Temporal response profiles of serum ubiquitin C-terminal hydrolase-L1 and the 145-kDa alpha II-spectrin breakdown product after severe traumatic brain injury in children

Metzger, Ryan R.; Sheng, Xiaoming; Niedzwecki, Christian; Bennett, Kimberly Statler; Morita, Denise C.; Zielinski, Brandon A.; Schober, Michelle E.

doi:10.3171/2018.4.peds17593

Cited by 11 publications

(4 citation statements)

References 31 publications

(45 reference statements)

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“…For example, elevated S100B and UCH‐L1 have been reported in multiple samples of athletes with SRC and in emergency department (ED) patients with mTBI . Current results also extend prior work demonstrating the potential utility of alpha‐II‐spectrin breakdown products for the acute assessment of brain injury . Consistent with some prior reports, we did not observe acute elevations in GFAP across the entire SRC group.…”

Section: Discussionsupporting

confidence: 90%

A Prospective Study of Acute Blood‐Based Biomarkers for Sport‐Related Concussion

Meier

Huber

Bohorquez‐Montoya

et al. 2020

Annals of Neurology

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Objective: Prospectively characterize changes in serum proteins following sport-related concussion and determine whether candidate biomarkers discriminate concussed athletes from controls and are associated with duration of symptoms following concussion. Methods: High school and collegiate athletes were enrolled between 2015 and 2018. Blood was collected at preinjury baseline and within 6 hours (early acute) and at 24 to 48 hours (late acute) following concussion in football players (n = 106), matched uninjured football players (n = 84), and non-contact-sport athletes (n = 50). Glial fibrillary acidic protein, ubiquitin c-terminal hydrolase-L1, S100 calcium binding protein B, alpha-II-spectrin breakdown product 150, interleukin 6, interleukin 1 receptor antagonist, and c-reactive protein were measured in serum. Linear models assessed changes in protein concentrations over time. Receiver operating curves quantified the discrimination of concussed athletes from controls. A Cox proportional hazard model determined whether proteins were associated with symptom recovery. Results: All proteins except glial fibrillary acidic protein and c-reactive protein were significantly elevated at the early acute phase postinjury relative to baseline and both control groups and discriminated concussed athletes from controls with areas under the curve of 0.68 to 0.84. The candidate biomarkers also significantly improved the discrimination of concussed athletes from noncontact controls compared to symptom severity alone. Glial fibrillary acidic protein was elevated postinjury relative to baseline in concussed athletes with a loss of consciousness or amnesia. Finally, early acute levels of interleukin 1 receptor antagonist were associated with the number of days to symptom recovery. Interpretation: Brain injury and inflammatory proteins show promise as objective diagnostic biomarkers for sportrelated concussion, and inflammatory markers may provide prognostic value.

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Section: Discussionsupporting

confidence: 90%

A Prospective Study of Acute Blood‐Based Biomarkers for Sport‐Related Concussion

Meier

Huber

Bohorquez‐Montoya

et al. 2020

Annals of Neurology

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“…Both SBDP 145kDA and GFAP-BDP are elevated in TBI. 17,45,50 Elevation of MMP-9 activity is a downstream consequence of calpain-1 hyperactivation 8 and was blocked by calpain inhibitor treatment. Calpain-1 activity is wellreported to be increased in activated glial cells after neurotrauma; 16,17 however, while both 5 and NYC-438 blocked GFAP proteolysis, only the nonselective inhibitor restored total GFAP, suggesting that calpain-independent anti-inflammatory effects may contribute to attenuation of astrocyte activation in response to mTBI.…”

Section: ■ Discussionmentioning

confidence: 99%

Extending the Calpain–Cathepsin Hypothesis to the Neurovasculature: Protection of Brain Endothelial Cells and Mice from Neurotrauma

Knopp

Jastaniah

Dubrovskyi

et al. 2021

ACS Pharmacol. Transl. Sci.

