Pretreatment with normobaric and hyperbaric oxygenation worsens cerebral edema and neurologic outcomes in a murine model of surgically induced brain injury.

BACKGROUND: Hyperbaric oxygenation is a readily available treatment modality, and its ability to improve neurological outcomes in a variety of animal models has been demonstrated. This study was designed to investigate the use of a single pretreatment regimen of either hyperbaric oxygenation or normobaric oxygenation to determine its effects in a murine model of surgically induced brain injury (SBI). MATERIALS AND METHODS: Hyperbaric oxygen (2.5ATM, 1 h), normobaric oxygen (100% FIO2, 1 h) or room air (21% FIO2, 1 h) was applied on CD-1 mice immediately, or at 1, 2 or 3 h followed by SBI or sham surgical operation. Neurological assessment of the animals was done by a blinded observer at 24 and 72 h using a 21-point modified Garcia scale, wire hanging test, and beam balance test. The brain edema was evaluated using brain water content at 24 and 72 h after SBI. RESULTS: There was no statistically significant difference in the mortality rate after treatment compared with the SBI group. The brain water content after SBI was significantly increased in the right (ipsilateral) frontal lobe surrounding the site of surgical resection compared with the sham group. Both hyperbaric and normobaric oxygen treatment significantly increased the brain edema and worsened the neurological outcomes using a 21-point Garcia score compared with the SBI group. The brain edema at 24 h after injury was most pronounced in the group treated with normobaric oxygenation 2 h prior to surgery. These differences disappeared at 72 h after SBI. CONCLUSION: Immediate pretreatment with either hyperbaric (2.5ATM, 1 h) or normobaric oxygen (100% FIO2, 1 h) increased brain edema and worsened neurological function at 24 h following SBI.

Reduced matrix metalloproteinase-9 activity and cell death after global ischemia in the brain preconditioned with hyperbaric oxygen.

Matrix metalloproteinase-9 (MMP-9) plays a deleterious role in cell death after global cerebral ischemia. Preconditioning with hyperbaric oxygen (HBO-PC) reduces neuronal damage in the post-ischemic brain; however, its effect on ischemia-induced increase in MMP-9 activity and expression remains unexplored.We investigated effects of HBO-PC on alterations in MMP-9 activity/tissue expression accompanying neuronal death after transient global cerebral ischemia.Male SD rats (300-350 g), were allocated either to non-ischemic (naive control or sham-operated) or ischemic (four-vessel occlusion, 4VO; 10 min) groups that were HBO-preconditioned (2.5 ATA, 1 h daily for 5 days; the last session 24 h before ischemia) or not. Neurobehavioral deficits were assessed prior to collection of brain tissue for gel zymography (MMP-9) and histology (MMP-9 immunofluorescence, TUNEL) at 0 (without ischemia), 6, 24, 72 h and 7 days after 4VO.Both, MMP-9 levels and cell death increased in the hippocampus at 72 h after 4VO. HBO-PC suppressed postischemic MMP-9 activity and CA1 cell damage, and improved functional performance. The increase in MMP-9 immunoreactivity in the brain was also detected after HBO-PC alone. HBO-PC suppresses MMP-9 activity and expression in the postischemic hippocampus. The mechanism of HBO preconditioning may depend on the induction of MMP-9 in the preischemic phase and may be in part mediated by exhaustion of MMP-9 stores in cerebral tissues.

Thrombin inhibition by argatroban ameliorates early brain injury and improves neurological outcomes after experimental subarachnoid hemorrhage in rats.

BACKGROUND AND PURPOSE: We investigated the role of thrombin in early brain injury after subarachnoid hemorrhage (SAH). METHODS: The standard intravascular perforation model was used to produce experimental SAH in Sprague Dawley rats. Low-dose (0.3 mg/h) and high-dose (0.9 mg/h) argatroban, a direct thrombin inhibitor, were evaluated for effects on brain edema, blood-brain barrier (BBB) disruption, apoptotic cell death, inflammatory marker, and neurological outcomes after SAH. RESULTS: Both doses of argatroban attenuated BBB disruption; however, only high-dose was effective in lowering edema in all brain regions, reducing cell death, and inflammatory marker expression, and improving neurological outcomes. CONCLUSIONS: Thrombin inhibition by argatroban improves neurological outcomes and provides neuroprotection against acute events after SAH such as BBB disruption, brain edema, and cell death.

Melatonin decreases mortality following severe subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (SAH) is a devastating disease that is associated with significant morbidity and mortality. There is substantial evidence to suggest that oxidative stress is significant in the development of acute brain injury following SAH. Melatonin is a strong antioxidant that has low toxicity and easily passes through the blood-brain barrier. Previous studies have shown that melatonin provides neuroprotection in animal models of ischemic stroke. This study hypothesizes that melatonin will provide neuroprotection when administered 2 hr after SAH. The filament perforation model of SAH was performed in male Sprague-Dawley rats weighing between 300 and 380 g. Melatonin (15 or 150 mg/kg), or vehicle was given via intraperitoneal injection 2 hr after SAH. Mortality and neurologic deficits were assessed 24 hr after SAH. A significant reduction in 24-hr mortality was seen following treatment with high dose melatonin. There was no improvement in neurologic scores with treatment. Brain water content and lipid peroxidation were measured following the administration of high dose melatonin to identify a mechanism for the increased survival. High dose melatonin tended to reduce brain water content following SAH, but had no effect on the lipid peroxidation of brain samples. Large doses of melatonin significantly reduces mortality and brain water content in rats following SAH through a mechanism unrelated to oxidative stress.