The temporal evolution of cerebral infarction was examined in rats subjected to transient occlusion of both common carotid arteries and the right middle cerebral artery. After severe (90-min) ischemia, substantial right-sided cortical infarction was evident within 6 h and fully developed after 1 day. After mild (30-min) ischemia, no cortical infarction was present after 1 day. However, infarction developed after 3 days; by 2 weeks, infarction volume was as large as that induced by 90-min ischemia. These data suggest that infarction after mild focal ischemia can develop in a surprisingly delayed fashion. Some evidence of neuronal apoptosis was present after severe ischemia, but only to a limited degree. However, 3 days after mild ischemia, neurons bordering the maturing infarction exhibited prominent TUNEL staining, and DNA prepared from the periinfarct area of ischemic cortex showed internucleosomal fragmentation. Furthermore, pretreatment with 1 mg/kg cycloheximide markedly reduced infarction volume 2 weeks after mild ischemia. These data raise the possibility that apoptosis, dependent on active protein synthesis, contributes to the delayed infarction observed in rats subjected to mild transient focal cerebral ischemia.

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Rationale: Acetylcholinesterase inhibitors are widely used for the treatment of patients with Alzheimer's disease (AD). However, the relationship between the capacity of such drugs to ameliorate the symptoms of AD and their ability to alter the underlying disease process is not well understood. Transgenic mice that overexpress the human form of amyloid precursor protein and develop deposits of b-amyloid (Ab) and behavioral deficits during adulthood are useful for investigating this question. Objectives: The effects of administration of two acetylcholinesterase inhibitors, physostigmine and donepezil, on Ab plaque formation and memory-related behaviors were investigated in the Tg2576 transgenic mouse model of AD. At 9-10 months of age, Tg2576 transgenic (Tg(+)) mice develop Ab plaques and impairments on paradigms related to learning and memory as compared to transgene negative (Tg(-)) mice. Methods: Beginning at 9 months of age, increasing doses of physostigmine (0.03, 0.1, and 0.3mg/kg), donepezil (0.1, 0.3 and 1.0mg/kg) or saline were administered over six weeks to cohorts of Tg(+) and Tg(-) mice. Performance on tests of spatial reversal learning and fear conditioning was evaluated at each drug dose throughout the period of drug administration. After drug administration was completed, the animals were sacrificed and Ab plaque number was quantified. Results: Administration of physostigmine and donepezil improved deficits in contextual and cued memory in Tg(+) mice so that their behaviors became more similar to Tg(-) mice. However, administration of physostigmine and donepezil tended to improve cued memory and deficits in spatial learning in both Tg(+) and Tg(-) mice. Physostigmine administration demonstrated more prominent effects in improving contextual memory than donepezil, while donepezil was more effective than physostigmine in improving deficits in the acquisition of the spatial memory paradigm. Administration of neither drug altered the deposition of Aß plaques. Conclusions: These studies suggest that acetylcholinesterase inhibitors can ameliorate memory deficits in Tg(+) mice without necessarily altering the deposition of Aß plaques. Tg2576 mice may be useful as an animal model to further investigate the mechanisms by which aceytlcholinesterase inhibitors improve cognitive deficits in patients with AD.

The effects of kainic acid (KA) on neurogenesis in the developing rat hippocampus were investigated. Neonatal [postnatal day (P) 7] rats received a single bilateral intracerebroventricular infusion of KA (50 nmol in 1.0 microl) or vehicle. At P14, P25, P40, and P60, the spatial and temporal relationships between the neurodegeneration and neurogenesis induced by KA were explored using terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) to detect the dying cells and 5-bromodeoxyuridine (BrdU) to label newly generated cells. There was progressive loss of neurons in the cornu ammonis (CA) 1 and CA3 subfields of the hippocampus at all time points in KA-treated rats. TUNEL staining identified dying cells at P14 through P60, mainly in the CA3 subfield. The number of TUNEL-positive cells decreased with age. Neurogenesis also was observed in the KA-treated hippocampus. The number of BrdU-positive cells in the dentate gyrus was significantly decreased at P14, when the number of TUNEL-positive cells is highest. However, at later time points (P40 and P60) the number of BrdU-positive cells in the dentate gyrus was significantly increased. In addition, the number of BrdU-positive cells was increased in the CA3 subfield at P40 and P60 in KA-treated rats. A substantial proportion (40%) of the newly generated cells in CA3 also expressed markers of immature and mature neurons (class III beta-tubulin and neuronal nuclei). Newly generated cells in the CA3 subfield only rarely expressed glial markers (8%). These results suggest that a single exposure to KA at P7 has both immediate (inhibition) and delayed (stimulation) effects on neurogenesis within the dentate gyrus of developing rats. KA administration resulted in both neuronal apoptosis and neurogenesis within the CA3 subfield, suggesting that the purpose of neurogenesis in the CA3 is to replace neurons lost to apoptosis.

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