The Long-Term Microvascular and Behavioral Consequences of Experimental Traumatic Brain Injury after Hypothermic Intervention

Abstract

Traumatic brain injury (TBI) has been demonstrated to induce cerebral vascular dysfunction that is reflected in altered responses to various vasodilators. While previous reports have focused primarily on the short-term vascular alterations, few have examined these vascular changes for more than 7 days, or have attempted to correlate these alterations with any persisting behavioral changes or potential therapeutic modulation. Accordingly, we evaluated the long-term microvascular and behavioral consequences of experimental TBI and their therapeutic modulation via hypothermia. In this study, one group was injured with no treatment, another group was injured and 1 h later was treated with 120 min of hypothermia followed by slow rewarming, and a third group was non-injured. Animals equipped with cranial windows for visualization of the pial microvasculature were challenged with various vasodilators, including acetylcholine, hypercapnia, adenosine, pinacidil, and sodium nitroprusside, at either 1 or 3 weeks post-TBI. In addition, all animals were tested for vestibulomotor tasks at 1 week post-TBI, and animals surviving for 3 weeks post-TBI were tested in a Morris water maze (MWM). The results of this investigation demonstrated that TBI resulted in long-term vascular dysfunction in terms of altered vascular reactivity to various vasodilators, which was significantly improved with the use of a delayed 120-min hypothermic treatment. In contrast, data from the MWM task indicated that injured animals revealed persistent deficits in the spatial memory test performance, with hypothermia exerting no protective effects. Collectively, these data illustrate that TBI can evoke long-standing brain vascular and spatial memory dysfunction that manifest different responses to hypothermic intervention. These findings further illustrate the complexity of TBI and highlight the fact that the chosen hypothermic intervention may not necessarily exert a global protective response.