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Interferon gamma (IFN-␥) is a cytokine predominantly involved in antiproliferative and antiviral responses, immune surveillance, and tumor suppression. However, it has been shown that IFN-␥ is also involved in central nervous system development. Here we studied the underlying mechanism for IFN-␥-induced neuronal differentiation using the human neuroblastoma Paju cell line. Our results indicate that IFN-␥ treatment led to neurite outgrowth followed by growth arrest in the G 1 phase of the cell cycle. IFN-␥ induced ERK1/2 phosphorylation and subsequently the transcription factor early gene response 1, which in turn up-regulated p35 expression and increased cyclin-dependent kinase 5 (Cdk5) activity. IFN-␥-induced neurite outgrowth was abolished by the treatment of MEK1/2 kinase inhibitors, such as U0126 and PD98059, which inhibit the ERK1/2 activation and subsequently prevent the up-regulation of p35 expression and Cdk5 activity. In agreement with the role of p35-Cdk5 in neuronal differentiation, small interfering RNA targeting Cdk5 abrogate the IFN-␥-induced neurite outgrowth. Together, these results demonstrate for the first time that IFN-␥-triggered neuronal differentiation mediated through the up-regulation of p35-associated Cdk5 depends on the activation of the ERK1/2 pathway. Therefore, the present study suggests that IFN-␥ is not only involved in tumorigenicity but also involved in neurogenesis by regulating cell proliferation and differentiation.

Background and Purpose-Cerebral edema develops very early after the onset of focal cerebral ischemia and may be a major factor in early disability after an acute ischemic stroke. There have been very limited studies on the usefulness of antiedemic agents as neuroprotective agents in the setting of focal cerebral ischemia. We tested the neuroprotective effects of a new potent nonpeptide vasopressin receptor V 1 antagonist, SR-49059, in a focal embolic stroke model in rats. Methods-Focal ischemic injury was induced by embolizing a preformed clot into the middle cerebral artery (MCA).Infarction volume was measured at 48 hours after the MCA occlusion. Neurological deficits, ischemic brain edema, seizure activity, and mortality and hemorrhage rates were also documented. Results-Treatment with SR-49059 (2 mg/kg), initiated immediately after MCA occlusion, significantly reduced infarction volume (PϽ0.05) measured at 48 hours after the arterial occlusion. In animals in which the treatment was delayed for 1 hour after MCA occlusion, infarction volume was also reduced significantly (PϽ0.05). Infarction volume in the rats that received the drug at 3 or 6 hours after MCA occlusion was not different from that in the vehicle-treated group. Treatment with SR-49059, when started early after the arterial occlusion, also reduced neurological deficits and ischemic brain edema. Injection of drug at a higher dose (30 mg/kg) also reduced infarction volume and improved functional recovery but was not superior to the lower dose (2 mg/kg) when the drug was administrated at 1 hour after MCA occlusion. Conclusions-Our data show that the selective vasopressin receptor antagonist SR-49059 is a potent neuroprotective agent when used early after onset of arterial occlusion in an embolic focal ischemia model in rats. Further studies are needed in stroke models to better understand its neuroprotective properties when used alone or in combination with thrombolysis. (Stroke. 2002;33:3033-3037.)

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In patients with thrombotic stroke, the occluded artery often reopens over time. This results through a natural dissolution of the occluding material, and fragments of the material may move downstream to obstruct distal arteries. The current study was undertaken to investigate the patency of brain microvessels at varying time intervals after injection of a preformed clot into the right internal carotid artery of rats. Cerebral microvessels in brain sections were visualized using immunohistochemistry for fibronectin (detecting existing microvessels) and Evans blue (visualizing perfused microvessels). The percentage of patent microvessels was calculated as the number of Evans blue-positive microvessels divided by the number of fibronectin-positive microvessels. In normal control animals, results showed that 98% +/- 3% (mean +/- SD) of microvessels in the cortex and 94% +/- 14% in the striatum were patent. In the ischemic animals, immediately after clot injection, microvessels in the cortex and striatum were occluded, mainly in the territory irrigated by the middle cerebral artery. One hour after clot injection, microvessels had reopened in most of the cortex but remained occluded in some portions of the striatum, possibly as a result of downstream movement of fragments formed from the original clot. By 3 hours after clot injection, microvessels in the cortex were patent in all animals, whereas in the striatum microvessels were patent in 50% of the animals. In the other 50%, small striatal perfusion deficits persisted. At 24 hours after clot injection, microvessels were patent in both the cortex and striatum of all animals except one. These findings suggest that intracerebral clots dissolve spontaneously in a relatively short period of time, but that fragments formed from the clot may obstruct more distal blood vessels. It is likely that clot fragments lodge in arteries with lower blood flow and poor collateral perfusion, where they continue to cause ischemia for a longer duration. These results may in part explain the resistance of the striatum to neuroprotective strategies used for the treatment of focal cerebral ischemia.

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