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The calpain–cathepsin hypothesis posits a key role for elevated calpain-1 and cathepsin-B activity in the neurodegeneration underlying neurotrauma and multiple disorders including Alzheimer’s disease (AD). AD clinical trials were recently halted on alicapistat, a selective calpain-1 inhibitor, because of insufficient exposure of neurons to the drug. In contrast to neuroprotection, the ability of calpain-1 and cathepsin-B inhibitors to protect the blood–brain barrier (BBB), is understudied. Since cerebrovascular dysfunction underlies vascular dementia, is caused by ischemic stroke, and is emerging as an early feature in the progression of AD, we studied protection of brain endothelial cells (BECs) by selective and nonselective calpain-1 and cathepsin-B inhibitors. We show these inhibitors protect both neurons and murine BECs from ischemia–reperfusion injury. Cultures of primary BECs from ALDH2 –/– mice that manifest enhanced oxidative stress were sensitive to ischemia, leading to reduced cell viability and loss of tight junction proteins; this damage was rescued by calpain-1 and cathepsin-B inhibitors. In ALDH2 –/– mice 24 h after mild traumatic brain injury (mTBI), BBB damage was reflected by significantly increased fluorescein extravasation and perturbation of tight junction proteins, eNOS, MMP-9, and GFAP. Both calpain and cathepsin-B inhibitors alleviated BBB dysfunction caused by mTBI. No clear advantage was shown by selective versus nonselective calpain inhibitors in these studies. The lack of recognition of the ability of calpain inhibitors to protect the BBB may have led to the premature abandonment of this therapeutic approach in AD clinical trials and requires further mechanistic studies of cerebrovascular protection by calpain-1 inhibitors.

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“…Thus, preclinical and clinical studies that will examine microbiome dysbiosis in pTBI are urgently needed and could provide insights into the development of therapies that mitigate pTBI associated long-term neurological sequelae in children. 175 - 236 …”

Section: A Putative Role For the Gut-brain Axis (Gba) In Ptbi Pathoph...mentioning

confidence: 99%

Pediatric Traumatic Brain Injury: An Update on Preclinical Models, Clinical Biomarkers, and the Implications of Cerebrovascular Dysfunction

Nwafor

Brichacek

Foster

et al. 2022

J Cent Nerv Syst Dis

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Traumatic brain injury (TBI) is a leading cause of pediatric morbidity and mortality. Recent studies suggest that children and adolescents have worse post-TBI outcomes and take longer to recover than adults. However, the pathophysiology and progression of TBI in the pediatric population are studied to a far lesser extent compared to the adult population. Common causes of TBI in children are falls, sports/recreation-related injuries, non-accidental trauma, and motor vehicle-related injuries. A fundamental understanding of TBI pathophysiology is crucial in preventing long-term brain injury sequelae. Animal models of TBI have played an essential role in addressing the knowledge gaps relating to pTBI pathophysiology. Moreover, a better understanding of clinical biomarkers is crucial to diagnose pTBI and accurately predict long-term outcomes. This review examines the current preclinical models of pTBI, the implications of pTBI on the brain’s vasculature, and clinical pTBI biomarkers. Finally, we conclude the review by speculating on the emerging role of the gut-brain axis in pTBI pathophysiology.

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Temporal response profiles of serum ubiquitin C-terminal hydrolase-L1 and the 145-kDa alpha II-spectrin breakdown product after severe traumatic brain injury in children

Cited by 11 publications

References 31 publications

A Prospective Study of Acute Blood‐Based Biomarkers for Sport‐Related Concussion

A Prospective Study of Acute Blood‐Based Biomarkers for Sport‐Related Concussion

Extending the Calpain–Cathepsin Hypothesis to the Neurovasculature: Protection of Brain Endothelial Cells and Mice from Neurotrauma

Pediatric Traumatic Brain Injury: An Update on Preclinical Models, Clinical Biomarkers, and the Implications of Cerebrovascular Dysfunction

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