Laboratoire Partenaire international (LPI)/ International Laboratory Partners (ILP)

Laboratoire Partenaire international (LPI)/ International Laboratory Partners (ILP)
(2024-2025)
Caen University Partner International University Partner
Name of PI: Carine ALI Name of PI: Elisa ZANIER
Current position: Professor Current position: MD, Head, Department of Acute Brain and Cardiovascular Injury
Research Unit: INSERM U1237 Research Unit: Laboratory of Traumatic Brain Injury and Neuroprotection
Institution: Mario Negri Institute
for Pharmacological Research, Milano, Italy

Our proposed IPL will focus on traumatic brain injury (TBI), which like ischemic stroke, is among the most frequent and devastating neurological disorders, with only few therapeutic options.
In Caen, we have an internationally recognized expertise on ischemic stroke (modeling, diagnosing, treating) and on the serine protease tPA (tissue-type plasminogen activator).
tPA is a pleiotropic protease initially characterized for its ability to activate plasminogen into plasmin in the blood stream, thus promoting vascular fibrinolysis. Recombinant tPA is thus the gold standard treatment at the acute phase of ischemic stroke. In the central nervous system, in addition to endothelial cells, brain cells (neurons, glial cells) also express tPA. In physiological conditions, tPA contributes either directly or indirectly to the modulation of process such as neuronal migration, neurite outgrowth, learning and memory as well as emotional responses and locomotor activity. tPA was also reported to contribute to the regulation of the neurovascular coupling. In pathological conditions such as ischemic stroke, tPA is known to influence neuronal fate, to modulate the integrity of the BBB and subsequent inflammatory processes (for recent reviews, see Thiebaut et al., Lancet Neurol, 2018; Seillier et al., Int J Mol Sci, 2022).
Following our princeps work (Nicole et al., Nat Med, 2001), a large number of tPA’s functions have been attributed to direct or indirect modulations of glutamate-dependent NMDA (N-methyl-D-aspartate) receptors. Caen’s partner is the worldwide discoverer of a peculiar mode of action of tPA in the brain: briefly, tPA was reported to bind amino-terminal domain of GluN1 subunit (NTD of GluN1) of NMDA receptors, with two critical amino-acids involved, Lysine 178 and Arginine 260. Accordingly, point mutation of the Lysine 178 prevents tPA-induced potentiation of NMDA-evoked calcium influx and neuronal death (Fernandez-Monreal et al., Mol Cell Neurosci, 2004; Lesept et al., Cell Death Dis, 2016). Our findings in Caen also suggest that such a mechanism occurs at the luminal side of endothelial cells, thus promoting transmigration of inflammatory cells across the BBB (Macrez et al., Brain, 2016).

Interestingly, ischemic stroke and traumatic brain injury display various common physiopathological features, especially excitotoxic neuronal death, and inflammatory processes associated with alterations of the blood-brain barrier (BBB). Caen’s team has already benefited from the expertise of Milan’s team, a world leader on translational research on TBI. Both partners have already collaborated to show by a unique innovative imaging modality (molecular imaging) that as a function of its severity, TBI can induce cerebrovascular inflammation (Vegliante et al., J Clin Med, 2019; Drieu et al., J Cerebr Blood F Met, 2022). Thus, TBI, like ischemic stroke, also has a neurovascular injury component in its natural history. tPA may play both beneficial and deleterious effects after TBI, maybe depending on which compartment (vascular/parenchymal) it acts (Armstead et al., J Neurotrauma, 2013; Meng et al., PlosOne, 2014; Hijazi et al., Blood, 2015; Xia et al., PNAS, 2018; Armstead et al., J Neurosci Res, 2018). But to our knowledge, no one has ever investigated the potential contribution of the interaction of tPA with NMDA receptor to TBI pathogenesis, and has never explored its possible therapeutic value for TBI.

Here we propose that investigating the interaction between tissue plasminogen activator (tPA) and NMDA receptors in both neurons and endothelial cells could:
1. Enhance our understanding of the pathophysiology of traumatic brain injury (TBI).
2. Unveil novel therapeutic opportunities for TBI.