Animal models of traumatic brain injury: A critical evaluation

O’Connor, W.T.; Smyth, Aoife; Gilchrist, Michael D.

doi:10.1016/j.pharmthera.2011.01.001

Cited by 142 publications

(87 citation statements)

References 59 publications

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“…10,21 We observed an evolution of the contusion-related histological features similar to those described in more detail previously. 7,28 In previous rat experiments, others have shown that intra-and extracellular edema formation peaks from 12 hours to 2 days following contusion, 3,15 which corresponds to a peak in the intracranial pressure.…”

Section: Discussionsupporting

confidence: 82%

Intracranial biomechanics following cortical contusion in live rats

Alfasi¹,

Shulyakov

Bigio

2013

JNS

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Object. The goal of this study was to examine the mechanical properties of living rat intracranial contents and corresponding brain structural alterations following parietal cerebral cortex contusion.Methods. After being anesthetized, young adult rats were subjected to parietal craniotomy followed by cortical contusion using a calibrated weight-drop method. Magnetic resonance imaging was used to visualize the contusion. At the site of contusion, instrumented force-controlled indentation was performed 2 hours to 21 days later on the intact dural surface. The force-deformation (stress-strain) relationship was used to calculate elastic (indentation modulus) and strain changes over time, and constant hold or cyclic stress was used to evaluate viscoelastic deformation. These measurements were followed by histological studies.Results. At contusion sites, the indentation modulus was significantly decreased at 1-3 days and tended to be above control values at 21 days. Multicycle indentation showed that the brain tended to accumulate more strain (an indicator of viscosity) by 1 day after the contusion. Imaging and histological studies showed local edema and hemorrhage at 6 hours to 3 days and accumulation of reactive astrocytes, which began at 3 days and was pronounced by 21 days.Conclusions. The viscoelastic properties of living rat brain change following contusion. Initially, edema and tissue necrosis occur, and the brain becomes less elastic and less viscous. Later, along with undergoing reactive astroglial changes, the brain tends to become stiffer than normal. These quantitative data, which are related to the physical changes in the brain following trauma and which reflect subjective impressions upon palpation, will be useful for understanding emerging diagnostic tools such as magnetic resonance elastography.

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Section: Discussionsupporting

confidence: 82%

Intracranial biomechanics following cortical contusion in live rats

Alfasi¹,

Shulyakov

Bigio

2013

JNS

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“…There is also a gap in the literature with respect to how the female brain responds to mTBI. Given that it is often difficult to study these cohorts in clinical settings, animal models offer a significant advantage 42, 43. This study provided a comprehensive examination of the outcomes associated with exposure to mild brain injuries during adolescence, for both male and female rodents.…”

Section: Discussionmentioning

confidence: 99%

Sex matters: repetitive mild traumatic brain injury in adolescent rats

Wright

O’Brien

Shultz

et al. 2017

Ann Clin Transl Neurol

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ObjectiveWhether sex differences contribute to the heterogeneity of mild traumatic brain injury (mTBI) and repeated mTBI (RmTBI) outcomes in adolescents is unknown. Therefore, this study examined changes in, and differences between, male and female rats following single mTBI and RmTBI.MethodsRats were given a single mTBI, RmTBI (i.e., 3x), or sham injuries. Injuries were administered using a lateral impact model that mimics forces common in human mTBI. After the final injury, rats underwent extensive behavioral testing to examine cognition, motor function, and anxiety‐ and depressive‐like behavior. Postmortem analyses investigated gene expression and structural changes in the brain.ResultsMany of the outcomes exhibited a sex‐dependent response to RmTBI. While all rats given RmTBI had deficits in balance, motor coordination, locomotion, and anxiety‐like behavior, only male rats given RmTBI had short‐term working memory deficits, whereas only females given RmTBI had increased depressive‐like behavior. Volumetric and diffusion weighted MRI analyses found that while RmTBI‐induced atrophy of the prefrontal cortex was greater in female rats, only the male rats exhibited worse white matter integrity in the corpus callosum following RmTBI. Sex‐dependent changes in brain expression of mRNA for glial fibrillary acidic protein, myelin basic protein, and tau protein were also observed following injury.InterpretationThese findings suggest that in adolescent mTBI, sex matters; and future studies incorporating both male and females are warranted to provide a greater understanding of injury prognosis and better inform clinical practice.

