Experimental stroke and neuroprotection in the aging rat brain.
Experimental stroke research has for the most part incorporated the use of young animals despite the importance of aging in cerebrovascular disease in humans. We hypothesized that age-related reductions in the density and function of cortical N-methyl-D-aspartate (NMDA) receptors might limit neuroprotective potential in the elderly. In this study, a model of occlusive stroke in the aging rat brain has been developed and used to establish the effects of age on cerebral infarction and to evaluate the scope for protecting the aging brain during ischemia. Focal cerebral ischemia was produced by thermocoagulation of the left middle cerebral artery in adult (11 to 17 months) and aged (28 to 36 months) male Wistar rats. Infarcts were assessed histologically with volumetric analysis of infarct size, hemodynamically 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 competitive NMDA receptor antagonist 3-(2-carboxy piperazin-4-yl)propyl-1-phosphonate (D-CPPene). Aging was associated with a significant increase in infarct size, with a mean infarct volume of 40.5 +/- 2.6% of the hemisphere volume in aged rats compared with 30.9 +/- 0.7% in adult 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-pretreated rats maintained higher cerebral blood flow than untreated animals 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, respectively, 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 gravity 4 hours after infarction was 1.0381 +/- 0.0013 in untreated aged rats and 1.0391 +/- 0.0014 in untreated adults compared with 1.0458 +/- 0.0031 in treated aged rats and 1.0442 +/- 0.0014 in treated adult rats (P < .05). Under similar experimental conditions, there was an age-related increase in cerebral infarct size. However, NMDA receptor antagonism was neuroprotective in the aging brain and resulted in a significant reduction in cerebral ischemic damage, less cortical edema, and preservation of cerebral blood flow.