Modulation of excitable tissue function by peripherally administered erythropoietin

Abstract

Methods and compositions are provided for protecting or enhancing excitable tissue function in mammals by systemic administration of an erythropoietin receptor activity modulator, such as erythropoietin, which signals via an EPO-activated receptor to modulate the function of excitable tissue. Excitable tissues include central neuronal tissues, such as the brain, peripheral neuronal tissues, retina, and heart tissue. Protection of excitable tissues provides treatment of hypoxia, seizure disorders, neurodegenerative diseases, hypoglycemia, and neurotoxin poisoning. Enhancement of function is useful in learning and memory. The invention is also directed to compositions and methods for facilitating the transport of molecules across endothelial cell tight junction barriers, such as the blood-brain barrier, by association of molecules with an erythropoietin receptor activity modulator, such as an erythropoietin.

1 . A method for enhancing the function of normal or abnormal excitable tissue in a mammal comprising administering peripherally to said mammal a peripherally effective excitable tissue enhancing amount of an EPO, an EPO receptor activity modulator, an EPO-activated receptor modulator, or combination thereof.  
     
     
         2 . The method of  claim 1  wherein said enhancing the function of excitable tissue results in the enhancement of associative learning or memory.  
     
     
         3 . The method of  claim 1  wherein said enhancing the function of excitable tissue is used in the treatment of mood disorders, anxiety disorders, depression, autism, attention deficit hyperactivity disorder, Alzheimer's disease, aging or cognitive dysfunction.  
     
     
         4 . The method of  claim 1  wherein said excitable tissue is central nervous system tissue or peripheral nervous system tissue.  
     
     
         5 . The method of  claim 1  wherein said administration comprises oral, topical, intraluminal or by inhalation or parenteral administration.  
     
     
         6 . The method of  claim 5  wherein said parenteral administration is intravenous, intraarterial, subcutaneous, intramuscular, intraperitoneal, submucosal or intradermal.  
     
     
         7 . The method of  claim 1  wherein said administration is acute or chronic.  
     
     
         8 . The method of  claim 1  wherein said EPO is nonerythropoietic.  
     
     
         9 . The method of  claim 1  wherein said EPO is administered at a dose greater than the dose necessary to maximally stimulate erythropoiesis.  
     
     
         10 . The method of  claim 1 , wherein said EPO is erythropoietin, an erythropoietin analog, an erythropoietin mimetic, an erythropoietin fragment, a hybrid erythropoietin molecule, an erythropoietin receptor-binding molecule, an erythropoietin agonist, a renal erythropoietin, a brain erythropoietin, an oligomer thereof, a multimer thereof, a mutein thereof, a congener thereof, a naturally-occurring form thereof, a synthetic form thereof, a recombinant form thereof, or a combination thereof.  
     
     
         11 . The method of  claim 10  wherein said EPO receptor-binding molecule is an antibody to the erythropoietin receptor.