Oxygen therapy in permanent brain ischemia: potential and limitations.

BACKGROUND: Both normobaric (NBO) and hyperbaric (HBO) oxygen therapy are protective in transient cerebral ischemia. In contrast, in permanent ischemia models, which reflect the majority of clinical strokes, the effectiveness of NBO is unknown, and the effectiveness of HBO is controversial. The goals of the present study were to compare both oxygen therapies in 2 models of permanent ischemia, to study the effect of time window, and to evaluate the combination of both oxygen therapies. METHODS: Distal or proximal permanent occlusion of middle cerebral artery (MCAO) was induced by coagulation or filament, respectively. Mice received air, NBO, a single or repeated HBO (3 ata) treatments. Infarct sizes were quantified at 7 days (coagulation) and 24 h (filament), respectively. RESULTS: Following MCA coagulation, infarct volume was 12.9+/-1.6 mm3 in mice breathing air. When started 45 min or 120 min after MCAO, NBO (10.8+/-2.2) and significantly more potently HBO (7.8+/-0.9) reduced infarct size. Repeated HBO treatments had no additional effect (8.3+/-2.3). HBO also significantly decreased TUNEL cell staining at 24 h. Combination of 60 min NBO plus 60 min HBO resulted in smaller cortical infarcts (8.7+/-1.5) than 120 min NBO alone (11.1+/-3.2). In contrast, infarct volumes in filament-induced permanent MCAO did not differ among rodents receiving air (50+/-24 mm3), NBO (48+/-16), or HBO (46+/-21). After filament-induced transient MCAO, however, HBO reduced infarct volume significantly. CONCLUSIONS: NBO and more effectively HBO protect the brain against permanent cortical ischemia. In extensive focal ischemia, however, oxygen therapy is only effective in case of early recanalization.

Hyperbaric oxygen reduces basal lamina degradation after transient focal cerebral ischemia in rats.

Hyperbaric oxygen (HBO) has been shown to preserve the integrity of the blood-brain barrier after cerebral ischemia. However, the underlying molecular mechanisms are currently unknown. We examined the effect of HBO on postischemic expression of the basal laminar component laminin-5 and on plasma matrix metalloproteinase-9 (MMP) levels. Wistar rats underwent occlusion of the middle cerebral artery (MCAO) for 2 h. With a delay of 45 min after filament introduction, animals breathed either 100% O2 at 1.0 atmosphere absolute (ata; NBO) or at 3.0 ata (HBO) for 1 h in an HBO chamber. Laminin-5 expression was quantified on immunohistochemical sections after 24 h of reperfusion. Plasma MMP-9 levels were measured using gelatin zymography before MCAO as well as 0, 6 and 24 h after reperfusion. Immunohistochemistry 24 h after ischemia revealed a decrease of vascular laminin-5 staining in the ischemic striatum to 43 +/- 26% of the contralateral hemisphere in the NBO group which was significantly attenuated to 73 +/- 31% in the HBO group. Densitometric analysis of zymography bands yielded significantly larger plasma MMP-9 levels in the NBO group compared to the HBO group 24 h after ischemia. In conclusion, HBO therapy attenuates ischemic degradation of cerebral microvascular laminin-5 and blocks postischemic plasma MMP-9 upregulation.

Hyperbaric oxygen reduces blood-brain barrier damage and edema after transient focal cerebral ischemia.

BACKGROUND AND PURPOSE: Hyperbaric oxygen (HBO) has been shown to protect the brain parenchyma against transient focal cerebral ischemia, but its effects on the ischemic microcirculation are largely unknown. We examined the potential of HBO to reduce postischemic blood-brain barrier (BBB) damage and edema. METHODS: Wistar rats and C57/BL6 mice underwent occlusion of the middle cerebral artery (MCAO) for 2 hours. Forty minutes after filament introduction, animals breathed either 100% O2 at 3.0 atmospheres absolute (ata; HBO group) or at 1.0 ata (control) for 1 hour in an HBO chamber. In rats, MRI was performed 15 minutes after MCAO and after 15 minutes and 3, 6, 24, and 72 hours of reperfusion. In mice, BBB permeability for sodium fluorescein was measured after 24-hour reperfusion. RESULTS: Increased BBB permeability on postcontrast T1-weighted (T1w) images had a biphasic pattern. HBO reduced volumes and intensity of enhancement. Mean abnormal enhancing volumes were 71+/-10 mm3 (control) versus 47+/-10 mm3 (HBO) at 15 minutes; 111+/-21 mm3 versus 69+/-17 mm3 3 hours; 147+/-44 mm3 versus 83+/-21 mm3 6 hours; 150+/-37 mm3 versus 89+/-14 mm3 24 hours; and 322+/-52 mm3 versus 215+/-21 mm3 72 hours (all P<0.05). Interhemispheric quotients of mean gray values on T1w were at 1.73+/-0.11 versus 1.57+/-0.07 15 minutes; 1.74+/-0.07 versus 1.60+/-0.06 at 3 hours; 1.77+/-0.07 versus 1.62+/-0.06 at 6 hours; 1.79+/-0.10 versus 1.60+/-0.05 at 24 hours; and 1.81+/-0.10 versus 1.62+/-0.07 at 72 hours (all P<0.05). HBO-treated mice had significantly lower postischemic BBB permeability than mice treated with either normobaric hyperoxia or room air. Vasogenic edema assessed on T2w images and histologic sections was significantly lower in HBO-treated rats. CONCLUSIONS: Intraischemic HBO therapy reduces early and delayed postischemic BBB damage and edema after focal ischemia in rats and mice.

Hyperbaric oxygen induces rapid protection against focal cerebral ischemia.

BACKGROUND AND PURPOSE: The timing and mechanisms of protection by hyperbaric oxygen (HBO) in cerebral ischemia have only been partially elucidated. We monitored the early in vivo effects of HBO after 2 h transient focal ischemia using repetitive MRI. METHODS: Wistar rats underwent filament occlusion of the middle cerebral artery (MCAO). 40 min after MCAO, rats were placed in a HBO chamber and breathed either 100% O(2) at 3.0 atmospheres absolute (ata; n = 24) or at 1.0 ata (control; n = 24) for 1 h. Diffusion, perfusion and T2-weighted MR-images were obtained after 15 min and 3, 6 and 24 h of reperfusion. In 6 axial MR slices, volume of abnormal diffusion and T2w signals were measured in the ischemic hemisphere. Furthermore, hemispheric mean apparent diffusion coefficient- (ADC) and T2 values were calculated for statistical analysis. RESULTS: HBO significantly reduced volume of abnormal DWI signal beginning immediately after reperfusion (control: 92 +/- 28 mm(3); HBO: 64 +/- 17) and lesion size on T2w (control: 375 +/- 91 mm(3); HBO: 225 +/- 39) after 24 h. Correspondingly, mean ADC levels were lower and T2 values higher in the ischemic hemisphere in the control group. HBO reduced histological infarct size at 24 h. CONCLUSION: High-dose intraischemic HBO therapy has an immediate protective on the brain which is superior to normobaric oxygen.