Mild traumatic brain injury increases vulnerability to cerebral ischemia in mice

Recent studies have reported that TBI is an independent risk factor for subsequent stroke. Here, we tested the hypothesis that TBI would exacerbate experimental stroke outcomes via alternations in neuroimmune and neurometabolic function. We performed a mild closed-head TBI and then one week later induced an experimental stroke in adult male mice. Mice that had previously experienced TBI exhibited larger infarcts, greater functional deficits, and more pronounced neuroinflammatory responses to stroke. We hypothesized that impairments in central metabolic physiology mediated poorer outcomes after TBI. To test this, we treated mice with the insulin sensitizing drug pioglitazone (Pio) after TBI. Pio prevented the exacerbation of ischemic outcomes induced by TBI and also blocked the induction of insulin insensitivity by TBI. However, tissue respiratory function was not improved by Pio. Finally, TBI altered microvascular responses including promoting vascular accumulation of serum proteins and significantly impairing blood flow during the reperfusion period after stroke, both of which were reversed by treatment with Pio. Thus, TBI appears to exacerbate ischemic outcomes by impairing metabolic and microvascular physiology. These data have important implications because TBI patients experience strokes at greater rates than individuals without a history of head injury, but these data suggest that those strokes may also cause greater tissue damage and functional impairments in that population.

Automated summary

Recent studies have shown that traumatic brain injury (TBI) can worsen outcomes after stroke by affecting neuroimmune and neurometabolic functions. In a mouse model, TBI led to larger stroke infarcts, more severe functional deficits, and increased neuroinflammation. Treatment with the insulin sensitizing drug pioglitazone was able to prevent the exacerbation of ischemic outcomes caused by TBI, suggesting that metabolic dysfunction plays a role in these processes.