The brain-specific tissue-type plasminogen activator inhibitor, neuroserpin, protects neurons against excitotoxicity both in vitro and in vivo
Molecular and Cellular Neuroscience. 2005-12-01; 30(4): 552-558
DOI: 10.1016/j.mcn.2005.09.005
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Considering its brain-specific expression, neuroserpin (NS), a potent inhibitor
of tissue-type plasminogen activator (tPA), might be a good therapeutic target to
limit the pro-excitotoxic effects of tPA within the cerebral parenchyma, without
affecting the benefit from thrombolysis in stroke patients. Here, we aimed at
determining the mechanisms of action responsible for the previously reported
neuroprotective activity of NS in rodent experimental cerebral ischemia. First,
we show in vivo that exogenous NS protects the cortex and the striatum against
NMDA-induced injury. Then, the cellular mechanisms of this neuroprotection were
investigated in primary cultures of cortical neurons. We show that NS fails to
prevent serum deprivation-induced apoptotic neuronal death, while it selectively
prevents NMDA- but not AMPA-induced excitotoxicity. This beneficial effect is
associated to a decrease in NMDA receptor-mediated intracellular calcium influx.
Altogether, these data suggest that an overexpression of neuroserpin in the brain
parenchyma might limit the deleterious effect of tPA on NMDA receptor-mediated
neuronal death, which occurs following experimental ischemia.