Decreased levels of active <scp>uPA</scp> and <scp>KLK</scp>8 assessed by [<sup>111</sup>In]<scp>MICA</scp>‐401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy

Missault, Stephan; Peeters, Lore M.; Amhaoul, Halima; Thomae, David; Eetveldt, Annemie Van; Favier, Barbara; Thakur, Anagha; Soom, Jeroen Van; Pitkänen, Asla; Augustyns, Koen; Joossens, Jurgen; Staelens, Steven; Dedeurwaerdere, Stefanie

doi:10.1111/epi.13845

Cited by 8 publications

(11 citation statements)

References 40 publications

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“…Complete deficiency of Neuropsin has been shown to shift the E-I balance in vivo towards excitation, in the hippocampus of mice treated with kainic acid, thus leading to a more severe progression of the status epilepticus than in control [13]. Similarly, in an animal model of epilepsy, a pathological condition associated with strong recurrent excitation, we have recently found that the frequency of seizures is higher in epileptic rats that show a more pronounced decrease in active uPA and Neuropsin [40]. While our results do not unanimously point to a shift of the E-I balance in either direction, the inhibition of uPA and Neuropsin certainly had a profound effect on the dynamics of the network.…”

Section: Discussionmentioning

confidence: 76%

The Effect of Acute Pharmacological Inhibition of Urokinase Plasminogen Activator and Neuropsin Extracellular Proteases on Neuronal Networks in vitro

Missault

et al. 2018

Preprint

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Neuronal networks are surrounded by the extracellular matrix (ECM), which functions both as a scaffold and as a regulator of neuronal function. The ECM is in turn dynamically altered through the action of serine proteases, which break down its constituents. This pathway has been implicated in the regulation of synaptic plasticity and intrinsic excitability. Here, we determined the effects of acutely inhibiting two important regulators of the ECM, Urokinase Plasminogen Activator and Neuropsin, selectively and potently with the inhibitor UAMC-01162. Spontaneous electrophysiological activity was recorded from in vitro primary rat cortical cultures using microelectrode arrays. While inhibition at a low dosage had no significant effect, at elevated concentrations network bursting dynamics and functional connectivity were drastically altered. These results indicate that serine protease inhibition affects neuronal and synaptic properties, likely through their actions on the ECM. We propose that in the acute phase, a transient increase of excitatory synaptic efficacy is compensated for by a downregulation of single-cell excitability.

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Section: Discussionmentioning

confidence: 76%

The Effect of Acute Pharmacological Inhibition of Urokinase Plasminogen Activator and Neuropsin Extracellular Proteases on Neuronal Networks in vitro

Missault

et al. 2018

Preprint

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“…Neuropsin deficiency impairs the activation of ErbB4 positive GABAergic interneurons (Figure 5), resulting in hyper-activity of pyramidal neurons in the stimulated state and breakdown of the neuronal excitation-inhibition balance in hippocampal networks [20]. Supporting this theory, a recent study shows that reduced levels of active neuropsin are observed in CA1-CA3 subfields of the hippocampus, dentate gyrus, extrahippocampal temporal lobe and parietal cortex during spontaneous seizures in kainic acidinduced status epilepticus rats [37].…”

Section: The Neurobiology Of Neuropsinmentioning

confidence: 84%

Neuropsin in Mental Health

Bukowski

Chernomorchenko

Starnawska

et al. 2019

Preprint

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Neuropsin is an extracellular matrix serine protease that governs the proteolytic cleavage of synaptic proteins and consequently synaptic structural plasticity. In the brain, its substrates include the cell adhesion molecules Neuregulin-1 and L1CAM, that have been linked to neurodevelopmental processes and disorders, such as schizophrenia and bipolar disorder. Neuropsin mRNA is abundant in the cerebellum and several peripheral tissues from mid-gestation but is mainly expressed in cortical and limbic tissues postnatally. Differential usage of neuropsin splice forms in the fetal and adult brain has only been reported in humans, suggesting that neuropsin may serve a specialized role in human neurodevelopment. Accordingly, both the expression and proteolytic activity of neuropsin are subject to regulation by neural activity as well as by environmental risk factors associated with mental illness, such as psychophysiological stress. Intriguingly, dysregulation of neuropsin has been reported in depression and Alzheimer’s disease and its implication in mental disorder is supported by genetic and epigenome wide studies. Here we review neuropsin regulation in mental health and provide a summary of clinical and preclinical evidence supporting a role for neuropsin in the pathogenesis of mental disorders.

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“…Neural extracellular matrix functions have been linked with epilepsy . The expression of urokinase‐type plasminogen activator and kallikrein‐related peptidase 8, proteins involved in remodeling of the matrix proteins, is reduced in a rodent model of temporal lobe epilepsy, and this reduced expression is related inversely with seizure burden in epileptic animals …”

Section: Possible Epileptogenic Mechanisms Influenced By Microglial Pmentioning

confidence: 99%

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

et al. 2020

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Owing to the complexity of the pathophysiological mechanisms driving epileptogenesis following traumatic brain injury (TBI), effective preventive treatment approaches are not yet available for posttraumatic epilepsy (PTE). Neuroinflammation appears to play a critical role in the pathogenesis of the acquired epilepsies, including PTE, but despite a large preclinical literature demonstrating the ability of anti‐inflammatory treatments to suppress epileptogenesis and chronic seizures, no anti‐inflammatory treatment approaches have been clinically proven to date. TBI triggers robust inflammatory cascades, suggesting that they may be relevant for the pathogenesis of PTE. A major cell type involved in such cascades is the microglial cells—brain‐resident immune cells that become activated after brain injury. When activated, these cells can oscillate between different phenotypes, and such polarization states are associated with the release of various pro‐ and anti‐inflammatory mediators that may influence brain repair processes, and also differentially contribute to the development of PTE. As the molecular mechanisms and key signaling molecules associated with microglial polarization in brain are discovered, strategies are now emerging that can modulate this polarization, promoting this as a potential therapeutic strategy for PTE. In this review, we discuss the relevant literature regarding the polarization of brain‐resident immune cells following TBI and attempt to put into perspective a role in epilepsy pathogenesis. Finally, we explore potential strategies that could polarize microglia/macrophages toward a neuroprotective phenotype to mitigate PTE development.

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Decreased levels of active uPA and KLK8 assessed by [¹¹¹In]MICA‐401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy

Cited by 8 publications

References 40 publications

The Effect of Acute Pharmacological Inhibition of Urokinase Plasminogen Activator and Neuropsin Extracellular Proteases on Neuronal Networks in vitro

The Effect of Acute Pharmacological Inhibition of Urokinase Plasminogen Activator and Neuropsin Extracellular Proteases on Neuronal Networks in vitro

Neuropsin in Mental Health

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

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Decreased levels of active uPA and KLK8 assessed by [111In]MICA‐401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy

Cited by 8 publications

References 40 publications

The Effect of Acute Pharmacological Inhibition of Urokinase Plasminogen Activator and Neuropsin Extracellular Proteases on Neuronal Networks in vitro

The Effect of Acute Pharmacological Inhibition of Urokinase Plasminogen Activator and Neuropsin Extracellular Proteases on Neuronal Networks in vitro

Neuropsin in Mental Health

Microglial polarization in posttraumatic epilepsy: Potential mechanism and treatment opportunity

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Decreased levels of active uPA and KLK8 assessed by [¹¹¹In]MICA‐401 binding correlate with the seizure burden in an animal model of temporal lobe epilepsy