title: Prothymosin alpha plays a key role in cell death mode-switch, a new concept for neuroprotective mechanisms in stroke.
abstract: After stroke or traumatic damages, both necrotic and apoptotic neuronal death cause a loss of functions including memory, sensory perception, and motor skills. From the fact that necrosis has a nature to expand, while apoptosis to cease the cell death cascade in the brain, it is considered that the promising target for the rapid treatment for stroke is the necrosis. In this study, I introduce the discovery of prothymosin alpha (ProTalpha), which inhibits neuronal necrosis, and propose its potentiality of clinical use for stroke. First of all, it should be noted that ProTalpha inhibits the neuronal necrosis induced by serum-free starvation or ischemia-reperfusion stress, which causes a rapid internalization of GLUT1/4, leading a decrease in glucose uptake and cellular ATP levels. Underlying mechanisms are determined to be through an activation of Gi/o, phospholipase C and PKCbetaII. ProTalpha also causes apoptosis later through a similar mechanism. However, we found that ProTalpha-induced apoptosis is completely inhibited by the concomitant treatment with neurotrophins, which are up-regulated by ischemic stress in the brain. Of most importance is the finding that the systemic injection of ProTalpha completely inhibits the brain damages, motor dysfunction and learning memory defect induced by cerebral ischemia-reperfusion stress. As ProTalpha almost entirely prevents the focal ischemia-induced motor dysfunction 4 h after the start of ischemia, this protein seems to have a promising potentiality for clinical use.
authors.affiliation: 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
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ueda
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D016503:Drug Delivery Systems; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D009336:Necrosis / Q000503:physiopathology / Q000517:prevention & control*; D009474:Neurons / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism / Q000494:pharmacology*; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology; D013947:Thymosin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D011498:Protein Precursors; C040782:prothymosin alpha; D013947:Thymosin; D000255:Adenosine Triphosphate; D005947:Glucose