Brief apnea with hypoventilation reduces seizure duration and shifts seizure location for several hours in a model of severe traumatic brain injury.

OBJECTIVE: Seizures can be difficult to control in infants and toddlers. Seizures with periods of apnea and hypoventilation are common following severe traumatic brain injury (TBI). We previously observed that brief apnea with hypoventilation (A&H) in our severe TBI model acutely interrupted seizures. The current study is designed to determine the effect of A&H on subsequent seizures and whether A&H has potential therapeutic implications. METHODS: Piglets (1 week or 1 month old) received multifactorial injuries: cortical impact, mass effect, subdural hematoma, subarachnoid hemorrhage, and seizures induced with kainic acid. A&H (1 min apnea, 10 min hypoventilation) was induced either before or after seizure induction, or control piglets received subdural/subarachnoid hematoma and seizure without A&H. In an intensive care unit, piglets were sedated, intubated, and mechanically ventilated, and epidural electroencephalogram was recorded for an average of 18 h after seizure induction. RESULTS: In our severe TBI model, A&H after seizure reduced ipsilateral seizure burden by 80% compared to the same injuries without A&H. In the A&H before seizure induction group, more piglets had exclusively contralateral seizures, although most piglets in all groups had seizures that shifted location throughout the several hours of seizure. After 8-10 h, seizures transitioned to interictal epileptiform discharges regardless of A&H or timing of A&H. SIGNIFICANCE: Even brief A&H may alter traumatic seizures. In our preclinical model, we will address the possibility of hypercapnia with normoxia, with controlled intracranial pressure, as a therapeutic option for children with status epilepticus after hemorrhagic TBI.

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

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 proinflammatory 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 proinflammatory activation of microglia in the lesion penumbra of the rostral gyrus of the cortex and decreased serum concentrations of proinflammatory biomarkers. These immunomodulatory effects elicited a 56% decrease in lesion volume. The results reported here demonstrate, to the best of our knowledge, a potential 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.