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.

Immunological response in early brain injury after SAH.

This study summarized the role of inflammation in the early brain injury after subarachnoid hemorrhage. Elevation of cytokines, activation of MMPs and phosphorylation of MAPK contributes to neuronal apoptosis and brain edema. Anti-inflammation may be potential strategy for the prevention and suppression of early brain injury after subarachnoid hemorrhage.

The effects of tetrahydrobiopterin on intracerebral hemorrhage-induced brain injury in mice.

Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthase (NOS) and is presently used clinically to treat forms of phenylketonuria. BH4 has been reported to restrain superoxide generation of NOS and chemically reduce superoxide. However, there has been no report concerning the effects of BH4 in intracerebral hemorrhage (ICH). In the present study, we investigated the neuroprotective effect of BH4 against ICH-induced brain injury in a mouse model.A total of 26 male CD1 mice (31-39 g) were divided into sham, ICH-vehicle, and ICH-treated with BH4 groups (n = 8 in each group). ICH was induced by collagenase injection into the right basal ganglia. BH4 (20 mg/kg) was administrated intraperitoneally at 1 h after ICH. The effect of BH4 was measured by neurological score and brain water content at 24 h after ICH.Our data demonstrates that ICH caused significant neurological deficit that is associated with brain edema. Treatment with BH4 did not reduce brain edema and neurological deficits at 24 h after ICH in mice. Further study is required to investigate the long-term effect of BH4 in ICH-induced brain injury.

Role of interleukin-1beta in early brain injury after subarachnoid hemorrhage in mice.

BACKGROUND AND PURPOSE: The role of interleukin (IL)-1beta remains unknown in early brain injury (EBI) after subarachnoid hemorrhage (SAH), although IL-1beta has been repeatedly reported to increase in the brain and cerebrospinal fluid. The aim of this study is to examine the effects of IL-1beta inactivation on EBI after SAH in mice. METHODS: The endovascular perforation model of SAH was produced and 112 mice were assigned to sham, SAH+ vehicle, and SAH+ N-Ac-Tyr-Val-Ala-Asp-chloromethyl ketone (Ac-YVAD-CMK, 6 and 10 mg/kg) groups. Ac-YVAD-CMK, a selective inhibitor of IL-1beta converting enzyme, or vehicle was administered intraperitoneally 1 hour post-SAH. EBI was assessed in terms of mortality within 24 hours, neurological scores, brain water content at 24 and 72 hours, Evans blue dye extravasation and Western blot for IL-1beta, c-Jun N-Terminal kinase (JNK), matrix metalloproteinase (MMP)-9, and zonula occludens (ZO)-1 at 24 hours after SAH. RESULTS: High-dose (10 mg/kg) but not low-dose (6 mg/kg) treatment group significantly improved neurological scores, mortality, brain water content, and Evans blue dye extravasation compared with the vehicle group. Although both dosages of Ac-YVAD-CMK attenuated the mature IL-1beta induction, only high-dose treatment group significantly inhibited the phosphorylation of JNK, MMP-9 induction, and ZO-1 degradation. CONCLUSIONS: IL-1beta activation may play an important role in the pathogenesis of EBI after SAH. The neurovascular protection of Ac-YVAD-CMK may be provided by the inhibition of JNK-mediated MMP-9 induction and the consequent preservation of tight junction protein ZO-1.

Effect of gap junction inhibition on intracerebral hemorrhage-induced brain injury in mice.

It has been reported that gap junction contributes to ischemic brain injury and gap junction inhibitors improve neurological outcome in ischemic brain injury models. In the present study, we investigated the effects of gap junction inhibitor, carbenoxolone, on mortality, neurological deficits and brain edema in mice with intracerebral hemorrhage. A total of 80 male CD-1 mice were divided into two parts with two end-points for this study. In part one, animals were divided into four groups: sham, vehicle treatment following intracerebral hemorrhage induction, low-dose carbenoxolone (33 mg/kg) treatment 1 hour after intracerebral hemorrhage induction and high-dose carbenoxolone (100 mg/kg) treatment 1 hour after intracerebral hemorrhage induction groups. Animals were euthanized after 24 hours. In part two, animals were divided into four groups: sham, vehicle treatment 1 hour after intracerebral hemorrhage induction, single high-dose of carbenoxolone treatment at 1 hour after intracerebral hemorrhage induction and three high-doses of carbenoxolone treatment 1, 24 and 48 hours respectively after intracerebral hemorrhage induction. Animals were euthanized after 72 hours. Intracerebral hemorrhage was induced by collagenase injection. Neurological deficits were evaluated using modified Garcia's neurological test, wire hanging and beam balance tests. Brain edema was measured by brain water content. Our results showed that intracerebral hemorrhage produced brain edema and neurological deficits in mice. Carbenoxolone treatment failed to reduce brain edema and neurological deficits. In fact, the high dose of carbenoxolone aggravated neurological deficits and increased mortality 72 hours after the treatment. In conclusion, inhibition of gap junction has no short-term neuroprotective effect on intracerebral hemorrhage-induced brain injury. Further studies are required to assess the long-term effects of gap junction inhibitors in intracerebral hemorrhage models.

The effects of nicotinamide adenine dinucleotide on intracerebral hemorrhage-induced brain injury in mice.

In the present study, we investigated whether the administration of nicotinamide adenine dinucleotide (NAD+) provides brain protection in a mouse model of intracerebral hemorrhage (ICH). Male CD-1 mice were divided into sham, ICH treated with vehicle and ICH treated with NAD+ (10 or 20 mg/kg, intranasal) groups. Intranasal delivery of NAD+ resulted in an increase in NAD+ contents in the brains. ICH was induced by collagenase injection. Neurological function, hemorrhage volume and brain edema were measured 24 hours after injection. ICH caused significant neurological deficit with associated brain edema. NAD+ (10 and 20 mg/kg) failed to reduce brain injury after ICH. These results suggest that NAD+ has no neuroprotective effect at 24 hours after ICH.