Glia limitans superficialis oxidation and breakdown promote cortical cell death after repetitive head injury

Abstract

Repetitive head injury promotes free radical dependent degradation of the glia limitans superficialis -a crucial structural barrier that protects the brain parenchyma.

Immune dynamics in the CNS and its barriers during homeostasis and disease*

“…Interestingly, repetitive mTBI was found to disrupt this reparative process entirely if the initial injury did not have sufficient time to recover. A second mTBI encountered within 1 day of the first impeded angiogenesis, elevated cell death / barrier leakage, and promoted a massive recruitment of inflammatory myelomonocytic cells 50,102 . Whether the calvaria bone marrow 29,30 plays a role in the rapid recruitment of infiltrative cells after mTBI is unknown, but this seems likely given the direct vascular channels from the skull bone marrow to the meninges.…”

“…Currently, there are no approved treatments that improve outcomes after TBI, and a deeper understanding of the immune response and repair process in patients with these injuries is essential. Intravital imaging in rodents has shown that treatment with the ROS scavenger, glutathione, is an excellent therapeutic, especially when applied transcranially to the mTBI lesion 74,100,102 . It preserves integrity of the glia limitans superficialis, which in turn reduces immune cell activation / recruitment and cell death in the underlying brain parenchyma.…”

“…Interestingly, this microglia response failed when a second mTBI was encountered within a day of the first injury, leading to enhanced leakiness of the glia limitans superficialis and increased cell death in the neocortex. 102 Focal laser models of brain damage have demonstrated that microglial rapidly extend processes (on a time scale of minutes) and attempt to wall off regions of cerebrovascular or parenchymal damage by responding to extracellular purines like adenosine triphosphate (ATP). [72][73][74]103 Purines can be released by dying cells or actively pumped into the extracellular space as an immunological alarmin by pannexin or connexin hemichannels.…”

“…High concentrations of meningeal ROS released after primary and secondary mTBI break down the glial limitans superficialis and cause cell death in the brain parenchyma. 50,74,102 Importantly, treatment with the free radical scavenger, glutathione, was shown to markedly reduce brain damage following both primary and secondary mTBI. 74,102 In addition to vascular damage, meningeal lymphatics also play a role in TBI pathogenesis.…”

“…Breakdown and damage to CNS barriers including the meninges, BBB, and blood–CSF barrier are common after TBI. Repair of vasculature and rapid restoration of barriers are essential for recovery, and this repair is further impaired by repeated injury 50,74,102 . Resident microglial have a small cell body and long processes during steady state, but rapidly respond to injury by changing their morphology.…”