Use of ketone esters for prevention of cns oxygen toxicity

Abstract

The present invention demonstrates the therapeutic use of ketone esters for seizure disorders, Alzheimer's disease and malignant brain cancer, which are associated with metabolic dysregulation. The administration of ketone esters resulted therapeutic ketosis and neuroprotection against seizures resulting from CNS oxygen toxicity. Supplemental ketones were also found to reduce superoxide production in cultured cortex neurons exposed to hyperbaric oxygen and Aβ-42, and to decrease proliferation and viability in U87 glioma cells. These observations support the therapeutic effect of ketones for seizure disorders, Alzheimer's disease and malignant brain cancer. The ketone esters may be derived from acetoacetate and can include R,S-1,3-butanediol acetoacetate monoester, R,S-1,3-butanediol acetoacetate diester, or a combination of the two.

1 - 19 . (canceled) 
     
     
         20 . A method of protecting against hyperoxia-induced stress comprising
 inducing ketosis in a subject in need of hyperbaric oxygen by administering a therapeutically effective dose of a composition comprising R,S-1,3-butanediol acetoacetate, R,S-1,3-butanediol acetoacetate diester, or a combination thereof, in a sufficient amount to elevate blood β-hydroxybutyrate (BHB) and acetoacetate (AcAc) ketones level in the blood to a total amount of at least 1 mM,   wherein administration of the composition reduces superoxide anion production and thus oxidative stress, and   wherein the composition is administered with an unrestricted diet.   
     
     
         21 . The method of  claim 20 , wherein the composition comprises R,S-1,3-butanediol acetoacetate ester. 
     
     
         22 . The method of  claim 21 , wherein the composition comprises R,S-1,3-butanediol acetoacetate monoester. 
     
     
         23 . The method of  claim 21 , wherein the composition comprises R,S-1,3-butanediol acetoacetate diester. 
     
     
         24 . The method of  claim 21 , wherein the composition comprises a combination of R,S-1,3-butanediol acetoacetate monoester and R,S-1,3-butanediol acetoacetate diester. 
     
     
         25 . A method of increasing latency time and resistance to hyperoxia-induced seizure due to hyperbaric oxygen (HBO 2 ) exposure comprising
 inducing ketosis in a subject in need of hyperbaric oxygen by administering a therapeutically effective dose of a composition comprising R,S-1,3-butanediol acetoacetate, R,S-1,3-butanediol acetoacetate diester, or a combination thereof, in a sufficient amount to elevate blood β-hydroxybutyrate (BHB) and acetoacetate (AcAc) ketones level in the blood to a total amount of at least 1 mM,   wherein administration of the composition reduces superoxide anion production and thus oxidative stress, and   wherein the composition is administered with an unrestricted diet.   
     
     
         26 . A method of protecting against central nervous system oxygen toxicity in a subject in need of hyperbaric oxygen comprising:
 inducing ketosis in a subject in need of hyperbaric oxygen by administering a therapeutically effective dose of a composition comprising R,S-1,3-butanediol acetoacetate, R,S-1,3-butanediol acetoacetate diester, or a combination thereof, in a sufficient amount to elevate blood β-hydroxybutyrate (BHB) and acetoacetate (AcAc) ketones level in the blood to a total amount of at least 1 mM,   wherein administration of the composition reduces superoxide anion production and thus oxidative stress, and   wherein the composition is administered with an unrestricted diet.