Recovery from trauma induced amnesia correlates with normalization of thrombin activity in the mouse hippocampus

Shimon, Marina Ben; Zeimer, Talya; Stein, Efrat Shavit; Artan-Furman, Avital; Harnof, Sagi; Chapman, Joab; Eisenkraft, Arik; Pick, Chaim G.; Maggio, Nicola

doi:10.1371/journal.pone.0188524

Cited by 13 publications

(10 citation statements)

References 40 publications

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“…Therefore, in this study, we aimed at assessing both thrombin activity and the expression of inflammatory markers in the mTBI-pilocarpine setting. The rationale of our assumption was that thrombin is known to rise in the brain both in hyperexcitable state as well as upon BBB breakdown following mTBI (Ben Shimon et al, 2017;De Luca et al, 2017). In the present study, thrombin was upregulated in all the experimental groups with the highest activity found in the combined mTBI-pilocarpine groups compared to the respective others.…”

Section: Discussionsupporting

confidence: 45%

Thrombin as Key Mediator of Seizure Development Following Traumatic Brain Injury

et al. 2020

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Traumatic brain injury (TBI) commonly leads to development of seizures, accounting for approximately 20% of newly diagnosed epilepsy. Despite the high clinical significance, the mechanisms underlying the development of posttraumatic seizures (PTS) remain unclear, compromising appropriate management of these patients. Accumulating evidence suggest that thrombin, the main serine protease of the coagulation cascade, is involved in PTS genesis by mediating inflammation and hyperexcitability following blood brain barrier breakdown. In order to further understand the role of thrombin in PTS, we generated a combined mild TBI (mTBI) and status epilepticus mice model, by injecting pilocarpine to mice previously submitted to head injury. Interestingly, mTBI was able to reduce seizure onset in the pilocarpine animal model as well as increase the death rate in the treated animals. In turn, pilocarpine worsened spatial orientation of mTBI treated mice. Finally, thrombin activity as well as the expression of IL1-b and TNF-a was significantly increased in the mTBI-pilocarpine treated animals. In conclusion, these observations indicate a synergism between thrombin and mTBI in lowering seizure in the pilocarpine model and possibly aggravating inflammation. We believe that these results will improve the understanding of PTS pathophysiology and contribute to the development of more targeted therapies in the future.

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Section: Discussionsupporting

confidence: 45%

Thrombin as Key Mediator of Seizure Development Following Traumatic Brain Injury

et al. 2020

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“…Fibrinolysis prevents unnecessary accumulation of intravascular fibrin and enables the removal of thrombin [4]. Thrombin, known as a serine protease, has been shown to have a close relationship with cognitive defects after traumatic brain injury [5]. Fibrin, transformed from fibrinogen, is an essential plasma protein for clot formation.…”

mentioning

confidence: 99%

Deficiency of tPA Exacerbates White Matter Damage, Neuroinflammation, Glymphatic Dysfunction and Cognitive Dysfunction in Aging Mice

Yu¹,

Venkat²,

Chopp³

et al. 2019

Aging and disease

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Tissue plasminogen activator (tPA) is a serine protease primarily involved in mediating thrombus breakdown and regulating catabolism of amyloid-beta (Aβ). The aim of this study is to investigate age-dependent decline of endogenous tPA and the effects of tPA decline on glymphatic function and cognitive outcome in mice. Male, young (3m), adult (6m) and middle-aged (12m) C57/BL6 (wild type) and tPA knockout (tPA -/- ) mice were subject to a battery of cognitive tests and white matter (WM) integrity, neuroinflammation, and glymphatic function were evaluated. Adult WT mice exhibit significantly decreased brain tPA level compared to young WT mice and middle-aged WT mice have significantly lower brain tPA levels than young and adult WT mice. Middle-aged WT mice exhibit significant neuroinflammation, reduced WM integrity and increased thrombin deposition compared to young and adult mice, and increased blood brain barrier (BBB) permeability and reduced cognitive ability compared to young WT mice. In comparison to adult WT mice, adult tPA -/- mice exhibit significant BBB leakage, decreased dendritic spine density, increased thrombin deposition, neuroinflammation, and impaired functioning of the glymphatic system. Compared to age-matched WT mice, adult and middle-aged tPA -/- mice exhibit significantly increased D-Dimer expression and decreased perivascular Aquaporin-4 expression. Compared to age-matched WT mice, young, adult and middle-aged tPA -/- mice exhibit significant cognitive impairment, axonal damage, and increased deposition of amyloid precursor protein (APP), Aβ, and fibrin. Endogenous tPA may play an important role in contributing to aging induced cognitive decline, axonal/WM damage, BBB disruption and glymphatic dysfunction in the brain.

