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).

Keywords: cerebral ischemia; excitotoxicity; middle cerebral artery occlusion (MCAo); neuroprotection; neurovascular unit (NVU); plasminogen; tissue-type plasminogen activator (tPA).

Figure 1

Proposed mechanism for tPA-induced neuroprotection. Tissue-type plasminogen activator (tPA) either released from the presynaptic terminal (red circles) or given as a treatment (rtPA; red circles with a black margin) interact with a co-receptor formed by the low density lipoprotein receptor-related protein (LRP1; orange line) and the NMDA receptor (yellow squares) on the surface of the dendritic spine (post-synaptic compartment), leading to mTOR activation and mTOR-induced synthesis of the glucose transporter GLU3 (orange arrows) with the resultant increase in the uptake of glucose (green triangles).