Transcranial amelioration of inflammation and cell death after brain injury

Abstract

Traumatic brain injury (TBI) is increasingly appreciated to be highly prevalent and deleterious to neurological function 1, 2 . At present no effective treatment options are available, and little is known about the complex cellular response to TBI during its acute phase. To gain novel insights into TBI pathogenesis, we developed a novel closed-skull brain injury model that mirrors some pathological features associated with mild TBI in humans and used long-term intravital microscopy to study the dynamics of the injury response from its inception. Here we demonstrate that acute brain injury induces vascular damage, meningeal cell death, and the generation of reactive oxygen species (ROS) that ultimately breach the glial limitans and promote spread of the injury into the parenchyma. In response, the brain elicits a neuroprotective, purinergic receptor dependent inflammatory response characterized by meningeal neutrophil swarming and microglial reconstitution of the damaged glial limitans. We additionally show that the skull bone is permeable to small molecular weight compounds and use this delivery route to modulate inflammation and therapeutically ameliorate brain injury through transcranial administration of the ROS scavenger, glutathione. Our results provide novel insights into the acute cellular response to TBI and a means to locally deliver therapeutic compounds to the site of injury.TBI encompasses injuries that range from mild to severe 1, 3 and occurs when the brain is exposed to external forces that induce focal and / or diffuse pathologies, including vascular damage, edema, axonal shearing, and neuronal cell death [4][5][6] . TBI is usually divided into two phases: the primary insult and ensuing secondary reaction. It is postulated that primary cell death cannot be prevented without avoiding the injury itself, but that secondary damage is amenable therapeutic intervention because it is driven by pathogenic parameters such as ROS 7,8 , calcium release 9 , glutamate toxicity 10, 11 , mitochondrial dysfunction 12 , inflammation 6 , etc. To date, animal models of TBI have been developed that reflect mild, Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests. In humans, primary injury to the meninges and vasculature can be observed in the absence of conspicuous brain damage following minor head trauma. As part of an ongoing study of mild TBI, we evaluated research MRI with contrast from patients presenting to the emergency room within 48 hours of minor head injury. Over a period of 30 months, 142 patients were enrolled with a baseline Glasgow Coma Scale (GCS) of 15, reporting loss-ofconsciousness or post-traumatic amnesia, and a clinical computed tomography (CT) scan without evidence of injury to the parenchyma. Meningeal hemorrhag...

Differential contribution of COX-1 and COX-2 derived prostanoids to cortical spreading depression—Evoked cerebral oligemia

“…This approach, although less efficient than direct parenchymal application, has been used previously to manipulate cortical function: [46][47][48] it is consistent with the notion that agents with molecular weights similar to the inhibitors used in our study undergo rapid transmeningeal diffusion into all layers of the cortex following topical epidural application, with a dilution factor of 1:100-500. [47][48][49] Such dilution could potentially explain why in our study epidural SC-560 treatment (at 500 mM) did not reduce resting CBF while previous studies noted decreased resting CBF and cerebral vasoconstriction following parenchymal superfusion of this inhibitor at concentrations !10 mM. 30,38,50 Because SC-560, as well naproxen, affected CBF only during the oligemic stage, it is also tempting to speculate that these COX inhibitors are more efficient in blocking the synthesis of vasoconstricting prostanoids that mediate the post-CSD oligemia than inhibiting the formation of vasodilating prostanoids that control basal CBF.…”

Abstracts from the ASENT 17th Annual Meeting

“…Results: Immunohistochemical labeling demonstrated elevated expression of Iba-1 and GFAP in the cortex, corpus callosum, and hippocampus 2, 24 h, and 1week after HIFU exposure, suggesting a diffuse neuroinflammatory response. This is in agreement with previous reports [1, 3,4]. Animals subjected to HIFU exposure exhibited significantly poorer performance in the rotarod behavioral tests than those with a sham exposure up to 1 month postinjury, indicating a chronic functional impairment in locomotor ability.…”

Purinergic mechanisms in neuroinflammation: An update from molecules to behavior

“…It is likely, therefore, that reducing neuroinflammation associated with pathology is not necessarily always of value. Roth et al (2014) investigated the role of purinergic signaling in neuroinflammatory responses following TBI and found that the P2X7-mediated inflammatory response contributes to better outcomes, with activated microglia protecting the parenchyma and myelomonocytic cells invading the damaged meninges. Both purinergic mechanisms and reactive oxygen species are key players in the response to injury.…”