Koji Iihara

Intravenous administration of MEK inhibitor U0126 affords brain protection against forebrain ischemia and focal cerebral ischemia

Brain subjected to acute ischemic attack caused by an arterial blockage needs immediate arterial recanalization. However, restoration of cerebral blood flow can cause tissue injury, which is termed reperfusion injury. It is important to inhibit reperfusion injury to achieve greater brain protection. Because oxidative stress has been shown to activate mitogen-activated protein kinases (MAPKs), and because oxidative stress contributes to reperfusion injury, MAPK may be a potential target to inhibit reperfusion injury after brain ischemia. Here, we demonstrate that reperfusion after forebrain ischemia dramatically increases phosphorylation level of extracellular signal-regulated kinase 2 (ERK2) in the gerbil hippocampus. In addition, i.v. administration of U0126 (100–200 mg/kg), a specific inhibitor of MEK (MAPK/ERK kinase), protects the hippocampus against forebrain ischemia. Moreover, treatment with U0126 at 3 h after ischemia significantly reduces infarct volume after transient (3 h) focal cerebral ischemia in mice. This protection is accompanied by reduced phosphorylation level of ERK2, substrates for MEK, in the damaged brain areas. Furthermore, U0126 protects mouse primary cultured cortical neurons against oxygen deprivation for 9 h as well as nitric oxide toxicity. These results provide further evidence for the role of MEK/ERK activation in brain injury resulting from ischemia/reperfusion, and indicate that MEK inhibition may increase the resistance of tissue to ischemic injury.

Intracranial hemorrhage associated with cerebral hyperperfusion syndrome following carotid endarterectomy and carotid artery stenting: retrospective review of 4494 patients.

OBJECT Intracranial hemorrhage associated with cerebral hyperperfusion syndrome (CHS) following carotid endarterectomy (CEA) or carotid artery stenting (CAS) is a rare but potentially devastating complication. In the present study the authors evaluated 4494 patients with carotid artery stenosis who had undergone CEA or CAS to clarify the clinicopathological features and outcomes of those with CHS and associated intracranial hemorrhage. METHODS Patients with postoperative CHS were retrospectively selected, and clinicopathological features and outcomes were studied. RESULTS Sixty-one patients with CHS (1.4%) were identified, and intracranial hemorrhage developed in 27 of them (0.6%). The onset of CHS peaked on the 6th postoperative day in those who had undergone CEA and within 12 hours in those who had undergone CAS. Results of logistic regression analysis demonstrated that poor postoperative control of blood pressure was significantly associated with the development of intracranial hemorrhage in patients with CHS after CEA (p = 0.0164). Note, however, that none of the tested variables were significantly associated with the development of intracranial hemorrhage in patients with CHS after CAS. Mortality (p = 0.0010) and morbidity (p = 0.0172) rates were significantly higher in patients with intracranial hemorrhage than in those without. CONCLUSIONS Cerebral hyperperfusion syndrome after CEA and CAS occurs with delayed classic and acute presentations, respectively. Although strict control of postoperative blood pressure prevents intracranial hemorrhage in patients with CHS after CEA, there appears to be no relationship between blood pressure control and intracranial hemorrhage in those with CHS after CAS. Finally, the prognosis of CHS in patients with associated intracerebral hemorrhage is poor.

Platelet-Derived Growth Factor-BB, But Not -AA, Prevents Delayed Neuronal Death After Forebrain Ischemia in Rats

Our previous studies demonstrated coordinate expression of platelet-derived growth factor (PDGF) -B chain and β-receptor in neurons at risk in the rat brain with focal ischemia. To clarify a role of the -B chain in the brain further, we examined whether PDGF-A or -B chain protects CA1 pyramidal neurons from delayed neuronal death after forebrain ischemia in rats. Pretreatment with PDGF-BB, but not -AA, at 120 ng/d for 2 days until forebrain ischemia was performed markedly ameliorated delayed neuronal death in CA1 pyramidal neurons on day 7 after ischemia. This neuroprotective effect of PDGF-BB was dose-dependent, and pretreatment with PDGF-BB at 240 ng/d showed almost complete inhibition of delayed neuronal death. In contrast, posttreatment with PDGF-BB at 120 ng/d starting 20 minutes after ischemia demonstrated no significant neuroprotective effect. The current study established marked neuroprotective actions of PDGF-BB in ischemic neuronal damage.

