Background and Purpose-The natural history and optimal management of incidentally found small unruptured aneurysms Ͻ5 mm in size remain unclear. A prospective study was conducted to determine the optimal management for incidentally found small unruptured aneurysms. Methods-From
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 mg͞kg), a specific inhibitor of MEK (MAPK͞ERK 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 MEK͞ERK activation in brain injury resulting from ischemia͞reperfusion, and indicate that MEK inhibition may increase the resistance of tissue to ischemic injury. C ardiac arrest or cerebral arterial occlusion can cause a brain attack. Quickly restoring the cerebral blood flow is needed to stop brain injury. The most exciting new development in the field of stroke research is the recent approval of i.v. injection of tissue plasminogen activator that dissolves the blood clot (1, 2). Restoration of blood flow not only brings oxygen and nutrients into the damaged brain, but also produces free radicals such as reactive oxygen and reactive nitrogen species. These free radicals have been shown to contribute to oxidative injury. The tissue damage by the restoration of blood flow is termed reperfusion injury (3, 4). Thus, inhibition of reperfusion injury may be important to achieve greater brain protection.Mitogen-activated protein kinase (MAPK) family members, including extracellular signal-regulated kinases (ERK1͞2), p38 MAPK, and c-Jun N-terminal kinase (JNK), respond to various extracellular stimuli, thereby transmitting extracellular signals into the nucleus. ERK1͞2 are activated by MAPK͞ERK kinase1͞2 (MEK1͞2) by phosphorylating these MAPKs (5). The MEK͞ERK pathway plays a crucial role in cell growth and differentiation (6, 7). ERK1͞2 are constitutively expressed in the adult brain (8); however, little is known about the function of ERK1͞2 in postmitotic, terminally differentiated neurons. The MEK͞ERK pathway is also activated by reactive oxygen and reactive nitrogen species (9-11). Several in vivo studies showed that ERK1͞2 are phosphorylated in the damaged brain after ischemia, hypoglycemia, a...
With the cooperation of 60 neurosurgical centers in Japan, a prospective randomized placebo-controlled double-blind trial of a new calcium antagonist AT877 (hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, or fasudil hydrochloride) was undertaken to determine the drug's effect on delayed cerebral vasospasm in patients with a ruptured cerebral aneurysm. A total of 276 patients, who underwent surgery within 3 days after subarachnoid hemorrhage (SAH) of Hunt and Hess Grades I to IV, were entered into the study. Nine patients were excluded because of protocol violation. The remaining 267 patients received either 30 mg AT877 or a placebo (saline) by intravenous injection over 30 minutes, three times a day for 14 days following surgery. Demographic and clinical data were well matched between the two groups. It was found that AT877 reduced angiographically demonstrable vasospasm by 38% (from 61% in the placebo group to 38% in the AT877 group, p = 0.0023), low-density regions on computerized tomography associated with vasospasm by 58% (from 38% to 16%, p = 0.0013), and symptomatic vasospasm by 30% (from 50% to 35%, p = 0.0247). Furthermore, AT877 reduced the number of patients with a poor clinical outcome associated with vasospasm (moderate disability or worse on the Glasgow Outcome Scale at 1 month after SAH) by 54% (from 26% to 12%, p = 0.0152). There were no serious adverse events reported in the AT877 group. This is the first report of a placebo-controlled double-blind trial that has demonstrated a significant reduction in angiographically revealed vasospasm by intravenous drug therapy.
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