Correlations between Blood–Brain Barrier Disruption and Neuroinflammation in an Experimental Model of Penetrating Ballistic-Like Brain Injury

Cunningham, Tracy; Cartagena, Casandra M.; Lu, Xi‐Chun M.; Konopko, Melissa; Dave, Jitendra R.; Tortella, Frank C.; Shear, Deborah A.

doi:10.1089/neu.2013.2965

Cited by 29 publications

(21 citation statements)

References 49 publications

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“…The microglia, inherent immune‐related cell in brain, is also rapidly activated (Cunningham et al., 2014; Glushakova, Johnson, & Hayes, 2014). Both of these partially contribute to brain edema and cognitive deficits after TBI (Xu et al., 2012).…”

Section: Discussionmentioning

confidence: 99%

“…After primary damages induced by TBI, a large number of immune and inflammatory cells infiltrate into brain tissue through the damaged blood-brain barrier (BBB) (Walsh & Kipnis, 2011). The microglia, inherent immune-related cell in brain, is also rapidly activated (Cunningham et al, 2014;Glushakova, Johnson, & Hayes, 2014).…”

Section: Cognitive Deficit Induced By Tbi Reduces the Quality Of Life Inmentioning

confidence: 99%

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Erythropoietin regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury

Zhou

Zheng

et al. 2017

Brain and Behavior

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IntroductionTraumatic brain injury (TBI) remains a leading cause of disability and death among young people in China. Unfortunately, no specific pharmacological agents to block the progression of secondary brain injury have been approved for clinical treatment. Recently, neuroprotective effects of erythropoietin (EPO) have been demonstrated in addition to its principal function in erythropoiesis, and hence it is viewed as a potential drug for TBI. In this study, we have investigated the neuroprotective effects of EPO associated with immune/inflammatory modulation in a mouse experimental TBI model.Methods EPO (5000 U/kg body weight, i.p.) was injected at 1 hr, 1, 2, and 3 days after TBI, and its effect on cognitive function, brain edema, immune/inflammatory cells including regulatory T cells (Tregs), neutrophils, CD3+ T cells, and microglia, cytokines including interleukin‐10 (IL‐10), transforming growth factor‐β (TGF‐β), interleukin‐1β (IL‐1β), and tumor necrosis factor‐α (TNF‐α) were evaluated at different time points after treatment.Results EPO treatment significantly decreased brain edema and improved cognitive function when compared to Saline‐treated mice (p < .05). EPO treatment also significantly increased Tregs level in spleen and injured brain tissue as well as significantly reduced the infiltration and activation of immune/inflammatory cells (neutrophils, CD3+T cells, and microglia) in the injured hemisphere compared to Saline‐treated control animals (p < .05). In addition, ELISA analysis demonstrated that EPO treatment increased the expression of anti‐inflammatory cytokine IL‐10, but decreased the expression of proinflammatory cytokine IL‐1β and TNF‐α in the injured brain tissue (p < .05).ConclusionsThese findings suggest that EPO could improve neurological and cognitive functional outcomes as well as regulate immune/inflammatory reaction in TBI.

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Section: Discussionmentioning

confidence: 99%

Section: Cognitive Deficit Induced By Tbi Reduces the Quality Of Life Inmentioning

confidence: 99%

Erythropoietin regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury

Zhou

Zheng

et al. 2017

Brain and Behavior

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“…First, we confirmed that serum changes in GFAP were limited to the early acute time points (≤ 24h) after injury. The sharp increase in serum GFAP after injury suggests brain protein efflux during transient opening of the blood brain barrier (BBB) which occurs during this time frame 28 .…”

Section: Gfap Rather Than Uch-l1 Is An Appropriate Indicator Of Pbbmentioning

confidence: 99%

Serum Glial Fibrillary Acidic Protein Predicts Tissue Glial Fibrillary Acidic Protein Break-Down Products and Therapeutic Efficacy after Penetrating Ballistic-Like Brain Injury