Induction of infarct tolerance by platelet-derived growth factor against temporary focal ischemia

Abstract Nerve growth factor, brain-derived neurotrophic factor, and other neurotrophic factors have been reported to have neuroprotective effects against global ischemia. To investigate whether the homodimer of platelet-derived growth factor B-chain (PDGF-BB) can protect neurons against focal temporary ischemia, PDGF-BB was administered to the rat brain for a prolonged period prior to, during, and after ischemia, since PDGF-BB protected rat neurons from global ischemia in our previous study. A total of 82 male Sprague–Dawley rats were used. Recombinant PDGF-BB, or saline was administered into the left neocortex via an implanted osmotic pump for 3 days (1.2 μ g in total), 7 days (2 μ g or 4 μ g in total), or 14 days (4 μ g in total) pre-ischemia and 2 days post-ischemia. In an additional group, PDGF-BB (4 μ g in total) was administered for 14 days by osmotic pump and focal ischemia was induced after an additional 7-day interval following removal of the pump. Focal temporary ischemia was induced in the left MCA territory by bilateral CCA and MCA occlusion for 2 h. All rats were sacrificed 2 days after ischemia and the volume of cerebral infarct was analyzed using TTC staining. In a separate set of animals, regional cerebral blood flow (rCBF) was monitored by the hydrogen clearance method and laser Doppler flowmetry (LDF) of the neocortex after 14 days of intracerebral administration of PDGF-BB or saline. In the group receiving PDGF-BB (4 μ g in total) for 7 or 14 days pre-ischemia, there was a significant reduction of neocortical infarction compared to that in the control or saline-infused group. The size of cerebral infarct was smallest in the group that received PDGF-BB for 14 days, when ischemia was induced 7 days after removal of the pump. Regarding rCBF measurement, there were no significant differences in groups receiving PDGF-BB or saline infusion for 14 days. The potent neuroprotective effect of PDGF-BB on global ischemia was also demonstrated in the focal ischemia model. However, prolonged intracerebral infusion for 7 to 14 days was necessary to achieve a significant reduction of infarct volume. Neuroprotection was not due to increased collateral flow during ischemia.

Contrast-Enhanced Ultrasound for the Evaluation of Neovascularization in Atherosclerotic Carotid Artery Plaques

Background and Purpose— Neovascularization associated with plaque vulnerability, particularly in the plaque shoulder, is susceptible to rupture, causing ischemic events. We aimed to use contrast-enhanced ultrasound to evaluate neovessels in carotid plaques quantitatively, focusing on plaque shoulders. Methods— Using contrast-enhanced ultrasound with perflubutane, we analyzed 50 consecutive patients who underwent carotid endarterectomy. We measured enhanced intensity and assessed the correlation between contrast effect and histopathology, comparing symptomatic and asymptomatic plaques. Results— Enhanced intensity of the plaque shoulder was associated with neovessel density (P<0.01; &rgr;=0.43). Enhanced intensity of the plaque shoulder was higher in plaques with rupture than in those without (P<0.05), and in symptomatic plaques (n=31) than in asymptomatic ones (n=19; P<0.01). Conclusions— Quantitative evaluation of the contrast effect using contrast-enhanced ultrasound enabled the assessment of neovascularization of plaque shoulders in vivo real time, which may help stratify plaque vulnerability.

Growth potential and response to multimodality treatment of partially thrombosed large or giant aneurysms in the posterior circulation

