Astroglial cytoprotection by erythropoietin pre-conditioning: implications for ischemic and degenerative CNS disorders.
Erythropoietin (Epo) is a glycoprotein secreted by the kidney in response to hypoxia that stimulates erythropoiesis through interaction with cell surface Epo receptors. Pre-treatment with Epo has been shown to protect neurons in models of ischemic injury. The mechanism responsible for this neuroprotection and the effects of Epo on astroglial and other non-neuronal cell populations remain unknown. In the present study, we determined whether Epo pre-treatment protects neonatal rat astrocytes from apoptotic cell death resulting from treatment with nitric oxide, staurosporine (STS) and arsenic trioxide and possible mechanisms mediating Epo-related cytoprotection. Epo (5-20 U/mL) significantly attenuated multiple hallmarks of apoptotic cell death in astroglia exposed to nitric oxide and STS but not arsenic trioxide. Epo (20 U/mL) induced mild oxidative stress as shown by increases in heme oxygenase (HO)-1 mRNA and protein expression that could be suppressed by antioxidant coadministration. Moreover, coincubation with tin-mesoporphyrin, a competitive inhibitor of HO activity, abrogated the cytoprotective effects of Epo (20 U/mL) in the face of STS treatment. Thus, induction of the ho-1 gene may contribute to the glioprotection accruing from high-dose Epo exposure. Epo may augment astroglial resistance to certain chemical stressors by oxidative stress-dependent and -independent mechanisms.
Diaz
Zuanel
Z
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada.
Assaraf
Michael I
MI
Miller
Wilson H
WH
Schipper
Hyman M
HM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002493:Central Nervous System Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D019194:Ischemic Preconditioning / Q000379:methods; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D004921:Erythropoietin