Head injury is one of the potential environmental factors in Alzheimer's disease (AD). To study the chronic stage of concussive brain injury, histological analyses were performed 2-6 months after right lateral fluid percussion (FP) brain injury (3.6-4.8 atm) in rats. Six months after injury, numerous normal-looking neurons in the telencephalon and brain stem were immunoreactive with either antibody to phosphorylated tau or with four antibodies to beta-amyloid protein. Neuronal counts in the cortices were gradually decreased after injury, up to 42% loss at 6 months after injury. These neuropathological changes suggest that this animal model could serve as a good animal model of neurodegenerative diseases such as AD.

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This review focuses on the in vitro and in vivo neuropharmacology of YM872, a potential neuroprotective agent currently undergoing clinical trials in the United States (trial name: AMPA Receptor Antagonist Treatment in Ischemic Stroke -ARTIST). Its neuroprotective properties in rats and cats with induced focal cerebral ischemia are described. YM872, [2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]-acetic acid monohydrate, is a selective, potent and highly water-soluble competitive á-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist. YM872 has a potent inhibitory effect on [ 3 H]AMPA binding with a K i value of 0.096 ìM. In contrast, YM872 has very low affinity for other ionotropic glutamate receptors. The solubility of YM872 is approximately 500 to 1000 times higher than that of the other competitive AMPA antagonists: YM90K, NBQX, or CNQX. The neuroprotective efficacy of YM872 was investigated in rats and cats subjected to permanent occlusion of the left middle cerebral artery. The animals were assessed either histologically or neurologically following ischemia. In rats with occluded middle cerebral artery (MCAO) YM872, by i.v. infusion, significantly reduced infarct volume measured at 24 h and 1 week after ischemia. Significant neuroprotection was maintained even when drug administration was delayed 337

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