Abstract
BackgroundThe combination of diffuse brain injury with a hypoxic insult is associated with poor outcomes in patients with traumatic brain injury. In this study, we investigated the impact of post-traumatic hypoxia in amplifying secondary brain damage using a rat model of diffuse traumatic axonal injury (TAI). Rats were examined for behavioral and sensorimotor deficits, increased brain production of inflammatory cytokines, formation of cerebral edema, changes in brain metabolism and enlargement of the lateral ventricles.MethodsAdult male Sprague-Dawley rats were subjected to diffuse TAI using the Marmarou impact-acceleration model. Subsequently, rats underwent a 30-minute period of hypoxic (12% O2/88% N2) or normoxic (22% O2/78% N2) ventilation. Hypoxia-only and sham surgery groups (without TAI) received 30 minutes of hypoxic or normoxic ventilation, respectively. The parameters examined included: 1) behavioural and sensorimotor deficit using the Rotarod, beam walk and adhesive tape removal tests, and voluntary open field exploration behavior; 2) formation of cerebral edema by the wet-dry tissue weight ratio method; 3) enlargement of the lateral ventricles; 4) production of inflammatory cytokines; and 5) real-time brain metabolite changes as assessed by microdialysis technique.ResultsTAI rats showed significant deficits in sensorimotor function, and developed substantial edema and ventricular enlargement when compared to shams. The additional hypoxic insult significantly exacerbated behavioural deficits and the cortical production of the pro-inflammatory cytokines IL-6, IL-1β and TNF but did not further enhance edema. TAI and particularly TAI+Hx rats experienced a substantial metabolic depression with respect to glucose, lactate, and glutamate levels.ConclusionAltogether, aggravated behavioural deficits observed in rats with diffuse TAI combined with hypoxia may be induced by enhanced neuroinflammation, and a prolonged period of metabolic dysfunction.
Highlights
The combination of diffuse brain injury with a hypoxic insult is associated with poor outcomes in patients with traumatic brain injury
Neurological outcome The impact of post-traumatic axonal injury (TAI) hypoxia on neurological dysfunction was explored using a number of sensorimotor tests over a period of 2 weeks in TAI, TAI followed by a 30-min systemic hypoxia (TAI+Hx), hypoxia alone and sham operated animal groups
TAI+Hx rats show greater deficits on the Rotarod compared to TAI The Rotarod test involves examining complex body movement and coordination, which showed severe impairment in rats following TAI and TAI+Hx when compared with shams
Summary
The combination of diffuse brain injury with a hypoxic insult is associated with poor outcomes in patients with traumatic brain injury. We investigated the impact of post-traumatic hypoxia in amplifying secondary brain damage using a rat model of diffuse traumatic axonal injury (TAI). Systemic hypoxia can be caused by extracranial injuries often co-existing with head trauma such as obstructed airways, lung puncture and excessive blood loss [9,17]. Despite these clinical observations, the exact mechanisms leading to the exacerbation of brain damage concomitant to posttraumatic hypoxia remain to be elucidated
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