Bench-to-Bedside and Bedside Back to the Bench; Seeking a Better Understanding of the Acute Pathophysiological Process in Severe Traumatic Brain Injury

Agoston, Denes V.

doi:10.3389/fneur.2015.00047

Cited by 15 publications

(15 citation statements)

References 79 publications

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“…To address this, many researchers have drawn comparisons between species in terms of key developmental milestones including brain maturation and behavioral phenotypes (Clancy et al, 2007; Prins and Hovda, 2003; Rice and Barone, 2000; Semple et al, 2013). However, differences in the time scale and rate of biological processes between species, under physiological conditions as well as in response to an insult, renders the equating of animal and human lifespan intrinsically complex (Agoston, 2015). Nevertheless, characterization of psychosocial and functional outcomes after injuries across a spectrum of brain maturation stages may reveal important insights into key developmental events which underpin age-specific vulnerabilities.…”

Section: Identifying Social Behavior Impairments In Brain-injured mentioning

confidence: 99%

Social dysfunction after pediatric traumatic brain injury: A translational perspective

Ryan

Catroppa

Godfrey

et al. 2016

Neuroscience & Biobehavioral Reviews

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Social dysfunction is common after traumatic brain injury (TBI), contributing to reduced quality of life for survivors. Factors which influence the emergence, development or persistence of social deficits after injury remain poorly understood, particularly in the context of ongoing brain maturation during childhood. Aberrant social interactions have recently been modeled in adult and juvenile rodents after experimental TBI, providing an opportunity to gain new insights into the underlying neurobiology of these behaviors. Here, we review our current understanding of social dysfunction in both humans and rodent models of TBI, with a focus on brain injuries acquired during early development. Modulators of social outcomes are discussed, including injury-related and environmental risk and resilience factors. Disruption of social brain network connectivity and aberrant neuroendocrine function are identified as potential mechanisms of social impairments after pediatric TBI. Throughout, we highlight the overlap and disparities between outcome measures and findings from clinical and experimental approaches, and explore the translational potential of future research to prevent or ameliorate social dysfunction after childhood TBI.

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Section: Identifying Social Behavior Impairments In Brain-injured mentioning

confidence: 99%

Social dysfunction after pediatric traumatic brain injury: A translational perspective

Ryan

Catroppa

Godfrey

et al. 2016

Neuroscience & Biobehavioral Reviews

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“…One practical explanation for the dearth of combined therapy studies may be due to the inherent complexity of such an approach. It is well known that TBI produces a plethora of secondary pathophysiological responses (Hayes et al, 1992; Raghupathi, 2004; Greve and Zink, 2009; Veenith et al, 2009; Algattas and Huang, 2013; Agoston, 2015; Laskowski et al, 2015; Fig. 1) at time points that are not well understood and hence, deciding when, how often, and at what dose, to administer a single treatment is difficult, and becomes exponentially more complicated when determining the correct course of action for dual or “cocktail” therapies.…”

Section: Introductionmentioning

confidence: 99%

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

Kline

Leary

Radabaugh

et al. 2016

Progress in Neurobiology

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Traumatic brain injury (TBI) is a significant health care crisis that affects two million individuals in the United Sates alone and over ten million worldwide each year. While numerous monotherapies have been evaluated and shown to be beneficial at the bench, similar results have not translated to the clinic. One reason for the lack of successful translation may be due to the fact that TBI is a heterogeneous disease that affects multiple mechanisms, thus requiring a therapeutic approach that can act on complementary, rather than single, targets. Hence, the use of combination therapies (i.e., polytherapy) has emerged as a viable approach. Stringent criteria, such as verification of each individual treatment plus the combination, a focus on behavioral outcome, and post-injury vs. pre-injury treatments, were employed to determine which studies were appropriate for review. The selection process resulted in 37 papers that fit the specifications. The review, which is the first to comprehensively assess the effects of combination therapies on behavioral outcomes after TBI, encompasses five broad categories (inflammation, oxidative stress, neurotransmitter dysregulation, neurotrophins, and stem cells, with and without rehabilitative therapies). Overall, the findings suggest that combination therapies can be more beneficial than monotherapies as indicated by 46% of the studies exhibiting an additive or synergistic positive effect versus on 19% reporting a negative interaction. These encouraging findings serve as an impetus for continued combination studies after TBI and ultimately for the development of successful clinically relevant therapies.

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“…Recent studies have shown that approximately 98% of small-molecule and 100% of largemolecule drugs cannot cross the BBB [23,24]. Thus the BBB is also a critical barrier hampering the treatment of major neurological disorders [25].…”

mentioning

confidence: 99%

In vitro modeling of the neurovascular unit: advances in the field

Bhalerao

Sivandzade

Archie

et al. 2020

Fluids Barriers CNS

115

103

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The blood-brain barrier (BBB) is a fundamental component of the central nervous system. Its functional and structural integrity is vital in maintaining the homeostasis of the brain microenvironment. On the other hand, the BBB is also a major hindering obstacle for the delivery of effective therapies to treat disorders of the Central Nervous System (CNS). Over time, various model systems have been established to simulate the complexities of the BBB. The development of realistic in vitro BBB models that accurately mimic the physiological characteristics of the brain microcapillaries in situ is of fundamental importance not only in CNS drug discovery but also in translational research. Successful modeling of the Neurovascular Unit (NVU) would provide an invaluable tool that would aid in dissecting out the pathological factors, mechanisms of action, and corresponding targets prodromal to the onset of CNS disorders. The field of BBB in vitro modeling has seen many fundamental changes in the last few years with the introduction of novel tools and methods to improve existing models and enable new ones. The development of CNS organoids, organ-on-chip, spheroids, 3D printed microfluidics, and other innovative technologies have the potential to advance the field of BBB and NVU modeling. Therefore, in this review, summarize the advances and progress in the design and application of functional in vitro BBB platforms with a focus on rapidly advancing technologies.The BBB consists of highly specialized vascular endothelial cells (EC) lining the brain microvessels in juxtaposition with closely associated pericytes [1], extracellular matrix components, and astrocytic end-feet processes [2]. Along with other cells such as neurons and microglia, this cellular milieu modulates the BBB properties, supports its viability and functions [3]. At the brain microvascular level, the BBB functions as a highly dynamic and active interface between the systemic circulation and the CNS. The BBB maintains a stable brain environment to protect the CNS from unsolicited cells, bacteria, viruses, and potentially harmful substances (either endogenous or exogenous) apart from protecting against systemic fluctuations. The BBB also regulates the transport of essential molecules and nutrients necessary to maintain the optimal CNS environment and support neuronal activities [4]. The BBB responds to many physiological and pathological cues, including rheological changes [5], inflammatory stimuli, oxidative stress [6], diabetes, and hypercholesterolemia [7-10], acute brain injury [3], etc. The intrinsically unique and utmost complex functional interaction between the BBB endothelium and the surrounding cellular milieu (including astrocytes, pericytes, neurons, microglia, myocytes as well as specialized cellular compartments such as endothelial glycocalyx [11,12] has been termed "neurovascular unit (NVU)" [2,13]. In addition, the basement membrane, which exerts essential functions in cellular support and signal transduction,

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Bench-to-Bedside and Bedside Back to the Bench; Seeking a Better Understanding of the Acute Pathophysiological Process in Severe Traumatic Brain Injury

Cited by 15 publications

References 79 publications

Social dysfunction after pediatric traumatic brain injury: A translational perspective

Social dysfunction after pediatric traumatic brain injury: A translational perspective

Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

In vitro modeling of the neurovascular unit: advances in the field

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