Molecular mechanisms of traumatic brain injury: the missing link in management

Veenith, Tonny; Goon, S.; Burnstein, Rowan

doi:10.1186/1749-7922-4-7

Cited by 43 publications

(41 citation statements)

References 63 publications

(65 reference statements)

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“…1 TBI is a major health concern with at least 1.7 million Americans injured each year 2 and with young people being the largest patient group 3 and military combat casualties adding to those numbers. 4 Although much is known about the cellular and molecular mechanisms of TBI, [5][6][7][8] that knowledge has not, as yet, resulted in a pharmacological therapeutic that improves outcome. 9,10 However, a therapeutic may be developed by identifying a molecular target that affects outcome and demonstrating that a compound that affects the target is efficacious in a TBI animal model using protocols that can translate into the clinic.…”

Section: Introductionmentioning

confidence: 99%

The Cysteine Protease Cathepsin B Is a Key Drug Target and Cysteine Protease Inhibitors Are Potential Therapeutics for Traumatic Brain Injury

Hook

Sipes

et al. 2014

Journal of Neurotrauma

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There are currently no effective therapeutic agents for traumatic brain injury (TBI), but drug treatments for TBI can be developed by validation of new drug targets and demonstration that compounds directed to such targets are efficacious in TBI animal models using a clinically relevant route of drug administration. The cysteine protease, cathepsin B, has been implicated in mediating TBI, but it has not been validated by gene knockout (KO) studies. Therefore, this investigation evaluated mice with deletion of the cathepsin B gene receiving controlled cortical impact TBI trauma. Results indicated that KO of the cathepsin B gene resulted in amelioration of TBI, shown by significant improvement in motor dysfunction, reduced brain lesion volume, greater neuronal density in brain, and lack of increased proapoptotic Bax levels. Notably, oral administration of the small-molecule cysteine protease inhibitor, E64d, immediately after TBI resulted in recovery of TBI-mediated motor dysfunction and reduced the increase in cathepsin B activity induced by TBI. E64d outcomes were as effective as cathepsin B gene deletion for improving TBI. E64d treatment was effective even when administered 8 h after injury, indicating a clinically plausible time period for acute therapeutic intervention. These data demonstrate that a cysteine protease inhibitor can be orally efficacious in a TBI animal model when administered at a clinically relevant time point post-trauma, and that E64d-mediated improvement of TBI is primarily the result of inhibition of cathepsin B activity. These results validate cathepsin B as a new TBI therapeutic target.

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Section: Introductionmentioning

confidence: 99%

The Cysteine Protease Cathepsin B Is a Key Drug Target and Cysteine Protease Inhibitors Are Potential Therapeutics for Traumatic Brain Injury

Hook

Sipes

et al. 2014

Journal of Neurotrauma

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show abstract

“…High level of IL-6 in the plasma and cerebrospinal fluid are found in post-traumatic brain injury patients. IL-6 may also promote vasopression secretion and plays a role in the pathogenesis of syndrome of inappropriate antidiuretic hormone (SIADH) after traumatic brain injury [4,5,7].…”

Section: Introductionmentioning

confidence: 99%

“…The role of proinflammatory mediator in formation of secondary lesions has been investigated, including serial mediators such as cytokine. Among the cytokines, IL-1β, TNF-a, IL-6 and IL-8 are especially important [4,5,7].…”

Section: Introductionmentioning

confidence: 99%

“…Patients with moderate head injury have increased levels of IL-1, IL-6, and TNF-α in their circulation and cerebrospinal fluid [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

“…Astroglial have demonstrated the relationship between upregulation with inflammatory cytokines such as IL-1α, IL-1β, and TNF-α in post-traumatic murine. In humans with head injury, as part of inflammatory response, microcelullar endothelial cells release IL-1β and TNF-α that will eventually stimulate the release of neurotoxic agents such as arachidonic acid and their metabolites [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Serum Interleukin-6 Level after Cyclooxygenase-2 Inhibitor Treatment in Moderate Traumatic Brain Injury

Bisri¹,

Wullur²,

Lalenoh³

et al. 2017

J Anesth Clin Res

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The most clinical scoring of traumatic brain injury patient is Glasgow Coma Scale (GCS) score. Lower GCS score higher IL-6 level and higher morbidity and mortality. Neuroinflammation is one mechanism of secondary brain injury. Selective cyclooxygenase (sCOX-2) inhibitors are drugs commonly used in treatment of postoperative pain but also possess an anti-inflammatory effect. The aim of this study is to determine the role of sCOX-2 inhibitors as inhibitors of inflammatory processes in patients with head injury measured by IL-6.

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Connectomic assessment of injury burden and longitudinal structural network alterations in moderate‐to‐severe traumatic brain injury

Osmanlıoğlu

Parker

Alappatt

et al. 2022

Human Brain Mapping

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Traumatic brain injury (TBI) is a major public health problem. Caused by external mechanical forces, a major characteristic of TBI is the shearing of axons across the white matter, which causes structural connectivity disruptions between brain regions. This diffuse injury leads to cognitive deficits, frequently requiring rehabilitation. Heterogeneity is another characteristic of TBI as severity and cognitive sequelae of the disease have a wide variation across patients, posing a big challenge for treatment. Thus, measures assessing network‐wide structural connectivity disruptions in TBI are necessary to quantify injury burden of individuals, which would help in achieving personalized treatment, patient monitoring, and rehabilitation planning. Despite TBI being a disconnectivity syndrome, connectomic assessment of structural disconnectivity has been relatively limited. In this study, we propose a novel connectomic measure that we call network normality score (NNS) to capture the integrity of structural connectivity in TBI patients by leveraging two major characteristics of the disease: diffuseness of axonal injury and heterogeneity of the disease. Over a longitudinal cohort of moderate‐to‐severe TBI patients, we demonstrate that structural network topology of patients is more heterogeneous and significantly different than that of healthy controls at 3 months postinjury, where dissimilarity further increases up to 12 months. We also show that NNS captures injury burden as quantified by posttraumatic amnesia and that alterations in the structural brain network is not related to cognitive recovery. Finally, we compare NNS to major graph theory measures used in TBI literature and demonstrate the superiority of NNS in characterizing the disease.

show abstract

Molecular mechanisms of traumatic brain injury: the missing link in management

Cited by 43 publications

References 63 publications

The Cysteine Protease Cathepsin B Is a Key Drug Target and Cysteine Protease Inhibitors Are Potential Therapeutics for Traumatic Brain Injury

The Cysteine Protease Cathepsin B Is a Key Drug Target and Cysteine Protease Inhibitors Are Potential Therapeutics for Traumatic Brain Injury

Serum Interleukin-6 Level after Cyclooxygenase-2 Inhibitor Treatment in Moderate Traumatic Brain Injury

Connectomic assessment of injury burden and longitudinal structural network alterations in moderate‐to‐severe traumatic brain injury

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