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Background and Purpose-It is not known whether a combination of intraischemic and postischemic mild hypothermia provides extra neuroprotection and if so, whether the neuroprotection is persistent. Methods-Sixty-eight Sprague-Dawley rats were used. In group 1, ischemia and reperfusion were performed under normothermic (N) conditions (control, N-N). In group 2, ischemia was induced and maintained under hypothermic conditions (33°C for 2 hours) and reperfusion was performed under normothermic conditions, H-N. In group 3, both ischemia and reperfusion were performed under hypothermic conditions for an additional 21 hours after the surgery, H-22H. In group 4, ischemia was induced and maintained under hypothermic conditions and reperfusion was performed under hypothermic conditions only for the initial 3 hours (H-3H). In group 5, ischemia was induced and maintained under normothermic conditions and reperfusion was performed under hypothermic conditions (33°C) (N-22H). All rats were perfused 48 hours after the induction of ischemia. In addition, the normothermic or hypothermic therapy used for groups 1, 3, and 4 was performed again, and these rats were killed 30 days after the induction of ischemia. Furthermore, neurological deficits were monitored in groups N-N and H-22H for 4 weeks. Results-In the H-3H and H-22H groups, the total infarct volume was significantly reduced by 41% or 66%, respectively, assessed 48 hours after ischemia. The significant reduction in group H-22H was again confirmed 30 days after ischemia, ie, 50% reduction was observed. In contrast, the reduction in group H-3H (31%) was not significant. The neurological deficits were significantly more severe in the N-N group than in the H-22H group during week 4. Conclusions-The neuroprotective effects against temporary focal ischemia evaluated by infarct volume and neurological functions by the combination therapy with intraischemic and prolonged postischemic mild hypothermia were persistent in rats. Appropriate design of mild hypothermia therapy extending into the late reperfusion period is important to maximize the neuroprotective effects of hypothermia. (Stroke. 1999;30:2720-2726.)Key Words: hypothermia Ⅲ cerebral infarction Ⅲ cerebral ischemia Ⅲ rats A treatment using hypothermic conditions has been recognized to be quite potent in protecting neurons against lethal ischemic stress. Intraischemic hypothermia has been shown to be neuroprotective in global 1-3 and focal cerebral ischemia. 4 -6 Even when hypothermia is initiated only after temporary cerebral ischemia (postischemic hypothermia), a significant neuroprotective effect has been observed in both global and focal cerebral ischemia. [7][8][9] In postischemic hypothermia, a prolonged application of hypothermia seems to be necessary to achieve significant and persistent neuroprotection for global ischemia. Colbourne and Corbett 10 reported that Ϸ90% hippocampal CA1 neuroprotection was achieved by 1 hour-delayed mild (32°C) postischemic hypothermia for 24 hours, compared with only Ϸ15% neuroprotect...

Background and Purpose-Status epilepticus and cerebral ischemia stimulate persistent neurogenesis in the adult brain, but both conditions cause neuronal damage. We determined whether spreading depression, a common epiphenomenon of these conditions, stimulates persistent neurogenesis. Methods-We analyzed the effect of KCl-induced spreading depression on persistent neurogenesis and the spatio-temporal distribution of cells exhibiting immunohistochemical markers for divided and early committed neurons (new neurons) in the adult rat brain. Results-After induction of spreading depression for 48 hours, the density of mitotic cells, divided cells, and new neurons in the subventricular zone increased at days 1 to 3, days 3 to 6, and day 6, respectively (PϽ0.05). The divided cell density in the rostral migratory stream and the stream size increased at day 12 (PϽ0.001). Vehicle (saline) infusion or induction of spreading depression for 4 hours only did not increase the divided cell density, but the latter increased new neuron density in the subventricular zone (PϽ0.001). Double-labeled new neuron-like cells also appeared in the caudate putamen or cortex in ectopic fashion at day 3, with dramatic increases at days 6 and 12. Administration of the NMDA receptor antagonist, MK-801, which inhibits the propagation of spreading depression, abolished the increase in new neurons in the subventricular zone and the appearance of ectopic new neuron-like cells after 48-hour KCl infusion. There was no neuronal damage, as evidenced by mature neuron density, neurite density, and apoptotic cell appearance after spreading depression for 48 hours. Conclusions-Spreading

Background and Purpose-New immature neurons appear out of the germinative zone, in cortical Layers V to VI, after induced spreading depression in the adult rat brain. Because neural progenitors have been isolated in the cortex, we set out to determine whether a subgroup of mature cells in the adult cortex has the potential to divide and generate neural precursors. Methods-We examined the expression of endogenous markers of mitotic activity, proliferating cell nuclear antigen, and vimentin as a marker for neuronal progenitor cells, if any, in the adult rat cortex after spreading depression stimulation. Immunohistochemical analysis was also performed using antibodies for proliferating cell nuclear antigen, for vimentin, and for nestin. Nestin is a marker for activity dividing neural precursors. Results-At

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