What evidence supports use of erythropoietin as a novel neurotherapeutic?
In its hormonal role, erythropoietin is produced by the kidney in response to hypoxic stress and signals the bone marrow to increase the number of circulating erythrocytes. It has become clear in recentyears, however, that erythropoietin and its receptor are members of a cytokine superfamily that mediates diverse functions in nonhematopoietic tissues. Nonhormonal erythropoietin actions include a critical role in the development, maintenance, protection, and repair of the central nervous system (CNS). Our group has found serendipitously that recombinant human erythropoietin administered into the systemic circulation is not strictly excluded from the brain. Human recombinant erythropoietin appears within the cerebrospinal fluid in neuroprotective concentrations, probably by translocation initiated by binding to the erythropoietin receptor on the luminal surface of the endothelium. This observation suggested that recombinant human erythropoietin could be therapeutic for CNS diseases, a possibility further supported by positive findings in a model of ischemic stroke. Recombinant human erythropoietin administered systemically either in advance of, or up to 3 hours after, a cerebral arterial occlusion in rats prevents apoptosis of neurons within the ischemic penumbra and reduces infarction volume by 75%. Erythropoietin also dramatically reduces postinfarct inflammation in this model. Other brain and spinal cord injuries such as mechanical trauma, experimental autoimmune encephalitis or subarachnoid hemorrhage also respond favorably to erythropoietin administered within a similar window of time. In addition to ameliorating neuronal injury, erythropoietic therapy also directly modulates neuronal excitability and acts as a trophic factor for neurons in vivo and in vitro. Erythropoietin may therefore provide benefit in epileptic or degenerative neurologic diseases. Given the outstanding safety record for recombinant human erythropoietin after more than a decade in widespread clinical use, the results of multiple preclinical investigations suggest that this cytokine or its derivatives may be useful for treatment of a variety of nervous system diseases.
Brines
Michael
M
The Kenneth S. Warren Institute, Kitchawan, New York 10562, USA. mbrines@kswi.org
D001921:Brain / Q000187:drug effects* / Q000473:pathology; D001927:Brain Diseases / Q000517:prevention & control*; D002986:Clinical Trials as Topic; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011994:Recombinant Proteins
D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068817:Epoetin Alfa