Ischemic preconditioning in 18- to 20-month-old gerbils: long-term survival with functional outcome measures.

BACKGROUND AND PURPOSE: In young animals, ischemic preconditioning protects CA1 hippocampal neurons against global ischemia. However, cerebral ischemia occurs most frequently in individuals aged >/=65 years. This study examined the protection provided by ischemic preconditioning in a population of aged (18- to 20-month-old) gerbils.

METHODS

One group of animals was exposed to two 1.5-minute episodes of global ischemia separated by 24 hours and followed 72 hours later by a 5-minute occlusion of both carotid arteries. A second group was given 2 episodes of preconditioning only. Two other groups were exposed to 5 minutes of ischemia or sham surgery. The animals survived 10, 30, or 60 days. Functional and histological assessments were used to determine the extent of protection.

RESULTS

Ten days after ischemia there was >80% protection of CA1 neurons in ischemic preconditioned animals compared with 6% in ischemic gerbils. Nevertheless, these preconditioned animals were impaired in open-field tests of habituation. In addition, CA1 dendritic field potentials were smaller in amplitude compared with those in sham animals. While there was a complete loss of staining for CA1 microtubule-associated protein-2 in ischemic animals, staining in ischemic preconditioned animals was normal. This suggests that dendritic abnormalities per se were not responsible for the observed functional deficits. CA1 cell survival declined to approximately 75% of sham values (P<0.05) at 60 days after ischemia.

CONCLUSIONS

Ischemic preconditioning provided substantial neuroprotection in aged gerbils. Nonetheless, the striking dissociation between histological and functional protection provided by ischemic preconditioning in aged animals emphasizes the need to use functional end points and long-term survival when assessing neuroprotection. Although functional recovery was evident with increasing survival time, CA1 cell death continued, thereby raising the possibility that the level of neuroprotection attained was not permanent.