Excitotoxicity in brain ischemia triggers neuronal death and neurological disability, and yet these are not prevented by antiexcitotoxic therapy (AET) in humans. Here, we show that in neurons subjected to prolonged oxygen glucose deprivation (OGD), AET unmasks a dominant death mechanism perpetuated by a Ca2+-permeable nonselective cation conductance (IOGD). IOGD was activated by reactive oxygen/nitrogen species (ROS), and permitted neuronal Ca2+ overload and further ROS production despite AET. IOGD currents corresponded to those evoked in HEK-293 cells expressing the nonselective cation conductance TRPM7. In cortical neurons, blocking IOGD or suppressing TRPM7 expression blocked TRPM7 currents, anoxic 45Ca2+ uptake, ROS production, and anoxic death. TRPM7 suppression eliminated the need for AET to rescue anoxic neurons and permitted the survival of neurons previously destined to die from prolonged anoxia. Thus, excitotoxicity is a subset of a greater overall anoxic cell death mechanism, in which TRPM7 channels play a key role.

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...

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.

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