Roadmap for Advancing Pre-Clinical Science in Traumatic Brain Injury

Abstract

Pre-clinical models of disease have long played important roles in the advancement of new treatments. However, in traumatic brain injury (TBI), despite the availability of numerous model systems, translation from bench to bedside remains elusive. Integrating clinical relevance into pre-clinical model development is a critical step toward advancing therapies for TBI patients across the spectrum of injury severity. Pre-clinical models include in vivo and ex vivo animal work—both small and large—and in vitro modeling. The wide range of pre-clinical models reflect substantial attempts to replicate multiple aspects of TBI sequelae in humans. Although these models reveal multiple putative mechanisms underlying TBI pathophysiology, failures to translate these findings into successful clinical trials call into question the clinical relevance and applicability of the models. Here, we address the promises and pitfalls of pre-clinical models with the goal of evolving frameworks that will advance translational TBI research across models, injury types, and the heterogenous etiology of pathology.

Raloxifene Modulates Microglia and Rescues Visual Deficits and Pathology After Impact Traumatic Brain Injury

“…These pressure gradients in turn generate biomechanical forces (e.g., shear, strain, and stretch) to which axons are highly sensitive. The precise magnitude, direction, and duration of these forces vary between regions of the brain and over time, albeit in ways that are not well understood, and may then differ in the pathological sequelae they initiate (Risling et al, 2019;Smith et al, 2021). In accord with this, we found similarities but also several important differences in the outcomes from the two types of TBI.…”

Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

“…Although sociability deficits occur in Service members with mTBI and in blast-exposed Veterans, preclinical studies addressing this issue are inconclusive ( 39 , 63 ). Shultz et al provides an overview of social interaction testing in the context of TBI, emphasizing the need for increased use of automated tracking capable of detecting social behaviors ( 64 ).…”

“…These features of TBI are required for certain clinical assessments including the Glasgow Coma Scale, or scores on the Repeatable Battery for Neuropsychological Status (RBANS) test to classify severity of neurologic injury (35). To better understand underlying mechanisms of mild blast injury, it requires the development of "scalable, realistic, reproducible, and controllable" militaryrelevant preclinical models (18,(36)(37)(38)(39). Preclinical models capable of mimicking the neurological basis of affective and cognitive disabilities in a reproduceable and reliable fashion offers the promise of improving understanding of mTBI as a spectrum disorder.…”

Neuroprotection treatment in traumatic brain injury - right now or later on?

“…w modelach zwierzęcych wykazano, że leki o pojedynczym punkcie uchwytu prawdopodobnie nie wywierają istotnego działania zarówno w fazie neuroprotekcji, jak i neurorehabilitacji, Q błędy metodologiczne związane z projektowaniem i planowaniem badań -np. zbyt niska dawka leku, brak grupy kontrolnej lub nieadekwatna liczebność próby, heterogeniczność populacji oraz brak standaryzowanego programu rehabilitacji i uwzględnienia wpływu chorób przewlekłych, Q zbyt mało czułe metody oceny stanu chorych nie oddające istotnych klinicznie zaburzeń funkcjonalnych lub zróżnicowane punkty końcowe i czas trwania obserwacji klinicznej [28].…”