OBJECTIVEThis study examined the growth potential and response to multimodality treatment of partially thrombosed large or giant aneurysms in the posterior circulation. METHODSThe 17 aneurysms arose from nonbranching sites of the vertebral artery (VA) in 6 patients and from branching sites in 11 patients (the VA-posteroinferior cerebellar artery [PICA], 3 cases; basilar artery [BA] fenestration, 1 case; BA-superior cerebellar artery [SCA], 5 cases; and BA tip, 2 cases). RESULTSEndovascular trapping was performed in 5 VA aneurysms at nonbranching sites, 2 VA-PICA cases with or without revascularization of the PICA, and 1 BA fenestration case. Endosaccular embolization was performed in 2 BA-SCA aneurysms as the sole treatment or after superficial temporal artery-SCA bypass for a broad-necked lesion. Surgical proximal occlusion (PO) with or without revascularization of the PICA was performed in 2 VA cases. Endovascular treatment failed to prevent growth in 1 VA-PICA case and the broad-necked BA-SCA case. Simple flow alteration by PO of 3 BA aneurysms, with gadolinium enhancement on T1-weighted images, did not prevent growth. Maximum flow reduction by various combinations of bypass (superficial temporal artery-posterior cerebral artery or superficial temporal artery-SCA) and BA PO, aimed at reducing hemodynamic stress on the neck, was tailored to 5 cases, including those refractory to PO; it achieved marked shrinkage in 2 cases and stabilization of the aneurysms in 3 cases. The aneurysms harboring neither gadolinium enhancement nor hyperintensity on fluid-attenuated inversion recovery images showed significantly lower growth potential before treatment and a lesser degree of shrinkage after tailored treatment than the remaining cases (P = 0.03 and P = 0.01, respectively). Overall, marked shrinkage was achieved in 27%, moderate shrinkage in 20%, stabilization in 47%, enlargement in 7%, and favorable outcome in 71%. Maximum flow reduction strategy for BA aneurysms tended to show higher shrinking efficacy than endovascular trapping for VA and BA aneurysms (P = 0.08). CONCLUSIONFor aneurysms at nonbranching sites, endovascular trapping may be effective, although its shrinking efficacy may be moderate. For the most formidable BA aneurysms at branching sites, maximum flow reduction may cause marked shrinkage, even of aggressive lesions.

Cerebral Blood Flow and Metabolism of Hyperperfusion after Cerebral Revascularization in Patients with Moyamoya Disease

In moyamoya disease (MMD), surgical revascularization may be complicated with postoperative hyperperfusion. We analyzed cerebral perfusion and metabolism using positron emission tomography (PET) or single-photon emission computed tomography (SPECT) before and after bypass surgery on 42 sides of 34 adult patients with MMD. In seven cases (16.7%) with symptomatic hyperperfusion, diagnosed by qualitative 123I-iodoamphetamine (IMP) SPECT, a subsequent PET study during postoperative subacute stages revealed significantly increased cerebral blood flow (CBF) from 34.1 ± 8.2 to 74.3 ± 12.8 mL/100 g per minute (P < 0.01), a persistent increase in cerebral blood volume (CBV)from 5.77 ± 1.67 to 7.01 ± 1.44 mL/100 g and a significant decrease in oxygen extraction fraction (OEF) from 0.61 ± 0.09 to 0.40 ± 0.08 (P < 0.01). Mean absolute CBF values during symptomatic hyperperfusion were more than the normal control +2 standard deviations, the predefined criteria of PET. Interestingly, two patients with markedly increased cerebral metabolic rate of oxygen (CMRO2) at hyperperfusion were complicated with postoperative seizure. Among preoperative PET parameters, increased OEF was the only significant risk factor for symptomatic hyperperfusion (P < 0.05). This study revealed that symptomatic hyperperfusion in MMD is characterized by temporary increases in CBF >100% over preoperative values caused by prolonged recovery of increased CBV.

Alogliptin, a dipeptidylpeptidase-4 inhibitor, for patients with diabetes mellitus type 2, induces tolerance to focal cerebral ischemia in non-diabetic, normal mice.

Effective interventions that provide obvious neuroprotection are currently fairly limited. Glucagon-like peptide-1 (GLP-1), an enhancer of insulin production with a trophic effect on β cells in the islets, has been found to be trophic for neuronal cells. Alogliptin benzoate (AGL), a selective inhibitor of dipeptidylpeptidase-4 (DPP-4) functioning as a long-acting agonist of GLP-1, is in clinical use worldwide for patients with diabetes mellitus type 2. To clarify whether administration of AGL, independent of the insulinotropic effect, protects the brain against focal ischemia, we investigated the effect of AGL on the development of cerebral infarction in non-diabetic normal mice. Male C57BL/6J mice were administered AGL (7.5, 15, or 30μg) once a day for three weeks by intragastric gavage. After the induction of temporary focal ischemia, volumes of infarcted lesions and neurological deficits were analyzed at 24h (acute phase) and seven days (chronic phase). In the acute phase, significant reductions were observed in the volumes of infarcted lesions (p=0.009), and in the severity of neurological deficits (p=0.004), in the group treated with 15μg of alogliptin benzoate, but not the 7.5 or 30μg-treated groups. This significant reduction in volumes of infarcted lesions persisted into the chronic phase. At the end of the AGL treatment; before the induction of ischemia, the levels of brain-derived neurotrophic factor (BDNF), a potent neuroprotectant in the brain, were elevated in the cortex (p=0.008), or in the whole forebrain (p=0.023). AGL could be used as a daily neuroprotectant or an enhancer of BDNF production aiming to attenuate cerebral injuries, for the growing number of people who have the risk of ischemic stroke.

