Methods and Compositions for Treating Degenerative and Ischemic Disorders

Abstract

Model systems have shown that shifting a cell's reliance from oxidative phosphorylation (OXPHOS) to glycolysis can protect against cell death. Exploiting the therapeutic potential of this strategy, however, has been limited by the lack of clinically safe agents that remodel energy metabolism. The present invention identifies non-toxic small molecules (e.g., drug-like compounds) that are capable of modulating oxidative metabolism. One identified compound comprises meclizine. As described herein, meclizine, and its enantiomer S-meclizine, redirects OXPHOS to glycolysis. Such compounds could be protective or therapeutic in degenerative disorders such as diabetes, Huntington's, Parkinson's, and Alzheimer's disease and/or ischemic disorders including, but not limited to, stroke, heart attack, or reperfusion injuries.

What is claimed is: 
     
         1 . The use of meclizine or an S-enantiomer thereof in the treatment or prevention of a condition associated with cell death associated with ischemic insult or a cellular degenerative disease. 
     
     
         2 . The use of meclizine or an S-enantiomer thereof in the treatment or prevention of type 2 diabetes. 
     
     
         3 . The use of  claim 1  or  2 , wherein the meclizine is S-meclizine. 
     
     
         4 . The use of any of  claims 1 - 3 , wherein the S-meclizine is substantially free of the R-enantiomer of meclizine. 
     
     
         5 . The use of  claim 1  or  2 , wherein the cellular degenerative disease is a neurodegenerative disease. 
     
     
         6 . The use of  claim 5 , wherein the neurodegenerative disease is Parkinson's, Disease, Alzheimer's Disease, Amyotrophic Lateral Sclerosis (ALS), Friedreich's ataxia, or Huntington's disease. 
     
     
         7 . The use of  claim 1  or  2 , wherein the condition is an ischemia-reperfusion injury. 
     
     
         8 . The method of  claim 7 , wherein the ischemia-reperfusion injury is myocardial ischemic injury, renal ischemic injury, or stroke. 
     
     
         9 . The use of any of  claims 1 - 8 , wherein meclizine is administered in a dose sufficient to produce a serum level of about 100 nm to 1 μM. 
     
     
         10 . The use of any of  claims 1 - 8 , wherein the meclizine is formulated for parenteral administration. 
     
     
         11 . The use of any of  claims 1 - 8 , wherein the meclizine is administered in a daily dose of about 25 mg/day or more. 
     
     
         12 . The use of meclizine or S-meclizine in the treatment of an infection with a parasite. 
     
     
         13 . The use of  claim 12 , wherein the S-meclizine is substantially free of the R-enantiomer of meclizine. 
     
     
         14 . The use of  claim 12 , wherein the parasite is selected from the group consisting of  Trypanosoma brucei, Trypanosoma cruzi , and  Plasmodium falciparum.    
     
     
         15 . A method of identifying a compound for the treatment of a condition associated with cell death associated with ischemic insult or a cellular degenerative disease, the method comprising:
 providing a sample comprising enzymatically active CTP:phosphoethanolamine cytidylyltransferase 2 (PCYT2);   contacting the sample with a test compound; and   determining activity of the PCYT2 in the sample in the presence and the absence of the test compound,   
       wherein a test compound that decreases activity of PCYT2 in the sample is a candidate compound for the treatment of the condition. 
     
     
         16 . The method of  claim 15 , wherein the sample is a living cell, and the method further comprises determining phosphoethanolamine (PEA) levels in the cell in the presence and absence of the test compound, wherein a test compound that increases levels of PEA in the cell is selected as a candidate compound for treatment of the condition.