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Author Notes:
Email Address:Manuel Yepes :myepes@emory.edu
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Subjects:
Research Funding:
This work was supported in part by National Institutes of Health Grant NS-079331 (to MY).
Keywords:
- cerebral ischemia, neurovascular unit (NVU)
- middle cerebral artery occlusion (MCAo)
- tissue-type plasminogen activator (tPA)
- neuroprotection
- excitotoxicity
- plasminogen
Tissue-type plasminogen activator is a neuroprotectant in the central nervous system
Abstract:
Tissue-type plasminogen activator (tPA) is a serine proteinase found not only in the intravascular space but also in a well-defined sub-set of neurons in the brain. tPA is rapidly released from neurons after either exposure to hypoxia or hypoglycemia in vitro, or the induction of cerebral ischemia in vivo. It has been proposed that tPA has a neurotoxic effect in the ischemic brain. However, recent evidence indicate that once released into the synaptic cleft tPA activates specific cell signaling pathways that promote the detection and adaptation to metabolic stress. More specifically, the non-proteolytic interaction of tPA with N-methyl-D-aspartate receptors (NMDARs) and a member of the low-density lipoprotein receptor (LDLR) family in dendritic spines activates the mammalian target of rapamycin (mTOR) pathway that adapts cellular processes to the availability of energy and metabolic resources. TPA-induced mTOR activation in neurons leads to hypoxia-inducible factor 1α (HIF-1α) accumulation, HIF-1α-induced expression and membrane recruitment of the neuronal transporter of glucose GLUT3, and GLUT3-mediated uptake of glucose. These and other data discussed in this Review suggest that the postulated neurotoxic effect of tPA needs to be reconsidered and instead indicate the emergence of a new paradigm: that tPA is an endogenous neuroprotectant in the central nervous system (CNS).
Copyright information:
© 2015 Yepes.
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits distribution of derivative works, distribution, public display, and publicly performance, making multiple copies, provided the original work is properly cited. This license requires copyright and license notices be kept intact, credit be given to copyright holder and/or author.
