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Prothymosin α plays a key role in cell death mode-switch, a new concept for neuroprotective mechanisms in stroke

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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 α (ProTα), which inhibits neuronal necrosis, and propose its potentiality of clinical use for stroke. First of all, it should be noted that ProTα 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 PKCβII. ProTα also causes apoptosis later through a similar mechanism. However, we found that ProTα-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 ProTα completely inhibits the brain damages, motor dysfunction and learning memory defect induced by cerebral ischemia-reperfusion stress. As ProTα 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.

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Acknowledgements

I cordially thank Dr Ryousuke Fujita for the great contribution to this study and manuscript. This study was supported by the Grants-in-Aid for Scientific Research (to H.U., B: 13470490 and B: 15390028) on Priority Areas—Research on Pathomechanisms of Brain Disorders (to H.U., 17025031) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and Encouragement of Young Scientists (to R.F., B: 17790066) from the Japan Society for the Promotion of Science (JSPS).

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  1. Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki, 852–8521, Japan

    Hiroshi Ueda

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Correspondence to Hiroshi Ueda.

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Ueda, H. Prothymosin α plays a key role in cell death mode-switch, a new concept for neuroprotective mechanisms in stroke. Naunyn-Schmied Arch Pharmacol 377, 315–323 (2008). https://doi.org/10.1007/s00210-007-0254-7

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