Impact of posterior cerebral artery involvement on long-term clinical and social outcome of pediatric moyamoya disease

OBJECT In the study of pediatric moyamoya disease, information on long-term social outcomes and risk factors for unfavorable social outcomes remains insufficient. The authors analyzed the long-term results of surgical revascularization for pediatric patients with moyamoya disease to determine whether the involvement of a stenoocclusive lesion in the posterior cerebral artery (PCA), relatively common in pediatric moyamoya disease, represents an underlying predictor for unfavorable social outcomes. METHODS Prospectively collected data on 61 consecutive patients with moyamoya disease who had undergone combined bypass surgery were analyzed. Neuroradiological features and other baseline clinical factors were incorporated into univariate and multivariate analyses to determine any association with an unfavorable social outcome, defined as difficulty attending regular school or obtaining regular employment. RESULTS Posterior cerebral artery involvement detected by angiography on admission was noted in 22 (36.1%) of the 61 patients. Follow-up data were acquired in 56 patients (91.8%), and the mean follow-up period was 15.8 years. While transient ischemic attacks were eliminated in 52 (92.9%) of these 56 patients after surgery, and late-onset ischemic stroke was observed in only 1 patient during the follow-up period, 10 (17.9%) experienced an unfavorable social outcome. Although younger age at onset, longer duration between onset and surgery, infarction present on preoperative neuroradiological images, and PCA involvement had been identified as risk factors for an unfavorable social outcome in univariate analysis, only infarction present on preoperative images and PCA involvement remained statistically significant after multivariate adjustment. CONCLUSIONS Posterior cerebral artery involvement can be considered one of the underlying risk factors for unfavorable social outcome and should be studied further to improve social outcome in pediatric moyamoya disease.

Haptoglobin phenotype predicts cerebral vasospasm and clinical deterioration after aneurysmal subarachnoid hemorrhage.

Vasospasm (VS) and delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) are thought to greatly affect prognosis. Haptoglobin (Hp) is a hemoglobin-binding protein expressed by a genetic polymorphism (1-1, 2-1, and 2-2). Our objects were to investigate whether the Hp phenotype could predict the incidence of cerebral infarction, favorable outcome, clinical deterioration by DCI, and angiographical VS after aneurysmal SAH. Ninety-five consecutive patients who underwent clipping or coil embolization were studied. Favorable functional outcome was defined as a modified Rankin Scale score of 0-2 at 3 months. Angiographical VS was diagnosed based on cerebral angiography findings performed between days 7 and 10 after SAH. The Hp 2-2 group had a significantly greater risk of angiographical VS than that of Hp 2-1 and 1-1 groups combined on univariate (odds ratio [OR]: 3.60, confidence interval [CI]: 1.49-8.67, P = .003) and multivariate logistic regression analyses after being adjusted for age, sex, Fisher groups, and other risk factors (OR: 3.75, CI: 1.54-9.16, P = .004). The Hp 2-2 group also showed the tendency of a greater risk of clinical deterioration by DCI with marginal significance on univariate and age- and sex-adjusted analyses (univariate OR: 2.46, CI: .90-6.74, P = .080; age- and sex-adjusted OR: 2.46, CI: .89-6.82, P = .080) but not after being adjusted for other multiple risk factors. The Hp 2-2 group was not associated with the favorable 3-month outcome and cerebral infarction (univariate: P = .867, P = .209; multivariate: P = .905, P = .292). The Hp phenotype seems to be associated with a higher rate of angiographical VS and clinical deterioration by DCI but does not affect the incidence of cerebral infarction and favorable outcome.