Effects of cerebral ischemia in mice deficient in Persephin

Andreas C. Tomac, Alan D. Agulnick, Norman Haughey, Chen Fu Chang, Yajun Zhang, Cristina Bäckman, Marisela Morales, Mark P. Mattson, Yun Wang, Heiner Westphal, Barry J. Hoffer

Research output: Contribution to journalArticle

Abstract

Persephin (Pspn), a recently cloned member of the transforming growth factor-β superfamily (TGF-β) and glial cell line-derived neurotrophic factor (GDNF) subfamily, is distributed throughout the nervous system at extremely low levels and is thought to function as a survival factor for midbrain dopaminergic and spinal motor neurons in vivo. Here, we report that mice lacking Pspn by homologous recombination show normal development and behavior, but are hypersensitive to cerebral ischemia. A 300% increase in infarction volume was observed after middle cerebral artery occlusion. We find that glutamate-induced Ca2+ influx, thought to be a major component of ischemic neuronal cell death, can be regulated directly by the Persephin protein (PSP) and that PSP can reduce hypoxia/reperfusion cell death in vitro. Neuronal cell death can be prevented or markedly attenuated by administration of recombinant human PSP in vivo before ischemia in both mouse and rat models. Taken together, these data indicate that PSP is a potent modulator of excitotoxicity in the central nervous system with pronounced neuroprotective activity. Our findings support the view that PSP signaling can exert an important control function in the context of stroke and glutamate-mediated neurotoxicity, and also suggest that future therapeutic approaches may involve this novel trophic protein.

Original languageEnglish (US)
Pages (from-to)9521-9526
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number14
DOIs
StatePublished - Jul 9 2002
Externally publishedYes

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ASJC Scopus subject areas

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Cite this

Tomac, A. C., Agulnick, A. D., Haughey, N., Chang, C. F., Zhang, Y., Bäckman, C., Morales, M., Mattson, M. P., Wang, Y., Westphal, H., & Hoffer, B. J. (2002). Effects of cerebral ischemia in mice deficient in Persephin. Proceedings of the National Academy of Sciences of the United States of America, 99(14), 9521-9526. https://doi.org/10.1073/pnas.152535899