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“…In the present study, a CCI model of brain trauma was established. The advantages of a CCI model include the ability to control deformation parameters, such as depth and velocity of the impact (19). Additionally, this model is able to imitate the spectrum of diffuse axonal injury and focal-type damage observed in TBI (19).…”

Section: Discussionmentioning

confidence: 99%

“…The advantages of a CCI model include the ability to control deformation parameters, such as depth and velocity of the impact (19). Additionally, this model is able to imitate the spectrum of diffuse axonal injury and focal-type damage observed in TBI (19). In the present study, any rats that did not display moderate to severe neurological deficits following the surgery were excluded from further investigations.…”

Section: Discussionmentioning

confidence: 99%

Hsp70 inducer, 17-allylamino-demethoxygeldanamycin, provides neuroprotection via anti-inflammatory effects in a rat model of traumatic brain injury

Wang

Zhou

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. Traumatic brain injury (TBI) is the predominant cause of mortality in young adults and children living in China. TBI induces inflammatory responses; in addition, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 are important pro-inflammatory cytokines. Considering the observation that Hsp-70 overexpression can exert neuroprotection, identifying a drug that is able to induce the upregulation of Hsp70 has the potential to be a promising therapy for the treatment of neurological diseases. Thus, the present study assessed the clinical effectiveness of an anticancer drug and Hsp70 activator, 17-allylamino-demethoxygeldanamycin (17-AAG), to evaluate its potential as a treatment for patients with TBI. The aim of present study was to determine the neuroprotective effects of 17-AAG following trauma and to investigate the underlying mechanisms of action. To establish rat models, rats were subjected to a controlled cortical impact injury and randomly divided into vehicle or 17-AAG groups. In the 17-AAG group, rats were administered with an intraperitoneal injection of 17-AAG (80 mg/kg) immediately following the establishment of TBI. The motor function was measured using Neurologic Severity Score, and neuronal death was evaluated using immunofluorescence. The expression levels of GLT-1, Bcl-2 and Hsp-70 were detected by western blot analysis and the expression levels of inflammatory cytokines were quantified using ELISA. The present study determined that 17-AAG significantly reduced brain edema and motor neurological deficits (P<0.05), in addition to increasing neuronal survival. The aforementioned findings are associated with a downregulation of the expression levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6. Conversely, no significant changes of glutamate transporter-1 expression were observed. The present results suggest that 17-AAG treatment may provide a neuroprotective effect by reducing inflammation following TBI. IntroductionTraumatic brain injury (TBI) is the leading cause of mortality in young adults and children living in China (1). Head trauma has numerous consequences in the brain, including axonal damage, microvascular alterations and blood-brain barrier disruption (2). The aforementioned outcomes are a result of both primary and secondary mechanisms following injury (3). Primary damage is a result of mechanical factors occurring immediately following trauma. Conversely, the fundamental mechanisms underlying secondary damage in TBI include inflammation, oxygen free radicals, brain edema formation and neuronal apoptosis (4). In particular, previous studies have demonstrated that tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 are crucial pro-inflammatory cytokines following trauma (5-7). Although the potential effects of TNF-α, IL-1β and IL-6 in human patients with TBI have yet to be elucidated, evidence from animal models has revealed that upregulated expression levels of the aforementioned cytokines are harmful, whereas their attenuation may alleviate tissue ...

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Animal models of traumatic brain injury: A critical evaluation

Cited by 142 publications

References 59 publications

Intracranial biomechanics following cortical contusion in live rats

Intracranial biomechanics following cortical contusion in live rats

Sex matters: repetitive mild traumatic brain injury in adolescent rats

Hsp70 inducer, 17-allylamino-demethoxygeldanamycin, provides neuroprotection via anti-inflammatory effects in a rat model of traumatic brain injury

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