66 Brain Research, 587 (1992166-72 c~ 1992 Elsevier Science Publishers B.V. All rights reserved (11106-8993/92/$05.(X) BRES 17931~ Immediate or delayed mild hypothermia prevents focal cerebral infarction Dong Xue, Z-Gao Huang, Karen E. Smith and Alastair M. Buchan Nt,ttroloh~.'.Nt'ttro.~t'ient'e Dt,parlmt,nt. Unicersityof Ottawa. Ottawa C~ric Hospital, Ottawa, Ont. (Canada) (Accepted 3 March 19921 Key words: Stroke: Rat; ttypothermia: Cytoproteclion; NMDA antagonist; Blood-brain harrier Thc protcclivc cft'eet of mild hypothcrmia was studied in rodent models of both permanent and transient local cerebral ischemia. In Expt. I, Wislar rats were exposed to h h permanent ischemia by bilateral occlusion of both common carotid arteries and right middle cerebral artery. In Expt. 2. animals werc exposed to 3 h tr:|llsicnl ischcmi;i followed by 21 h rcperfusion, and in Expt, 3, 3 h transient ischemia was followed by 69 h of rcpcrfusion. Expt. 4 used 3 h transient ischcmia followed by 3 h reperfusion, In Expt. I, animals maintained at 37°(" rectal (normothermia) suffered a mc:m infarct volume (± S.D,) of 142 ± 44 mm ~ (n = 6), which was reduced for those exposed to permanent hypothermic (32°C) ischcmia to 56±64 mm ~ (n = I01 (P < 0,05), In Expl. 2, normothermic ischemia and reperfusion resulted in an infarction of 211:t:35 mm "~ (n ~ fit. lntra.ischemic hypothertni:t (32°C) ftdlowed by 21 h of normothermic reperfusion resulted in 17± 12 mm 3 of infarctkm (n =9) (P < {|,0011, I lypothcrmia for either tile first or second 1,5 h of the 3 h ischemic insult reduced the infarct wdume to 116± 76 mm ~ (n = 6) (P < 0,051 or It)8 :t: 73 mm ~ (n ~ 7) (P < 4),01), respectively, Delaying the induction of hypothermia by 1.5 It and subsequently maintaining the tcntpcraturc at 320( ` durint~ the first 1,5 h of repcrfusion resulted in a reduction in infarct volume to 56 ± 66 mm 3 (n ,= 7) ( P < 11.01). In Expt. 3. hypt~lllcrmic ischcmiu followed hy prolonged reperfusion (3 days) resulted in 31 ± 25 mm '~ (n - 7) of infarction, versus 198 ± 28 mm '~ (P < 0.001) in normothermic controls (n ~ 7). In Expt. 4, normotherntic ischemi:t ;rod rcperfusion resulted in a mean infarct volumu of 166 t 27 mnr ~ (n - 7). Delaying the onset of hypolhcrmia unlil just prior to rcpcrfusion resulted in a reduction in infarc! volume to 65 ~ 54 mm ~ (n - 5) (P < {HIS), llypcrthermic ischemia I.t0"( '1 increased injury, 245 ~ 1'14 ntm ,~(n- 5)(P < 0,115),These results dcntonstraic that mild inlra-lschemic temperature reductions can attenuate cortical infarction with hoth perma.cnt and trLmsicnt focal tschemia, Furtherntorc, followin8 transient t'ocal ischemia. delayed hyptltl'tcrntia can still result in amelioration of Injury, INTRODUCTION Following severe tbrebrain ischemia, the process of selective ischcmic neuronal necrosis is dependent on the intra-ischcmic parenchymal temperature and the blood temperature at the time of reperfusion s:~'l'~,4n, Mild brain parenchymal hypothermia will prevent se- lective ischemic injury to neurons in the hippocampus, cortex and striatum, provided that the hypothcrmia is either intra-ischcmic '~,2¢'or induced at the time of re- perfusion ~'~'~".While the potent cytoprotectivc effcct of intra-ischcmic hypothcrmia is unquestioned, the effect of post-ischemic cooling remains controvcrsial 2,~,.~, Unanticipated mild hypothermia has been suggested as an explanation for the initial observation ~hat N- methyl-o-aspartate (NMDA) antagonists had potent cytoprotectivc effects in the wake of severe forcbrain ischcmia4,t.~. i~ecent provisional reports on the effects of hy- pothermia in the setting of focal ischcmiaz~''~" suggest that mild hypothermia will also reduce the effects of focal ischemic insults, although this remains controver- sial zs. In this study, we have tested the effects of mild cerebral hypothermia on permanent focal cerebral is- chemia, intra-ischemic hypothermia during transient focal ischemia (tollowed by normothermic reperfusion for up to 3 days), and we have sequentially delayed the onset of hypothermia during ischemia, delaying it to just prior to reperfusion to see if cooling after the onset of ischemia can still afford protection. We have previously reported part of these data in abstract form4t, MATERIALS AND METHODS Fasted male Wistar rats weighing 2110-2511 g were anesthetized with 3% halothane and subsequently maintained with I-2% Com'v~mdcm'c: A,M, Iiuchan, Neuroscicncc Research, Ottawa Civic Hospital, 1053 Carling Avenue, Ottawa, Ont,, Canada K IY 4E9. Fax: (I) (6131 761-51~9,