin in focal permanent cerebral ischemia in mice
J. Cereb. Blood Flow Metab.
(1999) - et al.
Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades
Nature
(2001) - et al.
Erythropoietin therapy for acute stroke is both safe and beneficial
Mol. Med.
(2002) - et al.
Transplantation of embryonic dopamine neurons for severe Parkinson's disease
N. Engl. J. Med.
(2001)
Adult neural stem and progenitor cells modified to secrete GDNF can protect, migrate and integrate after intracerebral transplantation in rats with transient forebrain ischemia
Eur. J. Neurosci.
Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease
Ann. Neurol.
Carbamylated erythropoietin to treat neuronal injury: new development strategies
Expert Opin. Investig. Drugs
Derivatives of erythropoietin that are tissue protective but not erythropoietic
Science
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