Thrombin regulation of synaptic transmission and plasticity: implications for health and disease

Shimon, Marina Ben; Lenz, Maximilian; Ikenberg, Benno; Becker, Denise; Stein, Efrat Shavit; Chapman, Joab; Tanné, David; Pick, Chaim G.; Blatt, Ilan; Neufeld, Miri Y.; Vlachos, Andreas; Maggio, Nicola

doi:10.3389/fncel.2015.00151

Cited by 59 publications

(65 citation statements)

References 81 publications

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“…In addition, as prothrombin is converted to thrombin upon an enzymatic cleavage by factor X (Ben Shimon et al . ; Stein et al . ), we also measured factor X mRNA levels.…”

Section: Resultsmentioning

confidence: 99%

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Increased thrombin activity following reperfusion after ischemic stroke alters synaptic transmission in the hippocampus

Bushi

Shimon

Stein

et al. 2015

Journal of Neurochemistry

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Thrombin, a key player in thrombogenesis, affects cells in the brain through activation of its receptors. Low levels of thrombin activity are protective while high levels are toxic. We sought to quantify thrombin activity levels and their spatial distribution in brains of mice following reperfusion after ischemic stroke focusing on infarct, peri-infarct and contralateral areas. In order to find out the contribution of brain-derived thrombin, mRNA levels of both prothrombin and factor X were determined. Furthermore, we assessed the effect of thrombin levels that were measured in the ischemic brain on synaptic transmission. We found that in the brains of mice following transient middle cerebral artery occlusion, thrombin activity is elevated throughout the ischemic hemisphere, including in peri-infarct areas (90 AE 33 and 60 AE 18 mU/mL, in the infarct and peri-infarct areas, respectively, compared to 11 AE 3 and 12 AE 5 mU/mL, in the corresponding contralateral areas; mean AE SE; p < 0.05). Brain mRNA levels of prothrombin and, in particular, factor X are up-regulated in the ischemic core. Hippocampal slices treated with thrombin concentrations as found in the ischemic hemisphere show altered synaptic responses. We conclude that high thrombin activity following reperfusion after ischemic stroke may cause synaptic dysfunction.

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“…In addition, as prothrombin is converted to thrombin upon an enzymatic cleavage by factor X (Ben Shimon et al . ; Stein et al . ), we also measured factor X mRNA levels.…”

Section: Resultsmentioning

confidence: 99%

“…Novel findings have shown that thrombin is synthesized in the brain with its levels being directly regulated in physiological and pathophysiological conditions (Ben Shimon et al . ). Specifically, upon OGD in vitro , we have found that brain‐derived thrombin rises and alters synaptic plasticity (Stein et al .…”

Section: Discussionmentioning

confidence: 97%

Increased thrombin activity following reperfusion after ischemic stroke alters synaptic transmission in the hippocampus

Bushi

Shimon

Stein

et al. 2015

Journal of Neurochemistry

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“…In this regard there are numerous anti-inflammatory approaches and, as recently reviewed by Bergold (2015), whereas many have been evaluated in animal models, few have translated to effective clinical development. An interesting agent under recent evaluation by our collaborative group is the small synthetic candidate drug 3,6′-dithiothalamide that inhibits the synthesis of tumor necrosis factor-alpha (TNF- α ) (Zhu et al, 2003; Greig et al, 2004).…”

Section: Pharmaceutical Treatments For Weight Drop-induced Damage mentioning

confidence: 99%

“…The uncovered N -terminal region then acts as a tethered ligand that activates the receptor (Gingrich and Traynelis, 2000). As recently reviewed by Maggio et al (2013a, b) and Ben Shimon et al (2015), PARs are present within the nervous system and whereas PAR-2 acts as a class of trypsin/tryptase-activated receptors, PAR-1, PAR-3, and PAR-4 are most efficiently triggered by thrombin (Gingrich and Traynelis, 2000). Within brain, PAR-1 is expressed on neurons and astrocytes, with stronger immunore-activity evident on astrocytces in human brain – particularly in the hippocampus, cortex, and striatum (Junge et al, 2004).…”

Section: Pharmaceutical Treatments For Weight Drop-induced Damage mentioning

confidence: 99%

Novel pharmaceutical treatments for minimal traumatic brain injury and evaluation of animal models and methodologies supporting their development

