EXPERIMENTAL STROKE AND NEUROPROTECTION IN THE AGING RAT-BRAIN

Background and Purpose Experimental stroke research has for the most p art incorporated the use of young animals despite the importance of ag ing in cerebrovascular disease in humans. We hypothesized that age-rel ated reductions in the density and function of cortical N-methyl-D-asp artate (NMDA) receptors might limit neuroprotective potential in the e lderly. In this study, a model of occlusive stroke in the aging rat br ain has been developed and used to establish the effects of age on cer ebral infarction and to evaluate the scope for protecting the aging br ain during ischemia. Methods Focal cerebral ischemia was produced by t hermocoagulation of the left middle cerebral artery in adult (11 to 17 months) and aged (28 to 36 months) male Wistar rats. Infarcts were as sessed histologically with volumetric analysis of infarct size, hemody namically by serial cerebral blood flow measurement using the hydrogen clearance technique, and by analysis of specific gravity as an index of brain edema. Neuroprotective potential was assessed using the compe titive NMDA receptor antagonist 3-(2-carboxy piperazin-4-yl)propyl-l-p hosphonate (D-CPPene). Results Aging was associated with a significant increase in infarct size, with a mean infarct volume of 40.5+/-2.6% o f the hemisphere Volume in aged rats compared with 30.9+/-0.7% in adul t rats (P<.01). D-CPPene reduced the mean infarct volume to 33+/-1.8% and 20.7+/-3.2% in aged and adult rats, respectively (P<.05). Cerebral blood flow fell markedly after infarction, but thereafter D-CPPene-pr etreated rats maintained higher cerebral blood flow than untreated ani mals throughout the duration of the experiment (22.8+/-3.2 and 30.1+/- 5.5 mL . 100 g(-1) . min(-1) in treated aged and adult rats, respectiv ely, compared with 11.3+/-2.7 and 16.5+/-3.2 mL . 100 g(-1) min(-1) in untreated aged and adult groups, 90 minutes after infarction [P<.05]) . Pretreatment also reduced cortical edema; mean cortical specific gra vity 4 hours after infarction was 1.038+/-0.0013 in untreated aged rat s and 1.0391+/-0.0014 in untreated adults compared with 1.0458+/-0.003 1 in treated aged rats and 1.0442+/-0.0014 in treated adult rats (P<.0 5). Conclusions Under similar experimental conditions, there was an ag e-related increase in cerebral infarct size. However, NMDA receptor an tagonism was neuroprotective in the aging brain and resulted in a sign ificant reduction in cerebral ischemic damage, less cortical edema, an d preservation of cerebral blood flow.