Spreading Depression Expands Traumatic Injury in Neocortical Brain Slices

Abstract

Traumatic brain injury (TBI) is particularly common in young people, generating healthcare costs that can span decades. The cellular processes activated in the first minutes following injury are poorly understood, and the 3-4 h following trauma are crucial for reducing subsequent injury. Spreading depression (SD) is a profound inactivation of neurons and glia lasting 1-2 min that arises focally and migrates outward across gray matter. In the hours following focal stroke, the metabolic stress of energy reduction and recurring SD-like events (peri-infarct depolarizations, PIDs) interact to promote neuronal injury. Similar recurring depolarizations might evolve immediately following TBI and exacerbate neuronal damage peripheral to the impact site. To test this possibility and examine if certain drugs might limit damage by inhibiting what we term traumatic spreading depression (tSD), we developed a technique whereby a small weight was dropped onto a live slice of rat neocortex while imaging changes in light transmittance (LT). Imaging revealed a propagating front of increased LT arising at the border of the impact site. Traumatic SD significantly expanded the region of ensuing damage. Both tSD and subsequent damage were blocked by the NMDA receptor antagonist MK-801 (100 microM) or the sigma-1 receptor (sigma1R) ligands dextromethorphan (30 microM) or BD-1063 (100 microM). Co-application of the sigma1R antagonist (+)3-PPP with DM reversed the block as did lowering temperature from 35 degrees C to 32 degrees C. This study provides evidence that an event similar to peri-infarct depolarization can arise from an injury site in neocortex within seconds following impact and act to expand the region of acute neuronal damage.

NR1 Knockdown Reveals CA1 Injuryduring a Developmental Period of High Seizure Susceptibility Despite Reduced Seizure Activity

“…The sensorimotor cortex overlying the hippocampus may have been spared at the acute time examined due to a more mature GABAergic system; and lack of limbic connections and target innervations of interneurons near our hippocampal injection site. In addition, the paradoxical neurotoxicity described may arise from sustained inward currents produced by our NMDA application that lead to spreading depression (Fifkova and Van Harreveld 1974), which is consistent with other models such as ischemia or traumatic brain injury (Obeidat and Andrew 1998;Church and Andrew 2005). In fact spreading depression can damage hippocampal pyramidal neurons in juvenile slice cultures even under normoxic conditions (Pomper et al 2006).…”

Traumatic Brain Injury in Adult Rats Causes Progressive Nigrostriatal Dopaminergic Cell Loss and Enhanced Vulnerability to the Pesticide Paraquat

“…This type of injury-induced vulnerability has also been well described in models of post-traumatic exposure to cellular activation (Maeda et al, 2005;Zanier et al, 2003), and/or physiological challenge (Bramlett et al, 1999;Church and Andrew, 2005;Dietrich et al, 1996;Griesbach, 2002;Hartings et al, 2009;Ip et al, 2003;Law et al, 1996;Suzuki et al, 2004;Taya, 2010;Van Putten et al, 2005). However, this induced vulnerability is expressed temporarily, and depending on the type of secondary challenge, can last from hours to days after injury in rodents.…”

Clinical Relevance of Cortical Spreading Depression in Neurological Disorders: Migraine, Malignant Stroke, Subarachnoid and Intracranial Hemorrhage, and Traumatic Brain Injury

“…There was no effect of these additional CSDs on injury volume at 24 hours, although secondary insults were specifically (and in one sense, commendably) minimized in this study. Different results were obtained in an in vitro cortical slice model of trauma, where a single wave of CSD caused by traumatic impact increased the volume of cortical damage compared with conditions under which the same cortical impact did not induce CSD (Church and Andrew, 2005).…”