Neuroprotective effects and intracellular signaling pathways of erythropoietin in a rat model of multiple sclerosis.
In multiple sclerosis (MS), long-term disability is primarily caused by axonal and neuronal damage. We demonstrated in a previous study that neuronal apoptosis occurs early during experimental autoimmune encephalomyelitis, a common animal model of MS. In the present study, we show that, in rats suffering from myelin oligodendrocyte glycoprotein (MOG)-induced optic neuritis, systemic application of erythropoietin (Epo) significantly increased survival and function of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. We identified three independent intracellular signaling pathways involved in Epo-induced neuroprotection in vivo: Protein levels of phospho-Akt, phospho-MAPK 1 and 2, and Bcl-2 were increased under Epo application. Using a combined treatment of Epo together with a selective inhibitor of phosphatidylinositol 3-kinase (PI3-K) prevented upregulation of phospho-Akt and consecutive RGC rescue. We conclude that in MOG-EAE the PI3-K/Akt pathway has an important influence on RGC survival under systemic treatment with Epo.
Sättler
M B
MB
Neurologische Universitätsklinik, Robert-Koch-Str. 40, 37075 Göttingen, Germany. msaettl@gwdg.de
Merkler
D
D
Maier
K
K
Stadelmann
C
C
Ehrenreich
H
H
Bähr
M
M
Diem
R
R
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004596:Electroretinography; D004921:Erythropoietin / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D020287:In Situ Nick-End Labeling / Q000379:methods; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000503:physiopathology; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000008:administration & dosage / Q000494:pharmacology*; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009900:Optic Nerve / Q000503:physiopathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011914:Rats, Inbred BN; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
C571328:Mog protein, rat; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D004921:Erythropoietin; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases