Neuroblast Distribution after Cortical Impact Is Influenced by White Matter Injury in the Immature Gyrencephalic Brain

Taylor, Sabrina R; Smith, Colin M.; Keeley, Kristen L.; McGuone, Declan; Dodge, Carter P.; Duhaime, Ann‐Christine; Costine, Beth A.

doi:10.3389/fnins.2016.00387

Cited by 5 publications

(2 citation statements)

References 46 publications

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“…Future studies will determine the effect of age on the pathophysiology of HH, determine if stopping seizures can prevent the extensive damage, and will explore the timing and the mediators of vasogenic edema. Identification of potential therapeutic targets may limit the evolution of this injury, improve innate repair efforts, 24 and reduce the burden of disability and death from this severe injury resulting from AHT.…”

Section: Discussionmentioning

confidence: 99%

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Development of a Model of Hemispheric Hypodensity (“Big Black Brain”)

Costine-Bartell

McGuone

Price

et al. 2019

Journal of Neurotrauma

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Subdural hematoma (SDH) is the most common finding after abusive head trauma (AHT). Hemispheric hypodensity (HH) is a radiological indicator of severe brain damage that encompasses multiple vascular territories, and may develop in the hemisphere(s) underlying the SDH. In some instances where the SDH is predominantly unilateral, the widespread damage is unilateral underlying the SDH. To date, no animal model has successfully replicated this pattern of injury. We combined escalating severities of the injuries and insults commonly associated with HH including SDH, impact, mass effect, seizures, apnea, and hypoventilation to create an experimental model of HH in piglets aged 1 week (comparable to human infants) to 1 month (comparable to human toddlers). Unilateral HH evolved over 24 h when kainic acid was applied ipsilateral to the SDH to induce seizures. Pathological examination revealed a hypoxic-ischemic injury-type pattern with vasogenic edema through much of the cortical ribbon with relative sparing of deep gray matter. The percentage of the hemisphere that was damaged was greater on the ipsilateral versus contralateral side and was positively correlated with SDH area and estimated seizure duration. Further studies are needed to parse out the pathophysiology of this injury and to determine if multiple injuries and insults act synergistically to induce a metabolic mismatch or if the mechanism of trauma induces severe seizures that drive this distinctive pattern of injury.

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Section: Discussionmentioning

confidence: 99%

“…6,22,23 Our cortical impact is reproducible and injures both gray and white matter. 24 We also induced mass effect, apnea, hypoventilation, and seizures to assess the role of these insults. No other model of AHT has induced or directly investigated seizures to determine if seizures are part of the pathophysiological cascade of HH.…”

Section: Introductionmentioning

confidence: 99%

Development of a Model of Hemispheric Hypodensity (“Big Black Brain”)

Costine-Bartell

McGuone

Price

et al. 2019

Journal of Neurotrauma

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Backpack-mediated anti-inflammatory macrophage cell therapy for the treatment of traumatic brain injury

Kapate,

Liao,

Sodemann

et al. 2023

PNAS Nexus

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Traumatic brain injury (TBI) is a debilitating disease with no current therapies outside of acute clinical management. While acute, controlled inflammation is important for debris clearance and regeneration after injury, chronic, rampant inflammation plays a significant adverse role in the pathophysiology of secondary brain injury. Immune cell therapies hold unique therapeutic potential for inflammation modulation, due to their active sensing and migration abilities. Macrophages are particularly suited for this task, given the role of macrophages and microglia in the dysregulated inflammatory response after TBI. However, maintaining adoptively transferred macrophages in an anti-inflammatory, wound-healing phenotype against the pro-inflammatory TBI milieu is essential. To achieve this, we developed discoidal microparticles, termed backpacks, encapsulating anti-inflammatory interleukin-4 and dexamethasone for ex vivo macrophage attachment. Backpacks durably adhered to the surface of macrophages without internalization and maintained an anti-inflammatory phenotype of the carrier macrophage through 7 days in vitro. Backpack-macrophage therapy was scaled up and safely infused into piglets in a cortical impact TBI model. Backpack-macrophages migrated to the brain lesion site and reduced pro-inflammatory activation of microglia in the lesion penumbra of the rostral gyrus of the cortex and decreased serum concentrations of pro-inflammatory biomarkers. These immunomodulatory effects elicited a 56% decrease in lesion volume. The results reported here demonstrate, to the best of our knowledge, the first use of a cell therapy intervention for a large animal model of TBI and highlight the potential of macrophage-based therapy. Further investigation is required to elucidate the neuroprotection mechanisms associated with anti-inflammatory macrophage therapy.