Deselms

Maggio

Rubovitch

et al. 2016

Journal of Neuroscience Methods

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Background The need for effective pharmaceuticals within animal models of traumatic brain injury (TBI) continues to be paramount, as TBI remains the major cause of brain damage for children and young adults. While preventative measures may act to reduce the incidence of initial blunt trauma, well-tolerated drugs are needed to target the neurologically damaging internal cascade of molecular mechanisms that follow. Such processes, known collectively as the secondary injury phase, include inflammation, excitotoxicity, and apoptosis among other changes still subject to research. In this article positive treatment findings to mitigate this secondary injury in rodent TBI models will be overviewed, and include recent studies on Exendin-4, N-Acetyl-l-cycteine, Salubrinal and Thrombin. Conclusions These studies provide representative examples of methodologies that can be combined with widely available in vivo rodent models to evaluate therapeutic approaches of translational relevance, as well as drug targets and biochemical cascades that may slow or accelerate the degenerative processes induced by TBI. They employ well-characterized tests such as the novel object recognition task for assessing cognitive deficits. The application of such methodologies provides both decision points and a gateway for implementation of further translational studies to establish the feasibility of clinical efficacy of potential therapeutic interventions.

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“…The signaling mechanisms that drive astrocytes toward a protective versus a toxic phenotype are not fully known (Bao, Hua, Keep, & Xi, ; H. Wang, Ubl, Stricker, & Reiser, ; Y. Wang, Luo, & Reiser, ). Cell–cell signaling via proteases acting on cell‐specific receptors underlies critical mechanistic steps in neurodevelopment and disease (Ben Shimon et al, ; Burda, Radulovic, Yoon, & Scarisbrick, ; De Luca, Virtuoso, Maggio, & Papa, ; Vaughan & Cunningham, ; Wagner et al, ; Yoon, Radulovic, Drucker, Wu, & Scarisbrick, ). The protease activated receptor (PAR), resides in multiple brain cell types, and the majority of PARs are found on astrocytes (Junge et al, ; H. Wang, Ubl, & Reiser, ) and endothelial cells, with lesser densities on neurons, pericytes, and oligodendroglia.…”

Section: Introductionmentioning

confidence: 99%

Neuron‐generated thrombin induces a protective astrocyte response via protease activated receptors

Rajput

Lamb

Kothari

et al. 2019

Glia

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Astrocytes protect neurons during cerebral injury through several postulated mechanisms. Recent therapeutic attention has focused on enhancing or augmenting the neuroprotective actions of astrocytes but in some instances astrocytes can assume a neurotoxic phenotype. The signaling mechanisms that drive astrocytes toward a protective versus toxic phenotype are not fully known but cell–cell signaling via proteases acting on cell‐specific receptors underlies critical mechanistic steps in neurodevelopment and disease. The protease activated receptor (PAR), resides in multiple brain cell types, and most PARs are found on astrocytes. We asked whether neuron‐generated thrombin constituted an important astrocyte activation signal because our previous studies have shown that neurons contain prothrombin gene and transcribed protein. We used neuron and astrocyte mono‐cell cultures exposed to oxygen‐glucose deprivation and a model of middle cerebral artery occlusion. We found that ischemic neurons secrete thrombin into culture media, which leads to astrocyte activation; such astrocyte activation can be reproduced with low doses of thrombin. Media from prothrombin‐deficient neurons failed to activate astrocytes and adding thrombin to such media restored activation. Astrocytes lacking PAR1 did not respond to neuron‐generated thrombin. Induced astrocyte activation was antagonized dose‐dependently with thrombin inhibitors or PAR1 antagonists. Ischemia‐induced astrocyte activation in vivo was inhibited after neuronal prothrombin knockout, resulting in larger strokes. Restoring prothrombin to neurons with a lentiviral gene vector restored astrocyte activation and reduced stroke damage. We conclude that neuron‐generated thrombin, released during ischemia, acts via PAR1 and may cause astrocyte activation and paracrine neuroprotection.

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Thrombin regulation of synaptic transmission and plasticity: implications for health and disease

Cited by 59 publications

References 81 publications

Increased thrombin activity following reperfusion after ischemic stroke alters synaptic transmission in the hippocampus

Increased thrombin activity following reperfusion after ischemic stroke alters synaptic transmission in the hippocampus

Novel pharmaceutical treatments for minimal traumatic brain injury and evaluation of animal models and methodologies supporting their development

Neuron‐generated thrombin induces a protective astrocyte response via protease activated receptors

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