Thrombin and protein C pathway in peripheral nerve Schwann cells

Gera, Orna; Shavit‐Stein, Efrat; Bushi, Doron; Harnof, Sagi; Shimon, Marina Ben; Weiss, Ronen; Golderman, Valery; Dori, Amir; Maggio, Nicola; Finegold, Kate; Chapman, Joab

doi:10.1016/j.neuroscience.2016.10.034

Cited by 20 publications

(23 citation statements)

References 46 publications

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“…Elevation of thrombin is in-line with previously observed nervous system disease models such as stroke [23], mild-traumatic brain injury (mTBI) [24], nerve crush [25] and the finding that thrombin activity influences synaptic function [24,26–28].…”

Section: Discussionsupporting

confidence: 82%

The role of thrombin in the pathogenesis of diabetic neuropathy

et al. 2019

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Diabetic neuropathy is common and disabling despite glycemic control. Novel neuroprotective approaches are needed. Thrombin and hypercoagulability are associated with diabetes and nerve conduction dysfunction. Our aim was to study the role of thrombin in diabetic neuropathy. We measured thrombin activity by a biochemical assay in streptozotocin (STZ)-induced diabetic neuropathy in male Sprague-Dawley rats. Neuropathy severity was assessed by thermal latency and nerve conduction measures. Thermal latencies were longer in diabetic rats, and improved with the non-specific serine-protease inhibitor Tosyl-L-lysine-chloromethyl ketone (TLCK) treatment (p<0.01). The tail nerve of diabetic rats showed slow conduction velocity (p˂0.01), and interestingly, increased thrombin activity was noted in the sciatic nerve (p˂0.001). Sciatic nodes of Ranvier and the thrombin receptor, protease activated receptor 1 (PAR1) reactivity showed abnormal morphology in diabetic animals by immunofluorescence staining (p<0.0001). Treatment of diabetic animals with either the specific thrombin inhibitor, N-alpha 2 naphtalenesulfonylglycyl alpha-4 amidino-phenylalaninepiperidide (NAPAP) or TLCK preserved normal conduction velocity, (p˂0.01 and p = 0.01 respectively), and prevented disruption of morphology (p˂0.05 and p˂0.03). The results establish for the first time an association between diabetic neuropathy and excessive activation of the thrombin pathway. Treatment of diabetic animals with thrombin inhibitors ameliorates both biochemical, structural and electrophysiological deficits. The thrombin pathway inhibition may be a novel neuroprotective therapeutic target in the diabetic neuropathy pathology.

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Section: Discussionsupporting

confidence: 82%

The role of thrombin in the pathogenesis of diabetic neuropathy

et al. 2019

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“…Nexin-1, instead, a member of the large serpin superfamily, directly inhibits thrombin proteolytic activity (Cavanaugh et al, 1990; Gurwitz and Cunningham, 1990). In injured sciatic nerves, thrombin levels are elevated immediately after damage and reach their peak 1 day post-injury, declining after one week (Smirnova et al, 1996; Gera et al, 2016). On the contrary, upregulation of Nexin-1 in injured nerves occurs 6–9 days after thrombin induction (Meier et al, 1989; Smirnova et al, 1996) and is required to neutralize excessive thrombin proteolytic activity.…”

Section: Plasminogen Activators and Related Proteasesmentioning

confidence: 99%

The Complex Work of Proteases and Secretases in Wallerian Degeneration: Beyond Neuregulin-1

Pellegatta

Taveggia

2019

Front. Cell. Neurosci.

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After damage, axons in the peripheral nervous system (PNS) regenerate and regrow following a process termed Wallerian degeneration, but the regenerative process is often incomplete and usually the system does not reach full recovery. Key steps to the creation of a permissive environment for axonal regrowth are the trans-differentiation of Schwann cells and the remodeling of the extracellular matrix (ECM). In this review article, we will discuss how proteases and secretases promote effective regeneration and remyelination. We will detail how they control neuregulin-1 (NRG-1) activity at the post-translational level, as the concerted action of alpha, beta and gamma secretases cooperates to balance activating and inhibitory signals necessary for physiological myelination and remyelination. In addition, we will discuss the role of other proteases in nerve repair, among which A Disintegrin And Metalloproteinases (ADAMs) and gamma-secretases substrates. Moreover, we will present how matrix metalloproteinases (MMPs) and proteases of the blood coagulation cascade participate in forming newly synthetized myelin and in regulating axonal regeneration. Overall, we will highlight how a deeper comprehension of secretases and proteases mechanism of action in Wallerian degeneration might be useful to develop new therapies with the potential of readily and efficiently improve the regenerative process.

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“…In ischemic and hemorrhagic stroke, microglia are recruited to the site of injury where they mediate neuronal death [ 54 ] and contribute to brain recovery [ 44 ]. In these settings, the upregulated brain concentrations of thrombin have been linked to neuronal damage [ 26 , 29 , 30 , 55 , 56 ]. In Alzheimer's disease and in vascular dementia, high levels of thrombin and other coagulation factors have been detected in the brain aside with the recruitment of microglia and additional inflammatory components [ 57 – 59 ].…”

Section: Discussionmentioning

confidence: 99%

Thrombin Inhibition Reduces the Expression of Brain Inflammation Markers upon Systemic LPS Treatment

et al. 2018

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Systemic inflammation and brain pathologies are known to be linked. In the periphery, the inflammation and coagulation systems are simultaneously activated upon diseases and infections. Whether this well-established interrelation also counts for neuroinflammation and coagulation factor expression in the brain is still an open question. Our aim was to study whether the interrelationship between coagulation and inflammation factors may occur in the brain in the setting of systemic inflammation. The results indicate that systemic injections of lipopolysaccharide (LPS) upregulate the expression of both inflammatory and coagulation factors in the brain. The activity of the central coagulation factor thrombin was tested by a fluorescent method and found to be significantly elevated in the hippocampus following systemic LPS injection (0.5 ± 0.15 mU/mg versus 0.2 ± 0.03 mU/mg in the control). A panel of coagulation factors and effectors (such as thrombin, FX, PAR1, EPCR, and PC) was tested in the hippocampus, isolated microglia, and N9 microglia cell by Western blot and real-time PCR and found to be modulated by LPS. One central finding is a significant increase in FX expression level following LPS induction both in vivo in the hippocampus and in vitro in N9 microglia cell line (5.5 ± 0.6- and 2.3 ± 0.1-fold of increase, resp.). Surprisingly, inhibition of thrombin activity (by a specific inhibitor NAPAP) immediately after LPS injection results in a reduction of both the inflammatory (TNFα, CXL9, and CCL1; p < 0.006) and coagulation responses (FX and PAR1; p < 0.004) in the brain. We believe that these results may have a profound clinical impact as they might indicate that reducing coagulation activity in the setting of neurological diseases involving neuroinflammation may improve disease outcome and survival.

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Thrombin and protein C pathway in peripheral nerve Schwann cells

Cited by 20 publications

References 46 publications

The role of thrombin in the pathogenesis of diabetic neuropathy

The role of thrombin in the pathogenesis of diabetic neuropathy

The Complex Work of Proteases and Secretases in Wallerian Degeneration: Beyond Neuregulin-1

Thrombin Inhibition Reduces the Expression of Brain Inflammation Markers upon Systemic LPS Treatment

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