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Developmental Regulation of Matrix Metalloproteinases in Response to Multifactorial, Severe Traumatic Brain Injuries during Immaturity

Hochstetler,

Price,

Baohan

et al. 2024

Dev Neurosci

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Introduction: A striking pattern in young children after severe TBI is when the entire cortical ribbon displays tissue damage: hemispheric hypodensity (HH). HH is often a result of abusive head trauma (AHT). We previously reported a model of HH in a gyrencephalic species where a combination of injuries consisting of 1) cortical impact, 2) midline shift, 3) subdural hematoma/subarachnoid hemorrhage, 4) traumatic seizures, and 5) brief apnea and hypoventilation, resulted in extensive, hypoxic-ischemic type injury. Importantly, this mechanism closely resembles that seen in children, with relative sparing of the contralateral cortex, thus, ruling out a pure asphyxia mechanism. In this model, piglets of similar developmental stage to human toddlers (postnatal day 30, PND30) have extensive hypoxic-ischemic damage to the cortical ribbon with sparing of the contralateral hemisphere and deep gray matter areas. However, piglets of similar developmental stage to human infants (postnatal day 7, PND7) have less hypoxic-ischemic damage that is notably bilateral and patchy. We therefore sought to discover whether the extensive tissue damage observed in PND30 was due to a greater upregulation of matrix metalloproteinases (MMPs). Materials and Methods: In PND 7 or PND 30 piglets receiving AHT injuries (cortical impact, midline shift, subdural hematoma/subarachnoid hemorrhage, traumatic seizures, and brief apnea and hypoventilation) or a sham injury, the pattern of albumin extravasation and MMP-9 upregulation throughout the brain was determined via immunohistochemistry, brain tissue adjacent to the cortical impact where the tissue damage spreads was collected for Western blots, and the gelatinase activity was determined over time in peripheral plasma. EEG was recorded and piglets survived up to 24 hours after injury administration. Results: The pattern of albumin extravasation, indicating vasogenic edema, as well as increase in MMP-9, were both present at the same areas of hypoxic-ischemic tissue damage. Evidence from immunohistochemistry, western blot, and zymogens demonstrate that MMP- 2,- 3 or -9 are constitutively expressed during immaturity and are not different between developmental stages; however, active forms are upregulated in PND30 but not PND7 after in response to AHT model injuries. Furthermore, peripheral active MMP-9 was downregulated after model injuries in PND7. Conclusions: This differential response to AHT model injuries might confer protection to the PND7 brain. Additionally, we find that immature gyrencephalic species have a greater baseline and array of MMP’s than previously demonstrated in rodent species. Treatment with an oral or intravenous broad-spectrum matrix metalloproteinase inhibitor might reduce the extensive spread of injury in PND30, but the exposure to metalloproteinase inhibitors must be acute as to not interfere with the homeostatic role of matrix metalloproteinases in normal postnatal brain development and plasticity as well as post-injury synaptogenesis and tissue repair.

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Neuroblast Distribution after Cortical Impact Is Influenced by White Matter Injury in the Immature Gyrencephalic Brain

Cited by 5 publications

References 46 publications

Development of a Model of Hemispheric Hypodensity (“Big Black Brain”)

Development of a Model of Hemispheric Hypodensity (“Big Black Brain”)

Backpack-mediated anti-inflammatory macrophage cell therapy for the treatment of traumatic brain injury

Developmental Regulation of Matrix Metalloproteinases in Response to Multifactorial, Severe Traumatic Brain Injuries during Immaturity

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