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“…ModTBI was induced by us in WT mice to create a primary lesion in brain. This initiates the previously described secondary process of neuronal cell dysfunction and death (involving PNCD, neuroinflammation, glutamate excitotoxicity, oxidative stress) that are targets for drug therapies . PhenT, evaluated at a clinically translatable dose of 2.5 mg/kg BID, substantially mitigated CCI modTBI‐induced behavioral impairments (elevated body swing test (EBST) and adhesive removal test: Figure ) .…”

Section: Introductionmentioning

confidence: 93%

“…Long‐term potentiation (LTP) results in the long‐lasting enhancement of synaptic strength consequent to repetitive activation of central glutamatergic synapses and is critical to memory encoding . LTP impairment is associated with memory deficits in rodents, has previously been noted to occur following TBI, and hence its mitigation by PhenT is potentially valuable as LTP is regarded as a necessity for hippocampal processing.…”

Section: Introductionmentioning

confidence: 99%

(−)‐Phenserine tartrate (PhenT) as a treatment for traumatic brain injury

et al. 2019

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Aim: Traumatic brain injury (TBI) is one of the most common causes of morbidity and mortality of both young adults and the elderly, and is a key contributing factor in about 30% of all injury-associated deaths occurring within the United States of America. Albeit substantial impact has been made to improve our comprehension of the mechanisms that underpin the primary and secondary injury stages initiated by a TBI incident, this knowledge has yet to successfully translate into the development of an effective TBI pharmacological treatment. Developing consent suggests that a TBI can concomitantly trigger multiple TBI-linked cascades that then progress in parallel and, if correct, the multifactorial nature of TBI would make the discovery of a single effective mechanism-targeted drug unlikely. Discussion:We review recent data indicating that the small molecular weight drug (−)-phenserine tartrate (PhenT), originally developed for Alzheimer's disease (AD), effectively inhibits a broad range of mechanisms pertinent to mild (m) and moderate (mod)TBI, which in combination underpin the ensuing cognitive and motor impairments. In cellular and animal models at clinically translatable doses, PhenT mitigated mTBI-and modTBI-induced programmed neuronal cell death (PNCD), oxidative stress, glutamate excitotoxicity, neuroinflammation, and effectively reversed injury-induced gene pathways leading to chronic neurodegeneration. In addition to proving efficacious in well-characterized animal TBI models, significantly mitigating cognitive and motor impairments, the drug also has demonstrated neuroprotective actions against ischemic stroke and the organophosphorus nerve agent and chemical weapon, soman. Conclusion:In the light of its tolerability in AD clinical trials, PhenT is an agent that can be fast-tracked for evaluation in not only civilian TBI, but also as a potentially protective agent in battlefield conditions where TBI and chemical weapon exposure are increasingly jointly occurring.

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Recovery from trauma induced amnesia correlates with normalization of thrombin activity in the mouse hippocampus

Cited by 13 publications

References 40 publications

Thrombin as Key Mediator of Seizure Development Following Traumatic Brain Injury

Thrombin as Key Mediator of Seizure Development Following Traumatic Brain Injury

Deficiency of tPA Exacerbates White Matter Damage, Neuroinflammation, Glymphatic Dysfunction and Cognitive Dysfunction in Aging Mice

(−)‐Phenserine tartrate (PhenT) as a treatment for traumatic brain injury

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