Prothymosin alpha and cell death mode switch, a novel target for the prevention of cerebral ischemia-induced damage.
Following stroke or traumatic damage, neuronal death via both necrosis and apoptosis causes loss of functions including memory, sensory perception and motor skills. Since necrosis has the nature to expand, while apoptosis stops the cell death cascade in the brain, necrosis is considered to be a promising target for rapid treatment for stroke. Pure neuronal necrosis occurs when cortical neurons are cultured under serum-free and low-density conditions. Prothymosin alpha (ProTalpha) isolated from conditioned medium after serum-free culture was found to prevent necrosis by recovering the energy crisis due to endocytosed glucose transporters. At a later time point under the same starvation conditions, ProTalpha causes apoptosis, which in turn seems to inhibit the rapidly occurring necrosis by cleaving poly (ADP-ribose) polymerase, a major machinery involved in ATP consumption. Indeed, ProTalpha administered via systemic routes markedly inhibits the histological and functional damage induced by cerebral and retinal ischemia. Although ProTalpha also causes a cell death mode switch from necrosis to apoptosis in vivo, the induced apoptosis was found to be completely inhibited by endogenously occurring brain-derived neurotrophic factor or erythropoietin. Since forced downregulation of ProTalpha deteriorates the ischemic damage, it is evident that ProTalpha plays in vivo neuroprotective roles after ischemic events. Analyses in terms of the therapeutic time window and potency suggest that ProTalpha could be the prototypic compound to develop the medicine useful for treatment of stroke in clinics.
Ueda
Hiroshi
H
Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. ueda@nagasaki-u.ac.jp
D000818:Animals; D017209:Apoptosis; D002545:Brain Ischemia / Q000150:complications / Q000503:physiopathology*; D016923:Cell Death; D016503:Drug Delivery Systems; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D006801:Humans; D007511:Ischemia / Q000150:complications / Q000503:physiopathology; D009336:Necrosis / Q000209:etiology / Q000517:prevention & control; D009474:Neurons / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D012164:Retinal Diseases / Q000150:complications / Q000503:physiopathology; D013947:Thymosin / Q000031:analogs & derivatives* / Q000378:metabolism
D051246:Glucose Transport Proteins, Facilitative; D011498:Protein Precursors; C040782:prothymosin alpha; D013947:Thymosin