In the present study, we demonstrated the neuroprotective effect of single-dose (100 mg/kg) VA against brain edema in a rat model of SBI. Our findings were that (1) VA pretreatment significantly attenuated brain edema at 24 h after SBI; (2) there were not significant suppressions of MMP activities associated with VA pretreatment; and (3) neurological deficits following SBI were not significantly improved by a single dose of VA pretreatment.

A rodent model of SBI introduced by our group has been shown to mimic the clinical human neurosurgery situation in that it results in the most typical postoperative consequences [7, 20]. It offers us a clinically relevant platform to study the basic pathophysiological mechanisms of SBI and to evaluate specific treatment strategies. In the right frontal lobe where brain tissue surrounds the resection site, there was a significant 3.3 % increase in water content compared with sham. Brain water content is a good indicator of brain swelling resulting from the edema. A 1 % increase in brain water content, equivalent to approximately a 4.3 % increase in tissue swelling, can lead to intracranial pressure elevation [9]. Our finding suggested the important role of brain edema associated with BBB disruption in the pathophysiology of SBI [7, 10, 20]. Neuroprotective strategies targeting brain edema would promise to limit postoperative complications; enabling more aggressive surgical approaches. The advantages and feasibility of preoperative treatment strategies rather than postoperative interventions for planned neurosurgical procedures have not been fully realized. In the present study, we demonstrated the efficacy of VA pretreatment against brain edema induced by SBI. When VA was administered 30 min before brain resection, it significantly reduced brain edema compared with vehicle-pretreated animals at 24 h after SBI. This result echoes studies in both transient and permanent middle cerebral artery occlusion (MCAO) models that show VA pretreatment attenuated ischemic brain damage and brain edema associated with BBB disruption [12, 18]. Similarly, 30 min post-injury administration of VA has also been shown to improve BBB integrity in a rodent model of traumatic brain injury [4]. The lack of protection persistent to 72 h implies that enhanced long-term neuroprotective effects may be achieved by multiple VA interventions before and after SBI.

MMPs are proteases that cleave the extracellular matrix, causing disruption of BBB, and play a critical role in brain injury associated with a variety of brain diseases [2, 3, 5]. In the current study, there was significantly higher MMP-9 activity at 24 h after SBI. It was consistent with our findings earlier using the SBI model that MMP-9 enzymatic activity was greatly elevated in the vulnerable peri-resection brain regions over the first 3 days post surgery [20]. VA pretreatment was associated with a lower level of MMP-9 activity, but this was not significantly different from that of vehicle-pretreated animals. The statistical insignificance may the result of the small sample size. On the other hand, it is possible that anti-inflammation and antioxidative effects also constitute the neuroprotective mechanisms of VA [17]. Following traumatic brain injury, BBB protection by VA may involve HDAC inhibition-mediated suppression of NF-κB and tight junction degradation in addition to MMP-9 suppression [18]. Additional research will help elucidate the underlying mechanism of VA against brain edema in the setting of SBI.