Reiko Tsuchiyama

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

Background and Purpose— The role of interleukin (IL)-1&bgr; remains unknown in early brain injury (EBI) after subarachnoid hemorrhage (SAH), although IL-1&bgr; has been repeatedly reported to increase in the brain and cerebrospinal fluid. The aim of this study is to examine the effects of IL-1&bgr; 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-1&bgr; 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-1&bgr;, 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-1&bgr; induction, only high-dose treatment group significantly inhibited the phosphorylation of JNK, MMP-9 induction, and ZO-1 degradation. Conclusion— IL-1&bgr; 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.

Role of Interleukin-1β in Early Brain Injury After Subarachnoid Hemorrhage in Mice

Background and Purpose— The role of interleukin (IL)-1&bgr; remains unknown in early brain injury (EBI) after subarachnoid hemorrhage (SAH), although IL-1&bgr; has been repeatedly reported to increase in the brain and cerebrospinal fluid. The aim of this study is to examine the effects of IL-1&bgr; 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-1&bgr; 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-1&bgr;, 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-1&bgr; induction, only high-dose treatment group significantly inhibited the phosphorylation of JNK, MMP-9 induction, and ZO-1 degradation. Conclusion— IL-1&bgr; 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.

A clinical review of cerebral vasospasm and delayed ischaemia following aneurysm rupture.

The continuation of a review of delayed vasospasm after aneurysmal subarachnoid haemorrhage, originally published in 1994 and partially updated at the ninth vasospasm conference in Turkey, is presented. Further online and physical searches have been made of the relevant literature. The incidence of delayed ischaemic deficit (DID) or symptomatic vasospasm reported in 1994 was 32.5% in over 30,000 reported cases. In recent years, 1994–2009, it was 6,775/23,806, or 28.5%. Many of the recent reports did not specify whether a calcium antagonist was used routinely, and when this was stated (usually nimodipine or nicardipine), DID was noted in 22.0% of 10,739 reported patients. The outcome of delayed ischaemia in the earlier survey was a death rate of 31.6%, with favourable outcomes in 36.2%. In recent reports, though with fewer than 1,000 patients, the outcome is possibly better, with death in 25.6% and good outcome in 54.1%. It thus appears likely that delayed vasospasm is still common but less so, and that the overall outcome has improved. This may be due to the more widespread use of calcium antagonists and more effective fluid management. A number of other mechanical and drug treatments are also mentioned.The continuation of a review of delayed vasospasm after aneurysmal subarachnoid haemorrhage, originally published in 1994 and partially updated at the ninth vasospasm conference in Turkey, is presented. Further online and physical searches have been made of the relevant literature. The incidence of delayed ischaemic deficit (DID) or symptomatic vasospasm reported in 1994 was 32.5% in over 30,000 reported cases. In recent years, 1994-2009, it was 6,775/23,806, or 28.5%. Many of the recent reports did not specify whether a calcium antagonist was used routinely, and when this was stated (usually nimodipine or nicardipine), DID was noted in 22.0% of 10,739 reported patients. The outcome of delayed ischaemia in the earlier survey was a death rate of 31.6%, with favourable outcomes in 36.2%. In recent reports, though with fewer than 1,000 patients, the outcome is possibly better, with death in 25.6% and good outcome in 54.1%. It thus appears likely that delayed vasospasm is still common but less so, and that the overall outcome has improved. This may be due to the more widespread use of calcium antagonists and more effective fluid management. A number of other mechanical and drug treatments are also mentioned.

Advances in experimental subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) remains to be a devastating disease with high mortality and morbidity. Two major areas are becoming the focus of the research interest of SAH: these are cerebral vasospasm (CVS) and early brain injury (EBI). This mini review will provide a broad summary of the major advances in experimental SAH during the last 3 years. Treatments interfering with nitric oxide (NO)- or endothelin-pathways continue to show antispasmotic effects in experimental SAH. HIF 1 may play both a detrimental and beneficial role in the setting of SAH, depending on its activation stage. Inflammation and oxidative stress contribute to the pathophysiology of both CVS and EBI. Apoptosis, a major component of EBI after SAH, also underlie the etiology of CVS. Since we recognize now that CVS and EBI are the two major contributors to the significant mortality and morbidity associated with SAH, ongoing research will continue to elucidate the underlying pathophysiological pathways and treatment strategies targeting both CVS and EBI may be more successful and improve outcome of patients with SAH.

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.

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

Abstract 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 Garcias 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.

Role of Interleukin-1 in Early Brain Injury After Subarachnoid Hemorrhage in Mice

Background and Purpose— The role of interleukin (IL)-1&bgr; remains unknown in early brain injury (EBI) after subarachnoid hemorrhage (SAH), although IL-1&bgr; has been repeatedly reported to increase in the brain and cerebrospinal fluid. The aim of this study is to examine the effects of IL-1&bgr; 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-1&bgr; 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-1&bgr;, 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-1&bgr; induction, only high-dose treatment group significantly inhibited the phosphorylation of JNK, MMP-9 induction, and ZO-1 degradation. Conclusion— IL-1&bgr; 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.

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

Abstract 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.

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.

Roles of Signal Transduction Mechanisms in Cerebral Vasospasm Following Subarachnoid Hemorrhage: Overview

The concept of “cortical spreading depression” following subarachnoid hemorrhage (SAH) drastically tends to change the direction of vasospasm research. It has been rather confuse whether classical idea, delayed long-lasting major cerebral arterial contraction is real cerebral vasospasm or it occurs just after SAH and classical arterial contraction is an epiphenomenon. However, it is true that such sustained arterial contraction occurs following SAH, and the mechanisms still remain unclear. Intracellular signal transduction plays a pivotal role in long-lasting arterial contraction. Although scientific research advances, each role of signal transduction system has been getting clarified; overview or interrelations among such systems have to be more investigated. Based on the previous results, some aspect or part of streams of interrelation of signal transduction systems can be getting clearer. Such way to clarify the overview is extremely important to understand the real mechanisms of long-lasting arterial contraction following SAH (“classical cerebral vasospasm”).