Effects of combined postischemic hypothermia and delayed N-tert-butyl-alpha-pheylnitrone (PBN) administration on histopathological and behavioral deficits associated with transient global ischemia in rats

Previous cerebral ischemia studies have reported the limitations of restric ted periods of postischemic hypothermia in producing long-term neuroprotect ion. The present experiment attempts to determine whether delayed treatment with the free radical scavenger N-tert-butyl-a-phenylnitrone (PBN) is prot ective at 2 months following transient global forebrain ischemia, and wheth er additive effects can be observed when PBN is administered in combination with moderate hypothermia. For this aim rats were subjected to 10 min of t wo-vessel forebrain ischemia followed by (a) 3 h of postischemic normotherm ia (37 degrees C); (b) 3 h of postischemic hypothermia (30 degrees C); (c) normothermic procedures combined with delayed injections of PBN (100 mg/kg) on days 3, 5 and 7 post-insult; (d) postischemic hypothermia combined with delayed PBN treatment; or (e) sham procedures. Outcome measures included c ognitive behavioral testing and quantitative histopathological analysis at 2 months. Postischemic PBN injections induced a systemic hypothermia (1.5 d egrees C-2.0 degrees C) that lasted for 2-2.5 h. Water maze testing reveale d significant performance deficits relative to shams in the normothermic is chemic group, with the postischemic hypothermia and PBN groups showing inte rmediate values. A significant attenuation of cognitive deficits was observ ed in the animal group receiving the combination postischemic hypothermia a nd delayed PBN treatment. Quantitative CA1 hippocampal cell counts indicate d that each of the ischemia groups exhibited significantly fewer viable CA1 neurons compared to sham controls. However, in rats receiving either delay ed PEN treatment or 3 h of postischemic hypothermia, significant sparing of CA1 neurons relative to the normothermic ischemia group was observed. Thes e data indicate that hypothermia combined with PBN treatment provides long- term cognitive improvement compared to nontreatment groups. PBN-induced mil d hypothermia could contribute to the neuroprotective effects of this pharm acological strategy. (C) 1999 Elsevier Science B.V. All rights reserved.