Hippocampal vulnerability following traumatic brain injury: a potential role for neurotrophin‐4/5 in pyramidal cell neuroprotection

Abstract

Traumatic brain injury (TBI) causes selective hippocampal cell death, which is believed to be associated with cognitive impairment observed both in clinical and experimental settings. Although neurotrophin administration has been tested as a strategy to prevent cell death following TBI, the potential neuroprotective role of neurotrophin-4/5 (NT-4/5) in TBI remains unknown. We hypothesized that NT-4/5 would offer neuroprotection for selectively vulnerable hippocampal neurons following TBI. Measurements of NT-4/5 in rats subjected to lateral fluid percussion (LFP) TBI revealed two-threefold increases in the injured cortex and hippocampus in the acute period (1-3 days) following brain injury. Subsequently, the response of NT-4/5 knockout (NT-4/5(-/-)) mice to controlled-cortical impact TBI was investigated. NT-4/5(-/-) mice were more susceptible to selective pyramidal cell loss in Ahmon's corn (CA) subfields of the hippocampus following TBI, and showed impaired motor recovery when compared with their brain-injured wild-type controls (NT-4/5(wt)). Additionally, we show that acute, prolonged administration of recombinant NT-4/5 (5 microg/kg/day) prevented up to 50% of the hippocampal CA pyramidal cell death following LFP TBI in rats. These results suggest that post-traumatic increases in endogenous NT-4/5 may be part of an adaptive neuroprotective response in the injured brain, and that administration of this neurotrophic factor may be useful as a therapeutic strategy following TBI.

Neuropsychology and clinical neuroscience of persistent post-concussive syndrome

“…The Viano et al (2005b) study demonstrated that the typical deformation of the hippocampus to be 4-6 mm in concussion associated with professional football. Numerous human and animal studies have demonstrated the vulnerability of the hippocampus (and fornix) to injury in TBI Geddes et al, 2003;Royo et al, 2006;Tashlykov et al, 2007;Tasker et al, 2005;Wilde et al, 2006b) and functional neuroimaging studies using SPECT also demonstrate medial temporal lobe hypoperfusion in mTBI (Gowda et al, 2006). Thus, given the location of the hippocampus in the medial temporal lobe and its connection and location to the fornix, these brain regions are key to understanding PPCS neuropsychology, and should be the focus of intense neuropsychological investigation.…”

Genetic Manipulation of Cell Death and Neuroplasticity Pathways in Traumatic Brain Injury

“…These knockout mouse studies provide support for the usefulness of NT-4/5 therapy after trauma. Indeed, supplementation of NT-4/5 levels through post-traumatic intracerebral infusion of recombinant protein reduced hippocampal CA2/3 pyramidal neuronal loss following lateral fluid percussion brain injury in rats [99].…”

“…Brain injury elicits an increase in expression of multiple growth factors including neurotrophins, which is often transient and limited to traumatic penumbra [99][100][101]. Supplementing this response by exogenous growth factor administration promotes functional improvement and neuroprotection following experimental TBI [99,101,102].…”

“…Brain injury elicits an increase in expression of multiple growth factors including neurotrophins, which is often transient and limited to traumatic penumbra [99][100][101]. Supplementing this response by exogenous growth factor administration promotes functional improvement and neuroprotection following experimental TBI [99,101,102]. Although no published studies in TBI, to our knowledge, have used transgenic mice to study overexpression of growth factors, 3 studies have used knockout mouse models to probe the role of endogenous growth factors in the response to TBI (Fig.…”

“…In the first of these 3 studies, the effects of CCI brain injury on mice with a targeted deletion of the NT-4/5 gene were evaluated [99]. Deficiency of the neurotrophin NT-4/5 increased the vulnerability of CA2/CA3 pyramidal neurons to trauma and impeded recovery of motor function, suggesting that endogenous NT-4/5 acts to limit damage after TBI.…”