BouttéAngela

Deng-BryantYing

Johnson

et al. 2016

Journal of Neurotrauma

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Acute traumatic brain injury (TBI) is associated with neurological dysfunction, changes in brain proteins, and increased serum biomarkers. However, the relationship between these brain proteins and serum biomarkers, and the ability of these serum biomarkers to indicate a neuroprotective/therapeutic response, remains elusive. Penetrating ballistic-like brain injury (PBBI) was used to systematically analyze several key TBI biomarkers, glial fibrillary acidic protein (GFAP) and its break-down products (BDPs)-ubiquitin C-terminal hydrolase-L1 (UCH-L1), α-II spectrin, and α-II spectrin BDPs (SBDPs)-in brain tissues and serum during an extended acute-subacute time-frame. In addition, neurological improvement and serum GFAP theranostic value was evaluated after neuroprotective treatment. In brain tissues, total GFAP increased more than three-fold 2 to 7 d after PBBI. However, this change was primarily due to GFAP-BDPs which increased to 2.7-4.8 arbitrary units (AU). Alpha-II spectrin was nearly ablated 3 d after PBBI, but somewhat recovered after 7 d. In conjunction with α-II spectrin loss, SBDP-145/150 increased approximately three-fold 2 to 7 d after PBBI (vs. sham, p<0.05). UCH-L1 protein levels were slightly decreased 7 d after PBBI but otherwise were unaffected. Serum GFAP was elevated by 3.2- to 8.8-fold at 2 to 4 h (vs. sham; p<0.05) and the 4 h increase was strongly correlated to 3 d GFAP-BDP abundance (r=0.66; p<0.05). Serum GFAP showed such a strong injury effect that it also was evaluated after therapeutic intervention with cyclosporin A (CsA). Administration of 2.5 mg/kg CsA significantly reduced serum GFAP elevation by 22.4-fold 2 h after PBBI (vs. PBBI+vehicle; p<0.05) and improved neurological function 1 d post-injury. Serum biomarkers, particularly GFAP, may be correlative tools of brain protein changes and feasible theranostic markers of TBI progression and recovery.

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“…Immunoreactivity of GFAP, OX-18, and b-APP was quantified by threshold analysis within the regions of interest using the ImageJ software (Version 1.44; NIH) at 20· magnification as described previously (Cunningham et al, 2014). The threshold value of immunoreactivity (i.e., grey level index) for each stain was set to consistently detect maximal positive staining with minimal artifacts.…”

Section: Histopathologymentioning

confidence: 99%

Comprehensive Evaluation of Neuroprotection Achieved by Extended Selective Brain Cooling Therapy in a Rat Model of Penetrating Ballistic-Like Brain Injury

Shear

Deng-Bryant

et al. 2016

Therapeutic Hypothermia and Temperature Management

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Brain hypothermia has been considered as a promising alternative to whole-body hypothermia in treating acute neurological disease, for example, traumatic brain injury. Previously, we demonstrated that 2-hours selective brain cooling (SBC) effectively mitigated acute (p24 hours postinjury) neurophysiological dysfunction induced by a penetrating ballistic-like brain injury (PBBI) in rats. This study evaluated neuroprotective effects of extended SBC (4 or 8 hours in duration) on sub-acute secondary injuries between 3 and 21 days postinjury (DPI). SBC (34°C) was achieved via extraluminal cooling of rats' bilateral common carotid arteries (CCA). Depending on the experimental design, SBC was introduced either immediately or with a 2-or 4-hour delay after PBBI and maintained for 4 or 8 hours. Neuroprotective effects of SBC were evaluated by measuring brain lesion volume, axonal injury, neuroinflammation, motor and cognitive functions, and post-traumatic seizures. Compared to untreated PBBI animals, 4 or 8 hours SBC treatment initiated immediately following PBBI produced comparable neuroprotective benefits against PBBI-induced early histopathology at 3 DPI as evidenced by significant reductions in brain lesion volume, axonal pathology (beta-amyloid precursor protein staining), neuroinflammation (glial fibrillary acetic protein stained-activated astrocytes and rat major histocompatibility complex class I stained activated microglial cell), and post-traumatic nonconvulsive seizures. In the later phase of the injury (7-21 DPI), significant improvement on motor function (rotarod test) was observed under most SBC protocols, including the 2-hour delay in SBC initiation. However, SBC treatment failed to improve cognitive performance (Morris water maze test) measured 13-17 DPI. The protective effects of SBC on delayed axonal injury (silver staining) were evident out to 14 DPI. In conclusion, the CCA cooling method of SBC produced neuroprotection measured across multiple domains that were evident days/weeks beyond the cooling duration and in the absence of overt adverse effects. These ''proof-of-concept'' results suggest that SBC may provide an attractive neuroprotective approach for clinical considerations.

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Correlations between Blood–Brain Barrier Disruption and Neuroinflammation in an Experimental Model of Penetrating Ballistic-Like Brain Injury

Cited by 29 publications

References 49 publications

Erythropoietin regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury

Erythropoietin regulates immune/inflammatory reaction and improves neurological function outcomes in traumatic brain injury

Serum Glial Fibrillary Acidic Protein Predicts Tissue Glial Fibrillary Acidic Protein Break-Down Products and Therapeutic Efficacy after Penetrating Ballistic-Like Brain Injury

Comprehensive Evaluation of Neuroprotection Achieved by Extended Selective Brain Cooling Therapy in a Rat Model of Penetrating Ballistic-Like Brain Injury

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